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Background: Pancreatic adenocarcinoma (PAAD) is a common malignancy with a very low survival rate. More and more studies have shown that SPTAN1 may be involved in the development and progression of a variety of tumors, including rectal cancer, Pancreatic adenocarcinoma, etc., and may affect their prognosis., Methods: Bioinformatics technology was used to analyze the relationship between SPTAN1 expression in PAAD and immune cell infiltration, immune regulatory factors and chemokines, and cell experiments were used to verify the relationship between SPTAN1 knock down and migration, invasion, apoptosis and cycle changes of PAAD cell lines. In addition, immunohistochemical staining of SPTAN1 was performed by tissue microarray (TMA) to study the relationship between high expression of SPTAN1 and clinicopathological features and overall survival rate., Results: The expression of SPTAN1 is significantly correlated with immune cell infiltration, immunomodulators, chemokines and their receptors. In addition, it was found that the knock-down of SPTAN1 inhibited the migration and invasion ability of PAAD cell lines, promoted the apoptosis of cell lines, and also affected the changes of cell cycle. Immunohistochemical staining using tissue microarray (TMA) showed that the high expression of SPTAN1 was associated with M stage (P = 0.004) and CA199 (P = 0.012), and the overall survival rate of the high expression group was significantly lower than that of the low expression group (P = 0.043)., Conclusion: Our results suggest that up-regulation of SPTAN1 is related to cell migration, invasion, apoptosis and cycle changes, and is associated with tumor immune invasion and poor prognosis of PAAD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objectives: SOX10 is crucially implicated in various cancer, yet the regulatory role in pancreatic cancer (PC) remains enigmatic. Underlying molecular mechanisms of SOX10 in PC were explored in our study., Methods: Relationships between SOX10 and immune landscape were estimated using bioinformatic approaches. The expression of SOX10 and CMTM7 was analyzed using quantitative real-time polymerase chain reaction and western blot. To assess cell functions, cell counting kit-8, flow cytometry, scratch test, and Transwell assays were performed. Dual-luciferase assay was performed to confirm the target-binding relationship of SOX10 and CMTM7. After knocking down SOX10 using lentiviral transfection, SOX10 action on Wnt/β-catenin pathway and ferroptosis, as well as its anti-tumor activity in tumor-bearing mice were explored., Results: SOX10 was significantly correlated with immune infiltrations, checkpoints, and characteristics in PC. Mechanically, SOX10 level was increased and CMTM7 was down-regulated in both PANC-1 cells and PC tissues. When SOX10 was downregulated or CMTM7 was overexpressed, it notably hindered the cells' activity, while also promoting cell apoptosis in vitro. Meanwhile, CMTM7 is regulated by SOX10 in the downstream, and its silencing significantly reversed the inhibition of sh-SOX10 on PANC-1 cells growth and Wnt/β-catenin pathway. Furthermore, overexpression of CMTM7 induced ferroptosis in PC by inhibiting the Wnt/β-catenin pathway. More interestingly, by targeting CMTM7-mediated Wnt/β-catenin signaling pathway, the knockdown of SOX10 was confirmed to induce ferroptosis in PC and suppress tumor progression in vivo., Conclusions: SOX10 is deemed as an immune-related gene. Its knockdown induces ferroptosis in PC and suppresses tumor progression via CMTM7-mediated Wnt/β-catenin pathway., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Experimental Animal Ethics Committee of Yangzhou University (No.202403221). Consent for publications: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: Docetaxel (DTX) represents an effective chemotherapeutic agent for treating triple-negative breast cancer (TNBC), but the efficacy is strongly limited by drug resistance. c-MYC-mediated ribosome biogenesis is considered a feasible strategy to confront chemoresistance in BC. We elucidated the impact of CMTM6 on TNBC DTX chemoresistance by governing c-MYC-mediated ribosome biogenesis, and its upstream ceRNA regulatory pathways., Methods: DTX-resistant TNBC cells MDA-MB-231R and HCC1937R were generated by exposing sensitive cells MDA-MB-231 and HCC1937 to escalating doses of DTX. The expression patterns of CMTM6 and c-MYC were assessed by Western blot. The relationships between CMTM6 and miR-340-5p, circUBR5 and miR-340-5p were determined using bioinformatics analysis, luciferase assay, RIP, RNA in situ hybridization and biotin-labeled miR co-precipitation assay. Following ectopic expression and depletion experiments in DTX-resistant cells, cell chemoresistance, apoptosis, colony formation and nascent protein synthesis were evaluated., Results: CMTM6 expression was elevated in DTX-resistant TNBC cells. CMTM6 knockdown enhanced apoptosis of DTX-resistant TNBC cells and increased their sensitivity to DTX by blocking c-MYC-mediated ribosome biogenesis. Mechanistically, miR-340-5p targeted CMTM6 and negatively regulated the expression of CMTM6 in DTX-resistant TNBC cells. Moreover, circUBR5 attenuated the repression on CMTM6 expression as a ceRNA for miR-340-5p. circUBR5 knockdown inactivated c-MYC-mediated ribosome biogenesis, and therefore enhanced DTX efficacy by promoting miR-340-5p binding to CMTM6., Conclusion: circUBR5 knockdown facilitated miR-340-5p-targeted CMTM6 via a ceRNA mechanism, thereby reducing c-MYC-mediated ribosome biogenesis and accelerating chemosensitization of DTX-resistant TNBC cells, which offered a theoretical guideline for clinical research on the feasibility of inhibiting ribosome biogenesis to reduce TNBC chemoresistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: CMTM6 has been closely associated with the onset and progression of various tumor types. However, the precise mechanism by which CMTM6 operates in hepatocellular carcinoma remains elusive, necessitating further investigation., Methods: Expression levels of CMTM6 in hepatocellular carcinoma tissues and cells were analyzed using immunohistochemistry and quantitative real-time PCR. The correlation between CMTM6 expression in hepatocellular carcinoma tissues and clinical pathological characteristics, as well as patient prognosis, was investigated. Proliferation and apoptosis of hepatocellular carcinoma cells with silenced or overexpressed CMTM6 were assessed, alongside measurements of β-catenin and Wnt1 protein expression levels. In vivo research was conducted utilizing a murine subcutaneous transplantation model. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to elucidate the regulatory mechanism of CMTM6. Additionally, CD66b expression levels in tumor tissue were examined using immunohistochemistry, and the immune infiltration of CMTM6 and tumor-associated neutrophils (TANs) was analyzed., Results: Elevated expression levels of CMTM6 in hepatocellular carcinoma tissues and cells were found to be associated with poor patient prognosis. Overexpression of CMTM6 in hepatocellular carcinoma cells was demonstrated to promote cellular proliferation and inhibit apoptosis. Mechanistically, CMTM6 expression levels in hepatocellular carcinoma tissues were observed to positively correlate with β-catenin expression. GSEA and KEGG analysis revealed significant enrichment of CMTM6 in the Wnt/β-catenin pathway, indicating its involvement in pathway regulation. Furthermore, CMTM6 was found to be associated with immune infiltration of TANs in hepatocellular carcinoma tissues., Conclusion: CMTM6 plays a pivotal role in the development and progression of hepatocellular carcinoma through regulation of the Wnt/β-catenin pathway via β-catenin. Moreover, CMTM6 demonstrates the capacity to promote immune infiltration of TANs in hepatocellular carcinoma tissues. Consequently, CMTM6 exhibits potential as both an early diagnostic marker and a novel therapeutic target for patients with hepatocellular carcinoma., Competing Interests: Declarations. Ethics approval and consent to participate: This study received approval from the Independent Ethics Committee of Tumor Hospital Affiliated to Xinjiang Medical University in 2023. The ethics approval number is G-2023032. Informed consent: Informed consent was obtained from all individual participants included in this study. The data supporting the conclusions presented in this article are incorporated within the manuscript. The raw datasets utilized and analyses performed in this study are available from the corresponding author upon submission of a reasonable request. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Regulation of neutrophil activation plays a significant role in managing sepsis. CKLF-like MARVEL transmembrane domain containing (CMTM)3 is a membrane protein involved in immune response. Here, we find that CMTM3 expression is elevated in sepsis and plays a crucial role in mediating the imbalance of neutrophil migration. Cmtm3 knockout improves the survival rate of septic mice, mitigate inflammatory responses, and ameliorate organ damage. Mechanistically, the deletion of Cmtm3 reduced the expression of Toll-like receptor 4 (TLR4) on neutrophils, leading to a decrease in the expression of C-X-C motif chemokine receptor 2 (CXCR2) on the cell membrane. This resulted in a reduced migration of neutrophils from the bone marrow to the bloodstream, thereby attenuating their recruitment to vital organs. Our findings suggest that targeting CMTM3 holds promise as a therapeutic approach to ameliorate the dysregulation of neutrophil migration and multi-organ damage associated with sepsis., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2024. The Author(s).)

