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Protein-carbohydrate interactions play important roles in various biological processes, such as organism development, cancer metastasis, pathogen infection and immune response, but they remain challenging to study and exploit due to their low binding affinity and non-covalent nature. Here we site-specifically engineered covalent linkages between proteins and carbohydrates under biocompatible conditions. We show that sulfonyl fluoride reacts with glycans via a proximity-enabled reactivity, and to harness this a bioreactive unnatural amino acid (SFY) that contains sulfonyl fluoride was genetically encoded into proteins. SFY-incorporated Siglec-7 crosslinked with its sialoglycan ligand specifically in vitro and on the surface of cancer cells. Through irreversible cloaking of sialoglycan at the cancer cell surface, SFY-incorporated Siglec-7 enhanced the killing of cancer cells by natural killer cells. Genetically encoding the chemical crosslinking of proteins to carbohydrates (GECX-sugar) offers a solution to address the low affinity and weak strength of protein-sugar interactions.

Gastric cancer (GC) is the most common gastrointestinal malignancy worldwide. However, the molecular mechanisms of the progression of GC are not fully understood. Ras-responsive element binding protein 1 (RREB1) is an oncogene in many types of cancer that is involved in various biological processes, such as DNA damage repair, cell growth and proliferation, cell differentiation, fat development, and fasting glucose balance. In this study, we demonstrate the role of RREB1 in gastric cancer. First, by immunohistochemistry staining (IHC) and bioinformatics analysis, we demonstrated the expression of RREB1 in gastric cancer and paired normal gastric tissues. Then, we established RREB1 overexpression and knockdown cell lines via lentiviral transfection and detected cell proliferation by using MTT, colony-forming, cell cycle and apoptosis assays in vitro. We demonstrated the effect of RREB1 on cell proliferation in vivo by using a subcutaneous xenograft tumor model in nude mice. Finally, by using Western blotting and IHC, we demonstrated the possible mechanism by which RREB1 affects cell proliferation. The IHC and bioinformatics analyses demonstrated that RREB1 was highly expressed in gastric cancer and showed that RREB1-expressing patients had a larger tumor size and more lymphovascular invasion than RREB1-negative patients. Knockdown of RREB1 inhibited cell proliferation in vivo and in vitro. Knockdown of RREB1 enhanced p16 expression in vivo and in vitro, and p16 expression was negatively related to RREB1 in gastric cancer tissue. RREB1 was highly expressed in gastric cancer, and knockdown of RREB1 inhibited cell proliferation via enhanced p16 expression.

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP–AMP synthase-stimulator of interferon genes (cGAS–STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy., Graphical abstract This review summarizes basic knowledge of DNA damage response (DDR) pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and its potential applications as therapeutic targets in cancer immunotherapy.Image 1

In 2020, the worldwide incidence and mortality of colorectal cancer (CRC) were third and second, respectively. As the 5‐y survival rate is low when CRC is diagnosed at an advanced stage, a reliable method to predict CRC susceptibility is important for preventing the onset and development and improving the prognosis of CRC. Therefore, we focused on the normal colonic mucosa to investigate changes in gene expression that may induce subsequent genetic alterations that induce malignant transformation. Comprehensive gene expression profiling in the normal mucosa adjacent to colon cancer (CC) compared with tissue from non‐colon cancer patients was performed. PCR arrays and qRT‐PCR revealed that the expression of 5 genes involved in the immune response, including MYD88, was increased in the normal mucosa of CC patients. The expression levels of MYD88 were strikingly increased in precancerous normal mucosa specimens, which harbored no somatic mutations, as shown by immunohistochemistry. Microarray analysis identified 2 novel RNA‐controlling molecules, EXOSC3 and CNOT4, that were significantly upregulated in the normal mucosa of CC patients and were clearly visualized in the nuclei. Forced expression of EXOSC3 and CNOT4 in human colonic epithelial cells increased the expression of IFNGR1, MYD88, NFκBIA, and STAT3 and activated ERK1/2 and JNK in 293T cells. Taken together, these results suggested that, in the inflamed mucosa, EXOSC3‐ and CNOT4‐mediated RNA stabilization, including that of MYD88, may trigger the development of cancer and can serve as a potential predictive marker and innovative treatment to control cancer development., RNA‐controlling CNOT4 was significantly expressed in normal mucosae adjacent to colon cancers. IHC for CNOT4 was performed in 17 CCs and 15 NCCs, and representative images in paracancerous normal colonic mucosae, the paired tumor lesions in CCs, and normal mucosae in NCCs were displayed.