Transmembrane domain-containing 7 (CMTM7) is a protein located at the plasma membrane. It plays a role in regulating the development and immune microenvironment of tumor cells. However, the impact of CMTM7 on hepatocellular carcinoma (HCC) is not well understood. To better understand the role of CMTM7 in HCC, the correlations of CMTM7 with clinical characteristics, patient prognosis, chronic inflammation, and immune cell infiltration were analyzed using tissue microarray slides, sequencing datasets and various analysis tools (Web). The bulk sequencing analysis indicated that elevated expression of CMTM7 appears to promote chronic inflammation, immunosuppression, M2 macrophage infiltration, a diminished response to cancer immunotherapy, and an unfavorable clinical prognosis in patients with hepatocellular carcinoma (HCC). Further investigation through single-cell RNA sequencing and multiple fluorescence staining demonstrated that CMTM7 serves as a molecular marker for M2 macrophages and is associated with T cell exhaustion as well as highly plastic stem-like characteristics. We propose that CMTM7 may represent a novel immune checkpoint for HCC patients experiencing suboptimal therapeutic outcomes. Utilizing the Connectivity Map and AutoDock Vina, we predicted two potential compounds targeting CMTM7-fasudil and arachidonyltrifluoromethane-as promising therapeutic candidates. Collectively, these findings suggest that CMTM7-positive macrophages play significant roles in establishing an immunosuppressive tumor microenvironment while promoting highly plastic and stem-like traits in HCC cells, ultimately contributing to poor prognostic outcomes., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This study was performed according to the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board at the First Affiliated Hospital of Xiamen University and Shanghai OUTDO Biotech Co., Ltd. Written informed consent was obtained from all patients., (© 2024. The Author(s).)

Glioma, a common malignancy, is characterized by high morbidity and mortality. Promoting ferroptosis can delay tumor progression. Here, we aimed to explore the underlying mechanism of ferroptosis in glioma. In vitro and in vivo experiments were conducted using glioma cells and nude mice. The expression of genes and proteins was evaluated by RT-qPCR, Western blot assay, and immunohistochemical staining. Malignant activities of glioma cells were evaluated using MTT, EdU, and Transwell assays. The levels of Fe 2+ , lipid reactive oxygen species, and malondialdehyde were determined using commercial kits. The interplays among CMTM5, WWP2, and LATS2 were validated using Co-immunoprecipitation assay. The UALCAN database predicted downregulation of CMTM5 expression in glioma, and low expression of CMTM5 was associated with poor survival outcomes. CMTM5 overexpression inhibited cell growth and invasion and promoted ferroptosis of glioma cells. Besides, CMTM5 protein interacted with WWP2 protein and decreased WWP2 expression. WWP2 silencing attenuated LATS2 ubiquitination to enhance LATS2 expression and phosphorylation of YAP1. CMTM5 exerted a suppressive effect on cell growth and invasion and promoted ferroptosis of glioma cells by regulating the WWP2/LATS2 pathway. In the in vivo experiments, CMTM5 overexpression suppressed tumor growth and enhanced ferroptosis. CMTM5 regulated Hippo/YAP signaling to inhibit cell growth and invasion and to promote ferroptosis in glioma by regulating WWP2-mediated LATS2 ubiquitination, thereby attenuating glioma progression., (© 2024 The Author(s). The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

While immune checkpoint blockade (ICB) has shown promise for clinical cancer therapy, its efficacy has only been observed in a limited subset of patients and the underlying mechanisms regulating innate and acquired resistance to ICB of tumor cells remain poorly understood. Here, we identified ependymin-related protein 1 (EPDR1) as an important tumor-intrinsic regulator of PD-L1 expression and tumor immune evasion. Aberrant expression of EPDR1 in hepatocellular carcinoma is associated with immunosuppression. Mechanistically, EPDR1 binds to E3 ligase TRIM21 and disrupts its interaction with IkappaB kinase-b, suppressing its ubiquitylation and autophagosomal degradation and enhancing NF-κB-mediated transcriptional activation of PD-L1. Further, we validated through a mouse liver cancer model that EPDR1 mediates exhaustion of CD8 + T cells and promotes tumor progression. In addition, we observed a positive correlation between EPDR1 and PD-L1 expression in both human and mouse liver cancer samples. Collectively, our study reveals a previously unappreciated role of EPDR1 in orchestrating tumor immune evasion and cancer progression., (© 2024. The Author(s).)

Chemokine like factor 1 (CKLF1) is a novel atypical chemokine, playing a crucial role in cardiovascular and cerebrovascular diseases (CCVDs) demonstrated by a growing body of works. In cardiovascular diseases including atherosclerosis and myocardial infarction, meanwhile in cerebrovascular diseases such as ischemic stroke and hemorrhagic stroke, the expression levels of CKLF1 change markedly, which triggers downstream signaling pathways by binding with its functional receptors, and then exerts multiple effects to participate in the occurrence and development of these CCVDs. The functional roles of CKLF1 are dynamic and CKLF1 may act as a double-edged sword. The CCVDs-promoting role is related to recruiting inflammatory cells, enhancing the proliferation of vascular smooth muscle cells and endothelial cells, while the CCVDs-suppressing role may correlate with migration of nerve cells and promotion of hematopoietic stem cell proliferation which contributes to disease recovery. Based on this, the paper intends to review expression shifts, potential roles, and molecular mechanisms of CKLF1 in CCVDs, and the current status of CKLF1 targeted therapeutic strategies is also included. We hope this review may provide a valuable reference for using CKLF1 as a diagnostic and prognostic biomarker for CCVDs or developing novel treatments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Liver metastasis of colorectal cancer (CRC) is a leading cause of death among cancer patients. The overexpression of glucose transporter 1 (Glut1) and enhanced glucose uptake that are associated with the Warburg effect are frequently observed in CRC liver metastases, but the underlying mechanisms remain poorly understood. CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) regulates the intracellular trafficking of programmed death-ligand-1 (PD-L1); therefore, we investigated whether CMTM6 regulates Glut1 trafficking and the Warburg effect in CRC cells. We found that knocking down of CMTM6 by shRNA induced the lysosomal degradation of Glut1, decreased glucose uptake and glycolysis in CRC cells, and suppressed subcutaneous CRC growth in nude mice and liver metastasis in C57BL/6 mice. Mechanistically, CMTM6 forms a complex with Glut1 and Rab11 in the endosomes of CRC cells, and this complex is required for the Rab11-dependent transport of Glut1 to the plasma membrane and for the protection of Glut1 from lysosomal degradation. Multiomics revealed global transcriptomic changes in CMTM6-knockdown CRC cells that affected the transcriptomes of adjacent cancer-associated fibroblasts from CRC liver metastases. As a result of these transcriptomic changes, CMTM6-knockdown CRC cells exhibited a defect in the G2-to-M phase transition, reduced secretion of 60 cytokines/chemokines, and inability to recruit cancer-associated fibroblasts to support an immunosuppressive CRC liver metastasis microenvironment. Analysis of TCGA data confirmed that CMTM6 expression was increased in CRC patients and that elevated CMTM6 expression was associated with worse patient survival. Together, our data suggest that CMTM6 plays multiple roles in regulating the Warburg effect, transcriptome, and liver metastasis of CRC., (© 2024. The Author(s).)

CKLF-like MARVEL transmembrane domain-containing 3 (CMTM3), a member of the CMTM family that is closely related to tumor occurrence and progression, plays crucial roles in the immune system, cardiovascular system, and male reproductive system. Recently, CMTM3 has emerged as a potential target for treating diseases related to bone formation. However, additional studies are needed to understand the mechanisms by which CMTM3 regulates the process of osteogenic differentiation. In this study, we observed a significant downregulation of Cmtm3 expression during the transdifferentiation of C2C12 myoblasts into osteoblasts induced by BMP4. Cmtm3 overexpression suppressed proliferation and osteogenic differentiation in BMP4-induced C2C12 cells, whereas its knockdown conversely facilitated the process. Mechanistically, Cmtm3 overexpression upregulated both the protein and mRNA levels of p53 and p21. Conversely, Cmtm3 knockdown exerted the opposite effects. Additionally, we found that Cmtm3 interacts with p53 and increases protein stability by inhibiting proteasome-mediated ubiquitination and degradation. Notably, Trp53 downregulation abrogated the inhibitory effect of Cmtm3 on BMP4-induced proliferation and osteogenic differentiation of C2C12 myoblasts. Collectively, our findings provide key insights into the role of CMTM3 in regulating myoblast proliferation and transdifferentiation into osteoblasts, highlighting its significance in osteogenesis research.