Cancer cells are often exposed to cell intrinsic stresses and environmental perturbations that may lead to accumulation of unfolded and/or misfolded proteins in the lumen of endoplasmic reticulum (ER), a cellular condition known as ER stress. In response to ER stress, the cells elicit an adaptive process called unfolded protein response (UPR) to cope with the stress, supporting cellular homeostasis and survival. The ER stress sensors inositol requiring protein 1α (IRE1α), eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK), and activating transcription factor 6 (ATF6) constitute the three branches of UPR to resolve ER stress. IRE1α, PERK, and ATF6 play an important role in tumor cell growth and survival. They are also involved in chemotherapy resistance of cancers. These have generated widespread interest in targeting these UPR branches for cancer treatment. In this review, we provide an overview of the role of IRE1α, PERK, and ATF6 in cancer progression and drug resistance and we summarize the research advances in targeting these UPR branches to enhance the efficacy of chemotherapy of cancers.

Immune checkpoint blockade (ICB) therapy has revolutionized clinical oncology. However, the efficacy of ICB therapy is limited by the ineffective infiltration of T effector (Teff) cells to tumors and the immunosuppressive tumor microenvironment (TME). Here, we report a programmable tumor cells/Teff cells bispecific nano-immunoengager (NIE) that can circumvent these limitations to improve ICB therapy. The peptidic nanoparticles (NIE-NPs) bind tumor cell surface α3β1 integrin and undergo in situ transformation into nanofibrillar network nanofibers (NIE-NFs). The prolonged retained nanofibrillar network at the TME captures Teff cells via the activatable α4β1 integrin ligand and allows sustained release of resiquimod for immunomodulation. This bispecific NIE eliminates syngeneic 4T1 breast cancer and Lewis lung cancer models in mice, when given together with anti-PD-1 antibody. The in vivo structural transformation-based supramolecular bispecific NIE represents an innovative class of programmable receptor-mediated targeted immunotherapeutics to greatly enhance ICB therapy against cancers.

Large amounts of tumor-associated macrophages (TAM), which are predominately localized in hypoxia area of the tumor tissue, are associated with the malignant progression of the tumor. In the present study, we investigated the inhibitory effects of modified citrus pectin (MCP), a natural dietary polysaccharide, on the survival and polarization of TAM in relation to its inhibition on the growth and migration of breast cancer. M2 macrophages polarized from human monocyte THP-1 were chosen as a model for TAM. We showed that MCP (0.06%–1%) concentration-dependently suppressed the survival of TAM through inhibiting glucose uptake with a greater extent in hypoxia than in normoxia. Furthermore, MCP treatment decreased ROS level in TAM through its reducibility and inhibiting galectin-3 expression, leading to inhibition of glucose transporter-1 expression and glucose uptake. In addition, MCP suppressed M2-like polarization via inhibiting STAT3 phosphorylation. Moreover, the tumor-promoting effect of TAM could be restrained by MCP treatment as shown in human breast cancer MDA-MB-231 cells in vitro and in mouse breast cancer 4T1-luc orthotopic and metastasis models. In both tumor tissue and lung tissue of the mouse tumor models, the number of TAM was significantly decreased after MCP treatment. Taken together, MCP may be a promising agent for targeting TAM in tumor hypoxic microenvironment for breast cancer treatment. [Image: see text]

The economic burden of tumors is increasing, so there is an urgent need to develop new therapies for their treatment. Killing tumors by activating complement is an effective strategy for the treatment. We used the ABO blood group system and the corresponding antibodies to activate the killer cell capacity of the complement system. After the construction of a mouse model containing blood group A antibodies and inoculating colorectal cancer and breast cancer cells into the axillae of the mice, intratumoural injection using a lentivirus carrying a blood group antigen as a drug significantly reduced the tumor volume of the mice. Compared with the control group, the content of the C5b-9 complement membrane attack complex in the tumors of mice treated with the blood group A antigen was significantly increased, and the proportion of NK cells was also significantly increased. In vitro cell-based experiments proved that tumor cells expressing blood group A antigens showed significantly inhibited cell proliferation when added to serum containing blood group A antibodies. These results all prove that the ABO blood group antigen may become a powerful tool for the treatment of tumors in patients.