There have been notable irregularities in CMTM6 expression observed in hepatocellular carcinoma (HCC), with an evident correlation between CMTM6 dysregulation and patient prognosis. The cell cycle progression came to a halt at the G2/M phase. In-depth RNA-sequencing analysis of CMTM6 knockdown Hep3B cells revealed that the most prominent effect of CMTM6 perturbation was on the expression of CXCL8, a chemokine involved in immune responses, particularly through the interleukin-17F (IL-17F) signaling pathway. By carefully examining the RNA-sequencing data obtained from CMTM6 knockdown Hep3B cells and cross-referencing it with the TCGA-LIHC database, we were able to discern that CMTM6 and programmed death-ligand 1 (PD-L1) collaboratively partake in immune regulation within T cells. Furthermore, CMTM6 exerted an influential role in modulating the infiltration of CD4+ and CD8+ T cells in the HCC microenvironment, thereby impacting the overall immune response. Our investigation found that HCC cases characterized by an elevated co-expression of CMTM6 and PD-L1, along with augmented CD4+ T cell infiltration, demonstrated comparatively longer overall and progression-free survival rates when contrasted with those displaying lower CD4+ T cell infiltration., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The dysfunction of innate immunity components is one of the major drivers for ulcerative colitis (UC), and increasing reports indicate that the gut microbiome serves as an intermediate between genetic mutations and UC development. Here, we find that the IL-17 receptor subunit, CMTM4, is reduced in UC patients and dextran sulfate sodium (DSS)-induced colitis. The deletion of CMTM4 (Cmtm4 -/- ) in mice leads to a higher susceptibility to DSS-induced colitis than in wild-type, and the gut microbiome significantly changes in composition. The causal role of the gut microbiome is confirmed with a cohousing experiment. We further identify that S100a8/9 is significantly up-regulated in Cmtm4 -/- colitis, with the block of its receptor RAGE that reverses the phenotype associated with the CMTM4 deficiency. CMTM4 deficiency rather suppresses S100a8/9 expression in vitro via the IL17 pathway, further supporting that the elevation of S100a8/9 in vivo is most likely a result of microbial dysbiosis. Taken together, the results suggest that CMTM4 is involved in the maintenance of intestinal homeostasis, suppression of S100a8/9, and prevention of colitis development. Our study further shows CMTM4 as a crucial innate immunity component, confirming its important role in UC development and providing insights into potential targets for the development of future therapies., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Glioblastoma multiforme (GBM) is identified as one of the most prevalent and malignant brain tumors, characterized by poor treatment outcomes and a limited prognosis. CMTM6, a membrane protein, has been found to upregulate the expression of programmed cell death 1 ligand 1 protein (PD-L1) and acts as an immune checkpoint inhibitor by inhibiting the programmed death 1 protein/PD-L1 signaling pathway. Recent research has demonstrated a high expression of CMTM6 in GBM, suggesting its potential role in influencing the pathogenesis and progression of GBM, as well as its association with immune cell infiltration in the tumor microenvironment. However, the underlying mechanism of CMTM6 in GBM requires further investigation., Methods: Data from cancer patients in The Cancer Genome Atlas, Gene Expression Omnibus and Chinese Glioma Genome Atlas cohorts were consolidated for the current study. Through multi-omics analysis, the study systematically examined the expression profile of CMTM6, epigenetic modifications, prognostic significance, biological functions, potential mechanisms of action and alterations in the immune microenvironment. Additionally, the study investigated CMTM6 expression in GBM cell lines and normal cells using reverse transcription PCR and western blot analysis. The impact of CMTM6 on GBM cell proliferation, migration and invasion was evaluated using a combination of cell counting kit-8 assay, clone formation assay, 5-ethynyl-2'-deoxyuridine incorporation assay, wound healing assay and Transwell assay. In order to explore the mechanism of CMTM6, the Wnt/β-catenin signaling pathway and autophagy-related genes were further verified through western blot analysis., Results: CMTM6 is highly expressed in multiple tumors, particularly GBM. CMTM6 has been shown to be a valuable diagnostic and prognostic biomarker by various bioinformatics approaches. Additionally, CMTM6 plays a pivotal role in the pathogenesis of cancer, specifically GBM, by modulating various biological processes such as DNA methyltransferase expression, RNA modification, copy number variation, genomic heterogeneity, tumor stemness and DNA methylation. The findings of the experiment indicate a significant correlation between elevated CMTM6 expression and the proliferation, invasion, migration and autophagy of GBM cells, with potential key roles mediated through the Wnt/β-catenin signaling pathway. Furthermore, CMTM6 is implicated in modulating tumor immune cell infiltration and is closely linked to the expression of various immune checkpoint inhibitors and immune modulators, particularly within the context of GBM. High levels of CMTM6 expression also enhance the responsiveness of GBM patients to radiotherapy and chemotherapy, thereby offering valuable insights for guiding treatment strategies for GBM., Conclusions: Autophagy-related CMTM6 is highly expressed in various types of cancer, especially GBM, and it can regulate GBM progression through the Wnt/β-catenin signaling pathway and is capable of being used as an underlying target for the diagnosis, treatment selection and prognosis of patients with GBM., (© 2024 John Wiley & Sons Ltd.)

Upper tract urothelial carcinoma (UTUC) accounts for 5-10% of all UCs. Immune checkpoint inhibitors (ICIs) have been established for UCs. The prognostic and predictive potential of programmed cell death ligand 1 (PD-L1) expression to stratify patients benefiting from ICIs is not fully understood, and additional markers influencing the impact of PD-L1-mediated ICI response are needed. Previously, the chemokine-like MARVEL transmembrane domain-containing protein 6 (CMTM6) was identified as a positive regulator of PD-L1. Our aim was to investigate the expression profiles and impact of PD-L1 and CMTM6 protein status on the prognostic parameters and survival of UTUC patients. In this retrospective study, the combined positive score (CPS), tumor proportion score (TPS), and immune cell score (ICS) for PD-L1 and CMTM6 were determined. High PD-L1 CPS, ICS, and TPS were found in 77.4%, 58.3%, and 45.2% of cases, and high CMTM6 CPS, ICS, and TPS were seen in 52.5%, 51.5%, and 55.5% of cases, respectively. The scores of both markers had a significant positive correlation. High PD-L1 and CMTM6 expression was coupled with higher pT status, WHO grade, necrosis, and metastasis ( p < 0.05, respectively). In the univariate survival analysis, patients with a PD-L1 ICS high and higher degree of intratumoral inflammation showed significantly longer overall survival. Compared to other studies on UC, our study shows a substantially higher rate of PD-L1-positive tumors. CMTM6 was associated with more aggressive tumors.