Immune composition in the tumor microenvironment (TME) of patient tumors has proven to play a central role in the development of metastases and response to therapy. Evidence has suggested that the metastatic TME is immune aberrant, however difficulty in obtaining biopsies of metastatic tumors has made assessment of the immune TME difficult. Here we utilize a rapid autopsy tissue collection protocol to assess the infiltration and composition of the immune TME in numerous metastatic tissue sites, paired disease-free tissue sites, and the associated tissue draining lymph nodes. Post-mortem tissues were collected from nine metastatic breast cancer patients shortly after death through City of Hope’s “Legacy Project for Rapid Tissue Donation” Program. The average post-mortem interval (PMI) for tissue collection was 6 hours. Collected specimens include metastatic lesions and paired non-cancer samples from every cancer-involved organ, disease-free specimens from non-involved major organs, distant and tumor-draining lymph nodes (both cancer-infiltrated and disease free), as well as blood and spleens. Immediately following collection, specimens were processed into single cell suspension for flow cytometry. Over 80 immune cell phenotypes were assessed, including CD8+ and CD4+ T cell subsets, B cell subsets, natural killer (NK) cells, tumor associated macrophages (TAMs), dendritic cell subsets, and other immune cells. Tumor infiltrated tissues were found to have comparable immune cell densities and composition compared to paired disease-free tissues of the same organ type. However, immune cell densities in metastatic tissues and disease-free tissues were significantly different between organ types, with lung immune infiltration consistently being greater than liver, brain, and skin tissues. Differences in immune composition between tissue sites were also observed. Notably, liver tissues favored the presence of IL-2 producing central memory CD8+ T cells, while lung tissues favored the presence of CD8+ tissue resident memory T cells and CD16+ NK cells. Relative to disease-free lung tissues, tumor infiltrated lungs contained diminished frequencies of CD8+ tissue resident memory T cells and altered B cell and monocyte phenotypes. Increased levels of targetable immune pathways were observed, including increased PD-L1 and CTLA-4 expressing cells in skin metastases, and increased GARP+ B cells in bone marrow metastases. These data suggest that immune monitoring and trafficking of metastatic tissues site is dictated by organ type, which can be altered in composition by tumor infiltration. Further studies such as these may reveal organ-specific mechanisms of response to therapeutic interventions. Identity of organ location for tumor metastases may guide choices for immunotherapeutic interventions. Citation Format: Colt Egelston, Weihua Guo, Eliza R. Bacon, Kena Ihle, Diana Simons, Christian Avalos, JIayi Tan, Jian Ye, Lei Wang, Minhui Lim, James R. Waisman, Peter P Lee. Metastatic tissues display organ specific immune infiltration archetypes; lessons from a rapid autopsy tissue collection study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-45.

In this work, we have designed a template-free multiple signal amplification method for the highly sensitive detection of cancer cell-derived exosomes. In this design, DNase I serves as a bridge to link the DNA-based amplification approach and terminal deoxynucleotidyl transferase (TdT)-mediated polymerization reaction. Consequently, a detection limit of 10 particles per μL can be achieved, while a complex nucleic acid sequence design can be avoided. This method also exhibits good performance in a complicated matrix and enables the differentiation of healthy individuals from colorectal cancer (CRC) patients.

Hepatocellular carcinoma (HCC), is one of the most common malignancies worldwide, which is globally the third most common cause of cancer-related mortality. This study aims to identify new potential early-stage diagnostic and prognostic biomarker for HCC. The candidate gene SLC26A6 expression was analyzed based on the Oncomine and Tumor Immune Estimation Resource (TIMER) databases and verified forwards with Gene Expression Omnibus (GEO) datasets. The protein expression was retrieved from Human Protein Atlas (HPA) database. We also validated the diagnostic and prognostic value in HCC, and the relationship between SLC26A6 and clinicopathologic parameters were also accessed. The Gene Set Enrichment Analysis (GSEA) and Protein-Protein Interaction (PPI) network were constructed to analyze the SLC26A6-related pathway. These results reveal that SLC26A6 expression was elevated in HCC, and the diagnostic sensitivity of SLC26A6 was higher than α-fetoprotein (AFP). SLC26A6 expression was independent prognostic factor for HCC. SLC26A6 up-regulation was mainly associated with excision repair, DNA replication, etc. SLC26A6-related mR-NAs was enriched in PI3K-AKT signaling pathway, axon guidance, pathways in cancer, and so on. PPI network indicated that SLC26A6 was interacted with solute carrier members, ABC transporters and other ion transport molecule. We further analyzed three positively correlated microRNAs and 10 negatively correlated microRNAs, all of these were reported participating or inhibiting in cancer progression. This is the first study demonstrated that SLC26A6 is up-regulated in HCC and correlated with poor prognosis, which might be served as a diagnostic marker or prognostic biomarker for HCC.

Aim MiR-326 has been investigated to be correlated with multiple types of malignancies; however, the role of miR-326 in endometrial cancer (EC) remains rarely reported. The aim of our research is to investigate the functions of miR-326 in EC and the potential molecular mechanism. Methods RT-qPCR was performed to compare the expression of miR-326 and Bcl-2 in normal endometrial epithelial cell line (End1/e6e7) and EC cells lines (HEC-1A, Ishikawa), respectively. Bioinformatic analysis and luciferase assay verified the relationship between miR-326 and the 3'-UTR of Bcl-2. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, soft agar colony formation assay and the flow cytometry were performed to investigate the functions of miR-326 and Bcl-2 on proliferation and apoptosis in EC. Western blotting was employed to explore the expression of Bcl-2, Bcl2-associated X (Bax) and caspase-3. Results The expression of miR-326 decreased in EC cell lines compared to normal endometrial epithelial cell line, while Bcl-2 expression was increased in EC cells. Results of MTT and soft agar colony formation assays showed that miR-326 suppressed proliferation in EC cells. In addition, flow cytometry revealed that miR-326 promoted apoptosis in EC cells. Western blotting showed that silencing miR-326 promoted the expression of Bcl-2. Bioinformatics analysis and luciferase assay verified the 3'-UTR of Bcl-2 was a target of miR-326. Furthermore, MTT assay, soft agar colony formation assay and the flow cytometry proved that miR-326 acts as tumor suppressor via inhibiting the expression of Bcl-2. Conclusion MiR-326 acts as a cancer suppressor to inhibit proliferation and promote apoptosis via targeting Bcl-2 axis in EC.

MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of anaplastic thyroid carcinoma (ATC). miR-199a-5p was previously reported to act as a tumor suppressor or oncomiRNA in various types of cancer. However, its accurate expression, function, and mechanism in ATC remain unclear. Here, we find that miR-199a-5p is significantly downregulated in ATC tissues compared with adjacent non-cancerous tissues. Overexpression of miR-199a-5p significantly inhibits migration and invasion of ATC cells in vitro, and lung metastasis in vivo. Importantly, miR-199a-5p suppresses epithelial-mesenchymal transition (EMT) both in vitro and in vivo by targeting Snail. Taken together, this study reveals that miR-199a-5p is critical to the EMT progression in ATC cells. Targeting the pathway described here may be a novel approach for inhibiting metastasis of ATC.

Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma of the head and neck region which mainly distributes in southern China and Southeast Asia and has a crucial association with the Epstein–Barr virus. Based on epidemiological data, both incidence and mortality of NPC have significantly declined in recent decades grounded on the improvement of living standard and medical level in an endemic region, in particular, with the clinical use of individualized chemotherapy and intensity-modulated radiotherapy (IMRT) which profoundly contributes to the cure rate of NPC patients. To tackle the challenges including local recurrence and distant metastasis in the current NPC treatment, we discussed the implication of using targeted therapy against critical molecules in various signal pathways, and how they synergize with chemoradiotherapy in the NPC treatment. Combination treatment including targeted therapy and IMRT or concurrent chemoradiotherapy is presumably to be future options, which may reduce radiation or chemotherapy toxicities and open new avenues for the improvement of the expected functional outcome for patients with advanced NPC.