Background: The chemokine-like factor (CKLF)-like Marvel transmembrane structural domain (CMTM) family is widely expressed in the tumor and immune systems and is essential in human cancer progression. However, the multi-omic profile of CMTM family genes and their role in tumor patient prognosis and immune microenvironment have not been explored., Methods: We collected data from 33 cancers and 33 non-cancers and then comprehensively analyzed the basal expression levels of CMTM family genes in normal human tissues as well as abnormal expression in diseases, genomic alterations, diagnostic and prognostic roles, subcellular localization, pathway enrichment, the immune microenvironment, associations with immune checkpoints, and drug sensitivities as well as to predict the immunotherapeutic response of patients to ICIs and targeting of small molecule drugs, the above results were validated by immunohistochemical staining, pathology sections and experiments. We also performed protein docking of immune checkpoints binding to CMTM6 and screening of small molecule drugs targeting CMTM6 based on mass spectrometry results and molecular docking techniques. Finally, we experimentally confirmed the role of CMTM6 in bladder cancer., Results: We found differential expression and diagnostic biomarker value of the CMTMs family in diseases (cancer and non-cancer). CMTMs were also found to play a key role in pan-cancer with the tumor microenvironment. CMTMs were closely associated with common immune checkpoints, TMB and MSI, so we scored CMTMs based on CMTMs expression in patients undergoing ICI, and patients with lower scores had better survival and showed higher immunotherapy response after immunotherapy. Finally, molecular docking was used to identify small molecule inhibitors that could target CMTM6 and binding poses of CMTM6 to other immune checkpoint genes. Finally, it was determined experimentally that knockdown of CMTM6 gene expression inhibited the proliferation and invasion of bladder cancer cells., Conclusions: Our findings provide a valuable strategy to guide the diagnostic and therapeutic direction of CMTM family genes in disease., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

In this research, polyethylenimine-functionalized gold nanoclusters (PEI-AuNCs) were synthesized for the delivery of plasmid CMTM5 (pCMTM5) to prostate cancer (PCa) cells, with the objective of elucidating the mechanism underlying its anticancer efficacy. The PEI-AuNCs loaded with pCMTM5 (PEI-AuNCs@pCMTM5) tumor-targeting drug delivery system was established. Subsequently, both the obtained PEI-AuNCs and PEI-AuNCs@pCMTM5 underwent characterization through a transmission electron microscope (TEM) and dynamic light scattering (DLS). Employing RT-qPCR, western blot, flow cytometry, immunofluorescence, and co-immunoprecipitation (co-IP) assays, the consequences of CMTM5 overexpression on the expression of EGFR were investigated. Moreover, the influence of PEI-AuNCs@pCMTM5 on PC-3 cells was assessed through CCK-8, wound healing assay, and Transwell experiments. As a result, the PEI-AuNCs and PEI-AuNCs@pCMTM5 were presented as uniformly dispersed spherical with stable particle sizes and positive charges, showcasing favorable dispersion within the solution. In comparison to Lip2000, the PEI-AuNCs demonstrated superior transfection efficiency and lower cellular toxicity. Following the overexpression of CMTM5, the proliferative capacity of PC-3 cells was markedly suppressed, while both migratory and invasive abilities exhibited noteworthy reduction, with the efficacy of PEI-AuNCs@pCMTM5 consistently outperforming that of free pCMTM5. Subsequent mechanistic investigations unveiled that CMTM5 does not directly inhibit the synthesis of EGFR or facilitate its degradation, but rather influences the endocytic process of EGFR. In conclusion, the PEI-AuNCs nano-delivery system exhibits good biocompatibility and efficaciously conveys pCMTM5 to PCa cells. Crucially, pCMTM5 does not directly interact with EGFR, and CMTM5 governs the malignant progression of PC3 cells by promoting EGFR endocytosis.

Thyroid cancer is the most common type of endocrine cancer. Chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 6 (CMTM6) is recognized as one of its potential immunotherapy targets. The purpose of this study was to investigate the role and molecular mechanism of CMTM6 in regulating the development of thyroid cancer cells. In this study, expression levels of CMTM6 and the sodium/iodide symporter (NIS) were detected by qRT-PCR. Additionally, colony formation assay and flow cytometry were used to detect cell proliferation and apoptosis, while expression levels of various proteins were assessed using Western blotting. Further, the apoptosis and invasion capacity of cells were investigated by scratch and transwell experiments. Finally, the effect of CMTM6 on the epithelial-mesenchymal transition (EMT) of thyroid cancer cells was determined by immunofluorescence assay, which measured the expression levels of epithelial and mesenchymal phenotypic markers. The results of qRT-PCR experiments showed that CMTM6 was highly expressed in thyroid cancer tissues and cells. In addition, knockdown of CMTM6 expression significantly increased NIS expression. Function experiments demonstrated that small interfering (si)-CMTM6 treatment inhibited the proliferation, migration, invasion, and EMT of thyroid cancer cells, while promoting apoptosis of FTC133 cells. Furthermore, mechanistic studies showed that mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) phosphorylation were inhibited by si-CMTM6, as demonstrated by Western blot experiments. In conclusion, our findings demonstrated the role of CMTM6 in the metastasis of thyroid cancer. Briefly, CMTM6 exerts its tumor-promoting effect through the MAPK signaling pathway and could potentially be used as a valuable biomarker for thyroid cancer diagnosis and prognosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing (CMTM) family includes CMTM1-8 and CKLF, and they play key roles in the hematopoietic, immune, cardiovascular, and male reproductive systems, participating in the physiological functions, cancer, and other diseases associated with these systems. CMTM family members activate and chemoattract immune cells to affect the proliferation and invasion of tumor cells through a similar mechanism, the structural characteristics typical of chemokines and transmembrane 4 superfamily (TM4SF). In this review, we discuss each CMTM family member's chromosomal location, involved signaling pathways, expression patterns, and potential roles, and mechanisms of action in pancreatic, breast, gastric and liver cancers. Furthermore, we discuss several clinically applied tumor therapies targeted at the CMTM family, indicating that CMTM family members could be novel immune checkpoints and potential targets effective in tumor treatment., Competing Interests: The authors declare that they have no competing interests., (© 2024 Duan et al.)

Purpose: To investigate the impact of transmembrane protein CMTM6 on the pathogenesis of dry eye disease (DED) and elucidate its potential mechanisms., Methods: CMTM6 expression was confirmed by database analysis, real-time polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry. Tear secretion was measured using the phenol red thread test. Immune cell infiltration was assessed through flow cytometry. Barrier function was evaluated by fluorescein sodium staining, immunofluorescence staining of zonula occludens 1 (ZO-1), and electric cell-substrate impedance sensing (ECIS) assessment. For silencing CMTM6 expression, siRNA and shRNA were employed, along with lentiviral vector-mediated overexpression of CMTM6. Proinflammatory cytokine levels were analyzed by RT-PCR and cytometric bead array (CBA) analysis., Results: CMTM6 showed high expression in healthy human and mouse corneal and conjunctival epithelium but was notably reduced in DED. Notably, this downregulation was correlated with disease severity. Cmtm6-/- dry eye (DE) mice displayed reduced tear secretion, severe corneal epithelial defects, decreased conjunctival goblet cell density, and upregulated inflammatory response. Additionally, Cmtm6-/- DE mice and CMTM6 knockdown human corneal epithelial cell-transformed (HCE-T) cells showed more severe barrier disruption and reduced expression of ZO-1. Knockdown of CMTM6 in HCE-T cells increased inflammatory responses induced by hyperosmotic stress, which was significantly mitigated by CMTM6 overexpression. Moreover, the level of phospho-p65 in hyperosmolarity-stimulated HCE-T cells increased after silencing CMTM6. Nuclear factor kappa B (NF-κB) p65 inhibition (JSH-23) reversed the excessive inflammatory responses caused by hyperosmolarity in CMTM6 knockdown HCE-T cells., Conclusions: The reduction in CMTM6 expression on the ocular surface contributes to the pathogenesis of DED. The CMTM6-NF-κB p65 signaling pathway may serve as a promising therapeutic target for DED.

Objectives: Cardiac hypertrophy is the heart's compensatory response stimulated by various pathophysiological factors. However, prolonged cardiac hypertrophy poses a significant risk of progression to heart failure, lethal arrhythmias, and even sudden cardiac death. For this reason, it is crucial to effectively prevent the occurrence and development of cardiac hypertrophy. CMTM is a superfamily of human chemotaxis, which is involved in immune response and tumorigenesis. CMTM3 expressed widely in tissues, including the heart, but its cardiac function remains unclear. This research aims to explore the effect and mechanism of CMTM3 in the development of cardiac hypertrophy., Methods and Results: We generated a Cmtm3 knockout mouse model (Cmtm3 -/- ) as the loss-of-function approach. CMTM3 deficiency induced cardiac hypertrophy and further exacerbated hypertrophy and cardiac dysfunction stimulated by Angiotensin Ⅱ infusion. In Ang Ⅱ-infusion stimulated hypertrophic hearts and phenylephrine-induced hypertrophic neonatal cardiomyocytes, CMTM3 expression significantly increased. However, adenovirus-mediated overexpression of CMTM3 inhibited the hypertrophy of rat neonatal cardiomyocytes induced by PE stimulation. In terms of mechanism, RNA-seq data revealed that Cmtm3 knockout-induced cardiac hypertrophy was related to MAPK/ERK activation. In vitro, CMTM3 overexpression significantly inhibited the increased phosphorylation of p38 and ERK induced by PE stimulation., Conclusions: CMTM3 deficiency induces cardiac hypertrophy and aggravates hypertrophy and impaired cardiac function stimulated by angiotensin Ⅱ infusion. The expression of CMTM3 increases during cardiac hypertrophy, and the increased CMTM3 can inhibit further hypertrophy of cardiomyocytes by inhibiting MAPK signaling. Thus, CMTM3 plays a negative regulatory effect in the occurrence and development of cardiac hypertrophy., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Breast cancer is the major cause of death in females globally. Chemokine-like factor like MARVEL transmembrane domain containing 7 (CMTM7) is reported as a tumor suppressor and is involved in epidermal growth factor receptor degradation and PI3K/AKT signaling in previous studies. However, other molecular mechanisms of CMTM7 remain unclear., Methods: The expression level of CMTM7 in breast cancer cells and tissues was detected by qRT-PCR and western blot, and the methylation of CMTM7 promoter was detected by BSP sequencing. The effect of CMTM7 was verified both in vitro and in vivo, including MTT, colony formation, EdU assay, transwell assay and wound healing assay. The interaction between CMTM7 and CTNNA1 was investigated by co-IP assay. The regulation of miR-182-5p on CMTM7 and TCF3 on miR-182-5p was detected by luciferase reporter assay and ChIP analysis., Results: This study detected the hypermethylation levels of the CMTM7 promoter region in breast cancer tissues and cell lines. CMTM7 was performed as a tumor suppressor both in vitro and in vivo. Furthermore, CMTM7 was a direct miR-182-5p target. Besides, we found that CMTM7 could interact with Catenin Alpha 1 (CTNNA1) and regulate Wnt/β-catenin signaling. Finally, transcription factor 3 (TCF3) can regulate miR-182-5p. We identified a feedback loop with the composition of miR-182-5p, CMTM7, CTNNA1, CTNNB1 (β-catenin), and TCF3, which play essential roles in breast cancer progression., Conclusion: These findings reveal the emerging character of CMTM7 in Wnt/β-catenin signaling and bring new sights of gene interaction. CMTM7 and other elements in the feedback loop may serve as emerging targets for breast cancer therapy., (© 2023. The Author(s).)

The Chemokine-like factor ( CKLF )-like MARVEL transmembrane domain-containing ( CMTM ) family, comprising nine members, is involved in the tumorigenesis and progression of various cancers. However, the expression profiles and clinical significance of CMTM family members in hepatocellular carcinoma (HCC) are not fully clarified. In this study, the RNA-sequencing and clinical data were downloaded from The Cancer Genome Atlas (TCGA) databases. The Kaplan-Meier method and the Cox proportional hazards regression analysis were used to evaluate the prognostic significance of CMTM family members. Single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE algorithms were employed to explore the relationship between CMTM family genes and the tumor microenvironment in HCC. Finally, the prognostic CMTM family gene expression was further validated by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical (IHC) staining in clinical HCC tissue specimens. The results indicated that, compared with normal tissues, the expression of CKLF , CMTM1 , CMTM3 , CMTM4 , CMTM7 , and CMTM8 were significantly upregulated in HCC, while the expression of CMTM2 , CMTM5 , and CMTM6 were significantly downregulated in HCC. Univariate and multivariate Cox regression analysis demonstrated that CKLF was an independent prognostic biomarker for the overall survival (OS) of HCC patients. In HCC, the expression of CKLF was found to be correlated with immune cell infiltration, immune-related functions, and immune checkpoint genes. The qRT-PCR and IHC confirmed that CKLF was highly expressed in HCC. Overall, this research suggested that CKLF is involved in immune cell infiltration and may serve as a critical prognostic biomarker, which provides new light on the therapeutics for HCC.

Chemokine-like factor-like MARVEL transmembrane domain containing member/chemokine-like factor superfamily member (CMTM/CKLFSF) including CKLF and CMTM1-CMTM8 are a new family of proteins linking chemokines and transmembrane superfamilies. CMTM not only have broad chemotactic activities, but also associate with hematopoietic system, immune system, and tumor development and metastasis closely. CMTM proteins are involved in key biological processes of cancer development, which include activation and recycling of growth factor receptors, cell proliferation and metastasis, and regulation of the tumor immune microenvironment. This is a new focus of research on the relationship between CMTM and tumors, because CMTM4/CMTM6 can be considered as a regulator for programmed cell death ligand 1 (PD-L1). This paper reviews the role of CMTM family members on cancer, especially in tumor growth, metastasis and immune escape, summarize the latest findings on the relationship between CMTM and non-small cell lung cancer, and explores the potential clinical value of CMTM as a novel drug target or biomarker.
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Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is characterized by invasive growth, rapid metastasis and chemoresistance. Trastuzumab is an effective treatment for HER2+ breast cancer; however, trastuzumab resistance leads to cancer relapse and metastasis. CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) has been considered as a new immune checkpoint for tumor-induced immunosuppression. The role of CMTM6 in trastuzumab resistance remains unknown. Here, we uncover a role of CMTM6 in trastuzumab-resistant HER2+ breast cancer. CMTM6 expression was upregulated in trastuzumab-resistant HER2+ breast cancer cell. Patients with high CMTM6 expressing HER2+ breast cancer had worse overall and progression-free survival than those with low CMTM6 expression. In vitro, CMTM6 knockdown inhibited the proliferation and migration of HER2+ breast cancer cells, and promoted their apoptosis, while CMTM6 overexpression reversed these effects. CMTM6 and HER2 proteins were co-localized on the surface of breast cancer cells, and CMTM6 silencing reduced HER2 protein levels in breast cancer cells. Co-immunoprecipitation revealed that CMTM6 directly interacted with HER2 in HER2+ breast cancer cells, and CMTM6 overexpression inhibited HER2 ubiquitination. Collectively, these findings highlight that CMTM6 stabilizes HER2 protein, contributing to trastuzumab resistance and implicate CMTM6 as a potential prognostic marker and therapeutic target for overcoming trastuzumab resistance in HER2+ breast cancer., (© 2023. The Author(s).)

Interleukin-17A (IL-17A) is a key mediator of protective immunity to yeast and bacterial infections but also drives the pathogenesis of several autoimmune diseases, such as psoriasis or psoriatic arthritis. Here we show that the tetra-transmembrane protein CMTM4 is a subunit of the IL-17 receptor (IL-17R). CMTM4 constitutively associated with IL-17R subunit C to mediate its stability, glycosylation and plasma membrane localization. Both mouse and human cell lines deficient in CMTM4 were largely unresponsive to IL-17A, due to their inability to assemble the IL-17R signaling complex. Accordingly, CMTM4-deficient mice had a severe defect in the recruitment of immune cells following IL-17A administration and were largely resistant to experimental psoriasis, but not to experimental autoimmune encephalomyelitis. Collectively, our data identified CMTM4 as an essential component of IL-17R and a potential therapeutic target for treating IL-17-mediated autoimmune diseases., (© 2022. The Author(s).)

Immune checkpoint proteins, such as programmed cell death receptor 1 (PD-1) and its ligand (PD-L1), play critical roles in the pathology of chronic inflammatory pathological conditions, particularly cancer. In addition, the activation of PD-1/PD-L1 pathway is involved in mediating resistance to certain anti-cancer chemo- and immuno-therapeutics. Unfortunately, targeting the PD-1/PD-L1 pathway by the available anti-PD-1/PD-L1 drugs can benefit only a small proportion of cancer patients. Thus, studying the factors that regulate the expression of these immune checkpoint proteins is of central importance in this context. Recent investigations have identified CMTM6 and, to a lesser extent, CMTM4, as master regulators of PD-L1 expression in various cancer cells. Understanding the mechanisms by which such proteins upregulate the expression of PD-L1 in tumor cells, and determining the potential regulators of CMTM6 expression in different types of cancers will accelerate the development of new therapeutic targets and/or lead to the enhancement of the currently available PD-1/PD-L1 blockade therapies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Previous study has shown that chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family member 4 (CMTM4) can bind and maintain programmed cell death ligand 1 (PD-L1) expression to promote tumor progression by alleviating the suppression of tumor-specific T cell activity, suggesting its potential role in tumor immunotherapy. However, the role of CMTM4 in tumor immunity has not been well clarified, especially in hepatocellular carcinoma (HCC)., Methods: The protein expression of CMTM4/PD-L1/CD4/CD8 was detected by immunohistochemistry (IHC) detection in 90 cases of HCC tissues. The mRNA expression profiles and related prognosis data were obtained from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC). Two immune therapy cohorts were from Imvigor210 and GSE176307., Results: Though the single protein expression of CMTM4, PD-L1, CD4 or CD8 in HCC tissues by IHC detection didn't show a significant relationship with the prognosis of HCC patients, we found that high co-expression of CMTM4/PD-L1/CD4 showed a good prognosis of HCC patients. Further Timer 2.0 analysis identified that HCC patients with high expression of CMTM4/PD-L1 and high infiltration of CD4 + T cells had a better overall survival than those with low infiltration of CD4 + T cells. Moreover, a series of bioinformatics analyses revealed that CMTM4-related genes posed important effects on prognosis and immunity in HCC patients, and CMTM4 had a positive correlation with infiltration of CD4 + and CD8 + T cells in HCC. At last, we used two immunotherapy cohorts to verify that the combination of CMTM4 with PD-L1 could improve the prognosis of tumor patients underwent immunotherapy., Conclusions: CMTM4 and PD-L1 co-expression with T cell infiltration shows prognostic significance in HCC, suggesting combined effect from multiple proteins should be considered in HCC treatment., (© 2022. The Author(s).)