Background Exosomes are small, cellular membrane-derived vesicles with a diameter of 50–150 nm. Exosomes are considered ideal drug delivery systems with a wide range of applications in various diseases, including cancer. However, nonspecific delivery of therapeutic agents by exosomes in vivo remains challenging. Human epidermal growth factor receptor 2 (HER2) is an epidermal growth factor receptor tyrosine kinase, and its overexpression is usually associated with cell survival and tumor progression in various cancers. In this study, we aim to develop novel exosomes with dual HER2-targeting ability as a nanoparticle delivery vehicle to enhance antitumor efficacy in vivo. Results Here, we report the generation of two kinds of exosomes carrying miRNAs designed to block HER2 synthesis, which consequently showed a distinct anti-tumor effect. The 293-miR-HER2 exosomes package and deliver miRNAs targeting HER2 to recipient cells to block HER2 synthesis. The anti-tumor effect of these exosomes on cancer cells dependent on HER2 for survival but do not affect cells that lack HER2 or that are engineered to express HER2 but are not dependent on it for survival. In contrast, 293-miR-XS-HER2 exosomes carry an additional peptide, which enables them to adhere to HER2 on the surface of cancer cells. Consequently, these exosomes preferentially enter these cells with surface expression of HER2 and further displayed a tumoricidal effect. The 293-miR-XS-HER2 exosomes are significantly more effective than the 293-miR-HER2 exosomes in shrinking HER2-positive tumors implanted in mice. Conclusions Collectively, as novel antitumor drug delivery vehicles, HER2 dual-targeting exosomes exhibit increased target-specific delivery efficiency and can be further utilized to develop new nanoparticle-based targeted therapies.

Photothermal therapy (PTT) has emerged as one of the most promising cancer therapeutic tools owing to its advantages of minimal invasiveness, convenient operation, and low toxicity. Imaging techniq...

Background LncRNA PTCSC3 (PTCSC3) inhibits thyroid cancer cervical carcinoma and glioma, while its roles in gastric cancer are unknown. Studies have reported that HULC could serve as a potential biomarker for the diagnosis and prognosis of gastric cancer (GC). Our study aimed to investigate the potential interaction between PTCSC3 and HULC in gastric cancer. Methods This study enrolled 77 gastric cancer patients at the First Affiliated Hospital of Anhui Medical University from January 2016 to January 2018. RT-qPCR was performed to analyze gene expression levels. Cell transfections were carried out to evaluate gene interactions. Transwell assays and wound healing assays were used to analyze the effects of transfection on cell invasion and migration. Western blotting was also used to illustrate the possibility that lncRNA PTCSC3 and lncRNA HULC negatively affected each other through WNT signal path. Results We showed that PTCSC3 was downregulated in tumor tissues of gastric cancer patients in comparison to that in adjacent healthy tissues, and an inverse correlation between the expression levels of PTCSC3 and AJCC stage was observed. LncRNA HULC (HULC) was upregulated in tumor and inversely correlated with PTCSC3 in tumor tissues. Overexpression of PTCSC3 mediated the inhibition of HULC, while overexpression of HULC also mediated the inhibition of PTCSC3. PTCSC3 inhibited, while HULC promoted invasion and migration of gastric cancer cells. In addition, overexpression of HULC attenuated the effects of overexpression of PTCSC3. However, overexpression of PTCSC3 showed no significant effects on cell proliferation. We also found that PTCSC3/HULC affected each other to regulate cell invasion and migration through the Wnt/β-catenin signaling. Conclusion Therefore, overexpression of PTCSC3 inhibited the invasion and migration of gastric cancer cells, and the function of PTCSC3 is associated with HULC.

BackgroundPathogenic mutation in BRCA genes causes high cancer risk. Identifying the mutation carriers plays key roles in preventing BRCA mutation-related cancer. Population screening has demonstrated its power for comprehensive identification of the mutation carriers. However, it is only recommended for the Ashkenazi Jewish population with high prevalence of three founder mutations, but not for non-Ashkenazi Jewish populations as the cost-effectiveness could be too low due to their lower mutation prevalence and lack of founder mutation. Population screening would not benefit the majority of the human population for BRCA mutation-related cancer prevention.MethodsWe used population BRCA screening in 6000 residents, 1% of the Macau population, an ethnic Chinese population with unique genetic, linguistic and cultural features, and its BRCA mutation has not been analysed before.ResultsWe called BRCA variants, identified 18 carriers with 14 pathogenic mutations and determined the prevalence of 0.29% in the population (95% CI 0.15% to 0.42%). We compared the testing cost between the Ashkenazi Jewish population, the Sephardi Jewish population and the Macau population, and observed only a few fold differences.ConclusionOur study shows that testing cost is not the most important factor in considering population BRCA screening, at least for the populations in the developed countries/regions, regardless of the status of mutation prevalence and founder mutation.