The tumor microenvironment (TME) plays crucial roles in regulating tumor occurrence, progress, metastasis and drug resistance. However, it remains largely elusive how the components of TME are regulated to govern its functions in tumor biology. Here, we discussed how the two novel functional proteins, chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing 6 (CMTM6) and CMTM4, which involved in the post-translational regulation of PD-L1, modulate the TME functions. The roles of CMTM6 and CMTM4 in regulating TME components, including immune cells and tumor cells themselves were discussed in this review. The potential clinical applications of CMTM6 and CMTM4 as biomarkers to predict therapy efficacy and as new or combined immunotherapy targets are also highlighted. Finally, the current hot topics for the biological function of CMTM6/4 and several significant research directions for CMTM6/4 are also briefly summarized in the review., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Yu, Dai and Zhang.)

Background: Interactions between malignant cells and neighboring normal cells are important for carcinogenesis. In addition, cancer cell-derived exosomes have been shown to promote the malignant transformation of recipient cells, but the mechanisms remain unclear., Methods: The level of miR-224-5p in CRC cell-derived exosomes was determined by RT-qPCR assay. In addition, PKH26 dye-labeled exosomes were used to assess the efficacy of the transfer of exosomes between SW620 and normal colon epithelial cell line CCD 841 CoN., Results: In this study, we found that overexpression of miR-224-5p significantly promoted the proliferation, migration, and invasion and inhibited the oxidative stress of SW620 cells. In addition, miR-224-5p can be transferred from SW620 cells to CCD 841 CoN cells via exosomes. SW620 cell-derived exosomal miR-224-5p markedly promoted proliferation, migration, and invasion of CCD 841 CoN cells. Meanwhile, SW620 cell-derived exosomal miR-224-5p notably decreased the expression of CMTM4 in CCD 841 CoN cells. Furthermore, SW620 cell-derived exosomal miR-224-5p significantly promoted tumor growth in a xenograft model in vivo ., Conclusion: These findings suggested that SW620 cell-derived exosomal miR-224-5p could promote malignant transformation and tumorigenesis in vitro and in vivo via downregulation of CMTM4, suggesting that miR-224-5p might be a potential target for therapies in CRC., Competing Interests: The authors declare no potential conflicts of interest., (Copyright © 2022 Feng Wu et al.)

Programmed death-ligand 1 (PD-L1) expression has long been used as a biomarker to stratify patients with cancer who will benefit from anti-PD-1/PD-L1 immunotherapy. However, the use of PD-L1 as a biomarker to guide treatment decisions has recently been called into question due to its dynamic and heterogeneous expression within each tumor and among different tumors as well as during tumor cell plasticity. Therefore, understanding the molecular basis of PD-L1 expression would enable delineating its value as a reliable biomarker in the clinic. Here, we provide our perspective on the involvement of CMTM6 and CMTM7 as new lead candidates for the regulation of PD-L1 in breast tumors undergoing an epithelial to mesenchymal transition., (© 2022 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.)

In inflammatory bowel disease (IBD), the impaired intestinal barrier is mainly characterized by changes in tight junction protein expression. The functional role of the tight junction-associated MARVEL protein MARVELD3 (MD3) in IBD is yet unknown. (i) In colon biopsies from IBD patients we analyzed MD3 expression and (ii) in human colon HT-29/B6 cells we studied the signaling pathways of different IBD-relevant cytokines. (iii) We generated a mouse model with intestinal overexpression of MD3 and investigated functional effects of MD3 upregulation. Colitis, graded by the disease activity index, was induced by dextran sodium sulfate (DSS) and the intestinal barrier was characterized electrophysiologically. MD3 was upregulated in human ulcerative colitis and MD3 expression could be increased in HT-29/B6 cells by IL-13 via the IL13Rα1/STAT pathway. In mice DSS colitis, MD3 overexpression had an ameliorating, protective effect. It was not based on direct enhancement of paracellular barrier properties, but rather on regulatory mechanisms not solved yet in detail. However, as MD3 is involved in regulatory functions such as proliferation and cell survival, we conclude that the protective effects are hardly targeting the intestinal barrier directly but are based on regulatory processes supporting stabilization of the intestinal barrier.

Background: The present study aimed to explore the changes in the expressions of six tumor-related genes in myeloproliferative neoplasms (MPNs). The study population included 130 patients with MPNs (52 with chronic myeloid leukemia (CML), 49 with essential thrombocythemia (ET), 20 with polycythemia vera (PV), and 9 with primary myelofibrosis (PMF)) and 51 healthy individuals., Methods: The expression profiling of six genes (ADAMTS18, CMTM5, CDKN2B, DCC, FHIT, and WNT5B) in the peripheral blood granulocyte cells was explored by real-time quantitative reverse transcription polymerase chain reaction., Results: The patients with MPNs showed significant downregulation of CMTM5 (EFC = 0.66) and DCC (EFC = 0.65) genes in contrast to a non-significant upregulation of ADAMTS18, CDKN2B, FHIT, and WNT5B genes. Downregulation of DCC was consistent in all subtypes of MPN (EFC range: 0.591-0.860). However, CMTM5 had a 1.22-fold upregulation in PMF in contrast to downregulation in other MPN subtypes (EFC range: 0.599-0.775). The results revealed a significant downregulation in CMTM5 and DCC at below 60-years of age. Furthermore, female patients showed a clear-cut downregulation in both CMTM5 and DCC (EFC DCC: 0.436 and CMTM5: 0.570), while male patients presented a less prominent downregulation with a borderline p-value only in DCC (EFC: 0.69; p = 0.05)., Conclusions: Chronic myeloid leukemia cases showed a significant upregulation of WNT5B, as a known oncogenesis gene. Two tumor suppressor genes, namely DCC and CMTM5, were downregulated in the patients with MPNs, especially in females and patients below 60 years of age., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Renal cell carcinoma (RCC) is a lethal urinary malignancy. Circular RNAs (circRNAs) contribute to the malignant phenotype and progression of several types of human cancers, including RCC. In this study, we identified relatively low hsa&#95;circ&#95;0060927 (circCYP24A1) expression in RCC tissue through high-throughput sequencing and RT-qPCR. Fluorescence in situ hybridization (FISH) was used to validate the expression and subcellular localization of circCYP24A1 in RCC tissues. CCK-8, Transwell, EdU, and wound-healing assays indicated that circCYP24A1 overexpression inhibited the proliferation, invasion, and migration of RCC cells. Dual-luciferase reporter, RNA immunoprecipitation (RIP), FISH, and RNA-pulldown assays verified that circCYP24A1 inhibited RCC progression by sponging miR-421, thus inducing CMTM-4 expression. Xenograft assays and metastasis models further indicated that circCYP24A1 significantly inhibited the metastasis and proliferation of RCC cells in vivo. Taken together, circCYP24A1 is a prognosis-related circRNA in RCC that functions through the circCYP24A1/miR-421/CMTM-4 axis to modulate RCC progression., (© 2022. The Author(s).)

Malignant melanoma is the main cause of death in patients with skin cancer. Overexpression of Proteolipid protein 2 (PLP2) increased tumor metastasis and the knockdown of PLP2 inhibited the growth and metastasis of melanoma cells. In the present work, we studied the antitumor activity of peptide Rb4 derived from protein PLP2. In vitro, Rb4 induced F-actin polymerization, prevented F-actin depolymerization and increased the ER-derived cytosolic calcium. Such effects were associated with necrosis of murine melanoma B16F10-Nex2 cells and with inhibition of the viability of human cancer cell lines. Loss of plasma membrane integrity, dilation of mitochondria, cytoplasm vacuolation and absence of chromatin condensation characterized tumor cell necrosis. Cleavage of PARP-1 and inhibition of RIP1 expression were also observed. In vivo, peptide Rb4 reduced the lung metastasis of tumor cells and delayed the subcutaneous melanoma growth in a syngeneic model. Rb4 induced the expression of two DAMPs molecules, HMGB1 and calreticulin, in B16F10-Nex2. Our results suggest that peptide Rb4 acts directly on tumor cells inducing the expression of DAMPs, which trigger the immunoprotective effect in vivo against melanoma cells. We suggest that peptide Rb4 is a promising compound to be developed as an anticancer drug., (© 2022. The Author(s).)

Recent studies have revealed that chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) promotes tumor progression and modulates tumor immunity by regulating programmed death-ligand 1 stability; however, its intrinsic functions and regulatory mechanisms in clear cell renal cell carcinoma (ccRCC) remain poorly understood. Here, we show that CMTM6 is upregulated in ccRCC tissues and is strongly associated with advanced tumor grades, early metastases, and a worse prognosis. CMTM6 depletion significantly impaired the proliferation, migration, and invasion of ccRCC cells in vitro and in xenograft mouse models in vivo . In addition, targeting CMTM6 promotes anti-tumor immunity, represented by increased infiltration of CD4 + and CD8 + T cells in syngeneic graft mouse models. Further research revealed that loss of CMTM6 triggered aberrant activation of DNA damage response, resulting in micronucleus formation and G2/M checkpoint arrest, finally leading to cellular senescence with robust upregulation of numerous chemokines and cytokines. Our findings show for the first time the novel role of CMTM6 in maintaining cancer genome stability and facilitating tumor-mediated immunosuppression, linking DNA damage signaling to the secretion of inflammatory factors. Targeting CMTM6 may improve the treatment of patients with advanced ccRCC., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Prostate cancer (PCa) endangers the life and health of older men. Most PCa cases develop into castration‑resistant PCa (CRPC) within 2 years. At present, the molecular mechanisms of the occurrence and development of PCa and its transformation to CRPC remain unknown. The present study aimed to investigate the role of CKLF‑like Marvel transmembrane domain containing family member 5 (CMTM5) in PCa and its molecular mechanism in vitro . PCa tissues and paired adjacent normal prostate tissues from 70 patients were collected to examine the expression levels of CMTM5 and EGFR via immunohistochemistry, reverse transcription‑quantitative PCR and western blotting. Then, CMTM5‑overexpressing DU145 cells were constructed, and CMTM5 expression in these transfected cells and vector control cells was examined via western blotting. Cell Counting Kit‑8 and plate clone formation assays were used to evaluate the proliferation and colony number of CMTM5‑overexpressing cells and vector control cells. Then, cell migration and invasion were assessed using wound healing assay, Transwell assay and immunofluorescence analysis with DAPI staining. The effect of CMTM5 on apoptosis and its underlying molecular mechanism were examined using western blotting and flow cytometry. The results demonstrated that CMTM5 expression in PCa tissues and cell lines was significantly downregulated, while EFGR expression was significantly upregulated. The proportion of high CMTM5 expression in PCa tissues was significantly lower compared with that in normal prostate tissues. By contrast, the proportion of high EGFR expression in PCa tissues was significantly increased compared with that in normal prostate tissues. Moreover, CMTM5 overexpression significantly inhibited cell proliferation, migration and invasion, and promoted cell apoptosis compared with vector control cells in vitro . Furthermore, the regulation of PCa by CMTM5 was associated with the downregulation of PI3K/AKT and its downstream Bcl‑2 expression, as well as the upregulation of Bax expression. In conclusion, CMTM5 may be an effective tumor suppressor gene for PCa, especially for castration‑resistant PCa, by downregulating EGFR and PI3K/AKT signaling pathway components.

Liver cancers consist primarily of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors have emerged as promising therapeutic agents against liver cancers. Programmed cell death protein 1 (PD-1) is an immunoinhibitory receptor present on T cells that interacts with its ligand programmed death-ligand 1 (PD-L1) found on cancer cells. Blocking PD-1/PD-L1 binding improves T-cell survival, proliferation and cytotoxicity, which enhances their antitumor activity. Better understanding of the molecular mechanisms governing PD-1/PD-L1 response is essential to the development of predictive markers and therapeutic combinations that could improve the efficiency of anti-PD-1/PD-L1 treatment. Chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing 6 (CMTM6) has been recently identified as a major regulator of PD-L1. Another member in the CMTM family, CKLF-like MARVEL transmembrane domain-containing 4 (CMTM4), has been shown to compensate for the effects of CMTM6 when CMTM6 is lost. Interestingly, we found that CMTM4 is the major regulator of PD-L1 in the context of liver cancer. Up-regulated CMTM4 in patients with HCC and ICC is associated with poor patient survival, potentially due to its function in stabilizing PD-L1 expression, hence facilitating escape from T cell-mediated cytotoxicity. We confirmed the role of CMTM4 as a positive regulator of PD-L1 in multiple HCC and ICC cell lines and demonstrated that CMTM4 stabilizes PD-L1 through posttranslational mechanisms. In vivo, suppression of Cmtm4 inhibited HCC growth and increased CD8 + T-cell infiltration in immunocompetent mice. Furthermore, we found that depletion of CMTM4 sensitized HCC tumor to anti-PD-L1 treatment compared with control. This suggests that CMTM4 expression level could be a predictive marker for patient response to anti-PD-L1 treatment, and CMTM4 depletion can potentially be used to enhance the clinical benefits of anti-PD-L1 immunotherapy in patients with liver cancer., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Triple-negative breast cancer (TNBC) commonly have aggressive properties. microRNA-582-5p (miR-582-5p) modulates the progression of several cancers. Yet, the role of miR-582-5p in TNBC progression is undetermined. In the current study, we investigated miR-582-5p expression levels and clinical significance in TNBC. The impact of miR-582-5p modulation on the biological behaviors of TNBC cells were measured. The downstream gene(s) regulated by miR-582-5p in TNBC was explored. We showed that compared to adjacent normal breast tissues, the miR-582-5p level was elevated in TNBC samples. The upregulation of miR-582-5p correlated with lymph node metastasis. Overexpression of miR-582-5p enhanced TNBC cell migration and invasion, whereas knockdown of miR-582-5p had an adverse impact on aggressive phenotype. In vivo xenograft mouse studies demonstrated that miR-582-5p overexpression accelerated TNBC growth and metastasis. Mechanistically, miR-582-5p selectively inhibited CMTM8, leading to a reduction of CMTM8 expression. CMTM8 showed suppressive effects on TNBC cell migration and invasion. Rescue experiments revealed that overexpression of CMTM8 impaired miR-582-5p-induced migration and invasion in TNBC cells. Overall, our data uncover an oncogenic role for miR-582-5p in TNBC metastasis through inhibition of CMTM8. We suggest miR-582-5p as a promising target for managing TNBC.