MicroRNAs (miRNAs) refer to a class of small endogenous non-coding RNAs that regulate gene expression at the post-transcriptional level. Emerging studies have shown that miRNAs play critical roles in tumorigenesis and cancer progression. However, roles and mechanisms of miRNA dysregulation in the pathogenesis of meningioma are not fully understood. Here, we first reviewed existing research of aberrantly expressed miRNAs identified by high throughput microarray profiling in meningioma. We also explored the potential of miRNA as biomarkers and therapeutic targets for novel treatment paradigms of meningiomas. In addition, we summarized recent researches that focused on the possible mechanisms involved in miRNA-mediate meningioma occurrence and progression. This review provides an overview of miRNA deregulation in meningioma and indicates the potential of miRNAs to be used as biomarkers or novel therapeutic targets.

About 90% cancer-related mortality results from the cancer metastasis, which generally undergoes after epithelial-mesenchymal transition (EMT) process. N-Cadherin, overexpressed on cancer cell surface during EMT, can enhance the migration of cancer cells. Herein, we design and synthesize a transformable peptide BP-KLVFF-SWTLYTPSGQSK (BFS) that can block N-cadherin for inhibiting cancer migration and metastasis. The peptide BFS consists of three modules including (1) the hydrophobic bis-pyrene (BP) unit for forming and locating nanoparticles, (2) the KLVFF peptide sequence for forming and stabilizing fibrous structures and (3) the targeting peptide sequence SWTLYTPSGQSK that can specifically bind to N-cadherin. The peptide BFS can form nanoparticles in PBS, which can transform to nanofibers when targeting and binding to N-cadherin. The nanofibers inhibit the migration of N-cadherin overexpressed MDA-MB-436 cancer cells. The peptide BFS shows 83.6% inhibiting rate in cells wound healing assay. In addition, the inhibition rate is 67.9% when the BFS applied in transwell migration assay. These results indicate that the BFS has excellent ability to inhibit migration of cancer cells. This self-assembly strategy could be potentially utilized to regulate the key protein during EMT for inhibiting the tumor metastasis.

Introduction Immune therapy has shown good results in small-cell lung cancer (SCLC), but the impact of immune microenvironment of the disease is unclear. In this work, we detected expression of programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and other immune biomarkers of cancer. We also analyzed the correlations between these markers and survival in SCLC. Patients and Methods Protein expression of PD-1, PD-L1, PD-L2, CD3, CD4, CD8, and FOXP3 was analyzed in surgical tissues from 102 SCLC patients by immunohistochemistry. Results Positive expression of PD-1 on tumor-infiltrating lymphocytes (TILs) was found in 40.2% of patients; 37.3% of patients showed positive expression of PD-L1 on TILs; and 3.9% showed positive expression of PD-L1 on tumor cells. PD-L2 protein was not expressed on tumor cells or TILs. Survival analysis showed that positive expression of PD-L1 on TILs was correlated with longer relapse-free survival (RFS) (p=0.004). Positive expression of PD-1 combined with a high ratio of lymphocytes (CD3, p=0.004; CD4, p=0.011; CD8, p=0.009; FOXP3, p=0.009) was associated with significantly better RFS than negative expression of PD-1 combined with a lower ratio of lymphocytes. Positive expression of PD-L1 combined with a high ratio of lymphocytes (CD3, p

Cytosolic DNA sensing, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, is an important novel role in the immune system. Multiple STING agonists were developed for cancer therapy study with great results achieved in pre-clinical work. Recent progress in the mechanical understanding of STING pathway in IFN production and T cell priming, indicates its promising role for cancer immunotherapy. STING agonists co-administrated with other cancer immunotherapies, including cancer vaccines, immune checkpoint inhibitors such as anti-programmed death 1 and cytotoxic T lymphocyte-associated antigen 4 antibodies, and adoptive T cell transfer therapies, would hold a promise of treating medium and advanced cancers. Despite the applications of STING agonists in cancer immunotherapy, lots of obstacles remain for further study. In this review, we mainly examine the biological characters, current applications, challenges, and future directions of cGAS-STING in cancer immunotherapy.