Objectives: This study aimed to evaluate the expression of chemokine-like factor superfamily 6 (CMTM6) and programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) in oral squamous cell carcinoma (OSCC) and to further explore its clinical significance in OSCC., Study Design: Samples of 44 OSCC and paracancerous tissues were investigated. We estimated the expression of the 3 proteins by immunohistochemistry and further detected mRNA expression by quantitative real-time polymerase chain reaction (qRT-PCR)., Results: Immunohistochemistry results demonstrated that the positive expression of CMTM6 and PD-1/PD-L1 in OSCC tissues was significantly higher than that in paracancerous tissues. Statistical significance was found between the 2 groups (all P < .05). Moreover, PD-L1 expression was related to OSCC clinical stage and lymph node metastasis (P < .05). The qRT-PCR results confirmed that the relative expression of CMTM6 and PD-1/PD-L1 mRNA in OSCC tissues was significantly higher than that in paracancerous tissues (all P < .05), and Spearman rank correlation showed that there was a significant relationship between mRNA and protein expression (all P < .05)., Conclusions: CMTM6 and PD-1/PD-L1 were upregulated in OSCC, and CMTM6 may play a synergistic role with PD-1/PD-L1 in the immune pathway. Therefore, we believe that CMTM6 and PD-1/PD-L1 will become checkpoints for immunotherapy of OSCC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The epithelial-mesenchymal transition (EMT) is a pivotal step involved in cancer recurrence and metastasis. In addition, the activation of the EMT program can induce a cancer stem cell (CSC)-like phenotype and programmed death-ligand 1 (PD-L1) expression in head and neck squamous cell carcinoma (HNSCC). The CMTM family has reported as an important regulator in this process. Here, we investigated the role of CMTM4 in HNSCC. We indicated that CMTM4 was overexpressed in human and mouse HNSCC samples and in HNSCC cell lines by immunohistochemistry and Western blot. A high expression level of CMTM4 was correlated with advanced lymph node metastasis and a negative prognosis. CMTM4-knockdown by small interfering RNA downregulated the EMT process and inhibited the migration and invasion abilities of tumor cells. Moreover, knockdown of CMTM4 decreased CSC-associated markers via the protein kinase B pathway. Notably, CMTM4-knockdown inhibited the expression of interferon-γ induced PD-L1 in HNSCC cells. A positive correlation was found between CMTM4 expression and CD8 + and PD-1 + cell density in the stroma. Our findings indicated that CMTM4 may play an important role in regulating EMT/CSC phenotypes and PD-L1 expression. This study may reinforce the interest in CMTM4 as a potential target for the prognosis and treatment of HNSCC., (© 2021 Wiley Periodicals LLC.)

Background: CMTM7 is a tumor suppressor that positively regulates EGFR degradation by promoting Rab5 activation, and plays a vital role in tumor progression. Rab5 forms complexes with Beclin1 and VPS34, and acts in the early stage of autophagy. However, the affects of CMTM7 on autophagy and its mechanism are still unclear., Methods: The effect of CMTM7 on autophagy induction was confirmed by western blotting, confocal microscopy and transmission electron microscopy. Co-immunoprecipitation was used to analyse the interaction of CMTM7 with autophagy initiation complex and Rab5. The xenograft model in nude mice was used to elucidate the function of CMTM7 in tumorigenicity and autophagy in vivo., Results: In this study, we first demonstrated that CMTM7 facilitated the initiation of autophagosome formation, which consequently promoted the subsequent multistage process of autophagic flux, i.e. from autophagosome assembly till autolysosome formation and degradation. Confocal and co-immunoprecipitation showed that CMTM7 interacted with Rab5, VPS34, Beclin1, and ATG14L, but not with ULK1, UVRAG and LC3B. CMTM7 also increased the activity of ATG14L-linked VPS34 complex and its association with Rab5. Both in vitro and in vivo experiments demonstrated that knockdown of CMTM7 enhanced tumor growth by impairing autophagy., Conclusion: These findings highlighted the role of CMTM7 in the regulation of autophagy and tumorigenicity, revealing it as a novel molecule that is associated with the interaction of Rab5 and ATG14L-Beclin1-VPS34 complex. Video Abstract., (© 2021. The Author(s).)

Tight junction complexes are involved in the establishment and maintenance of cell polarity and the regulation of signalling pathways, controlling biological processes such as cell differentiation and cell proliferation. MarvelD3 is a tight junction protein expressed in adult epithelial and endothelial cells. In Xenopus laevis, MarvelD3 morphants present differentiation defects of several ectodermal derivatives. In vitro experiments further revealed that MarvelD3 couples tight junctions to the MEKK1-JNK pathway to regulate cell behaviour and survival. In this work, we found that MarvelD3 is expressed from early developmental stages in the exocrine and endocrine compartments of the pancreas, as well as in endothelial cells of this organ. We thoroughly characterized MarvelD3 expression pattern in developing pancreas and evaluated its function by genetic ablation. Surprisingly, inactivation of MarvelD3 in mice did not alter development and differentiation of the pancreatic tissue. Moreover, tight junction formation and organization, cell polarization, and activity of the JNK-pathway were not impacted by the deletion of MarvelD3., (© 2021. The Author(s).)

Cisplatin (CDDP) is widely used as a broad-spectrum anticancer chemotherapeutic drug, often giving rise to nephrotoxicity due to the enhancement of inflammation, oxidative stress, and apoptosis. Hydroxytyrosol (HT), a representative and effective polyphenol component of Fructus Ligustri lucidi, has been known to have anti-inflammatory and anti-oxidative effects. Chemokine-like factor 1 (CKLF1) is a novel chemokine participates in inflammation and related to various inflammatory diseases. The present study is to investigate the protective effects and mechanism of HT on CDDP injured HK-2 cells and kidneys of mice. HT protected HK-2 cells against CDDP toxicity, and improved CDDP-induced histopathalogical damage and renal dysfunction in mice. HT suppressed the increased expression of CKLF1 and NF-κB activation caused by CDDP, attenuating followed inflammatory response manifested by declined levels of TNF-α and IL-1β. The protective effects of HT against CDDP-induced injury were partly reversed on CKLF1 overexpressed HK-2 cells, which shown by decreased cell viability and increased activation of NF-κB. HT also up-regulated the activities of GSH and SOD decreased by CDDP, and inhibited the increased production of MDA and NO induced by CDDP. Moreover, HT also inhibited CDDP-induced apoptosis in kidneys of mice. Our results demonstrated that HT protected CDDP-induced renal injury through inhibiting CKLF1 mediated inflammatory pathway, and also by anti-oxidative stress and anti-apoptosis. HT may be an effective therapeutic agent in CDDP-induced nephrotoxicity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometimes strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was thus to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6 in this disease., Materials and Methods: Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data., Results: TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had a worse prognosis for overall survival., Conclusions: UPS showed variation in CMTM6 copy number and CMTM6 expression. CMTM6 expression was significantly correlated with PD-L1 expression, especially with strong PD-L1 expression.

Aberrant energy status contributes to multiple metabolic diseases, including obesity, diabetes, and cancer, but the underlying mechanism remains elusive. Here, we report that ketogenic-diet-induced changes in energy status enhance the efficacy of anti-CTLA-4 immunotherapy by decreasing PD-L1 protein levels and increasing expression of type-I interferon (IFN) and antigen presentation genes. Mechanistically, energy deprivation activates AMP-activated protein kinase (AMPK), which in turn, phosphorylates PD-L1 on Ser283, thereby disrupting its interaction with CMTM4 and subsequently triggering PD-L1 degradation. In addition, AMPK phosphorylates EZH2, which disrupts PRC2 function, leading to enhanced IFNs and antigen presentation gene expression. Through these mechanisms, AMPK agonists or ketogenic diets enhance the efficacy of anti-CTLA-4 immunotherapy and improve the overall survival rate in syngeneic mouse tumor models. Our findings reveal a pivotal role for AMPK in regulating the immune response to immune-checkpoint blockade and advocate for combining ketogenic diets or AMPK agonists with anti-CTLA4 immunotherapy to combat cancer., Competing Interests: Declaration of interests G.J.F. has patents/pending royalties on the PD-1 pathway from Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Dako, and Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, NextPoint, IgM, Jubilant, Geode, and GV20. G.J.F. has equity in Nextpoint, Triursus, Xios, iTeos, IgM, Geode, and GV20. W.W. is a co-founder and consultant for ReKindle Therapeutics. The other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Lung cancer is the leading cause of cancer-related mortality worldwide and CMTM8 is a potential tumor suppressor gene, which is down-regulated in lung cancer. The objective of this research was to assess the association of CMTM8 genetic polymorphisms with lung cancer risk., Methods: To evaluate the correlation between CMTM8 polymorphisms and lung cancer risk, Agena MassArray platform was used for genotype determination among 509 lung cancer patients and 506 controls. Multiple genetic models, stratification analysis and Haploview analysis were used by calculating odds ratio (OR) and 95% confidence intervals (CIs)., Results: Significant associations were detected between CMTM8 rs6771238 and an increased lung cancer risk in codominant (adjusted OR = 1.57, 95% CI: 1.01-2.42, P = 0.044) and dominant (adjusted OR = 1.54, 95% CI: 1.01-2.36, P = 0.047) models. After sex stratification analysis, we observed that rs6771238 was related to an increased risk of lung squamous cell carcinoma, while rs6771238 was associated with an increased risk of lung adenocarcinoma. Rs9835916 was linked to increased risk of lymph node metastasis in lung cancer patients., Conclusion: Our study first reported that CMTM8 polymorphisms were a risk factor for lung cancer, which suggested the potential roles of CMTM8 in the development of lung cancer., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)