Cancer therapeutic strategies based on angiogenesis attract great attention from fundamental and clinical research. Blocking oxygen and nutrition supply to tumor cells could inhibit the growth of tumors based on occlusion of blood vessels in the tumor. Herein, we report a dual-responsive peptide-based nanoparticle, mimicking the laminin fibrillogenesis specifically and highly efficiently in tumor vessels, resulting in the blockage of tumor vessels and the growth inhibition of tumors. The laminin mimic peptide (LMMP) is designed with a fibrillation sequence, a pH-responsive sequence, and a targeting sequence. The LMMP in nanoformulations is delivered to blood vessels in the tumors, where the microenvironment (pH and microthrombus) enable LMMP to process laminin fibrillogenesis, constructing fibrous networks. The laminin-like fibrous networks capture red blood cells etc., forming occlusion specifically in the tumor blood vessels to inhibit the growth of the tumor.

Background The microbiome has been shown to affect the response to Immune Checkpoint Inhibitors (ICIs) in a small number of cancers and in preclinical models. Here, we sought to broadly survey cancers to identify those in which the microbiome may play a prognostic role using retrospective analyses of patients with advanced cancer treated with ICIs. Methods We conducted a retrospective analysis of 690 patients who received ICI therapy for advanced cancer. We used a literature review to define a causal model for the relationship between medications, the microbiome, and ICI response to guide the abstraction of electronic health records. Medications with precedent for changes to the microbiome included antibiotics, corticosteroids, proton pump inhibitors, histamine receptor blockers, non-steroid anti-inflammatories and statins. We tested the effect of medication timing on overall survival (OS) and evaluated the robustness of medication effects in each cancer. Finally, we compared the size of the effect observed for different classes of antibiotics to taxa that have been correlated to ICI response using a literature review of culture-based antibiotic susceptibilities. Results Of the medications assessed, only antibiotics and corticosteroids significantly associated with shorter OS. The hazard ratios (HRs) for antibiotics and corticosteroids were highest near the start of ICI treatment but remained significant when given prior to ICI. Antibiotics and corticosteroids remained significantly associated with OS even when controlling for multiple factors such as Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index score, and stage. When grouping antibiotics by class, β-lactams showed the strongest association with OS across all tested cancers. Conclusions The timing and strength of the correlations with antibiotics and corticosteroids after controlling for confounding factors are consistent with the microbiome involvement with the response to ICIs across several cancers.

Objective This study set out to explore the regulatory mechanism of miR-130a-5p in cisplatin (DDP)-resistant gastric cancer (GC) cells. Materials and methods Forty cases of GC and paracancerous tissues were collected, and the miR-130a-5p and CCL22 levels were detected by qRT-PCR. DDP-resistant cell lines of GC cells were established. Cell viability, invasion, and apoptosis were measured by CCK-8, Transwell, and flow cytometry, respectively. The relationship between miR-130a-5p and CCL22 was verified by dual-luciferase reporter enzyme, and the protein levels of caspase-3, bax, bcl-2, and CCL22 were determined by Western blot. Results miR-130a-5p was low expressed in GC tissues and cells, while CCL22 showed marked negative correlation, and the area under the curve (AUC) for diagnosing GC was not less than 0.850. Up-regulating miR-130a-5p or knocking down CCL22 expression can inhibit the proliferation and invasion of GC cells and promote their apoptosis, reverse the resistance of NCI-N87/DDP to DDP, and also enhance the chemosensitivity of GC cells. Dual-luciferase reporter enzyme identified that there was a targeted relationship between miR-130a-5p and CCL22. At the same time, miR-130a-5p and CCL22 were up-regulated or down-regulated, and the malignant proliferation, invasion, apoptosis, and DDP chemotherapy resistance of the cells had no difference compared with miR-NC with transfection-unrelated sequences. Conclusion Up-regulating miR-130a-5p can enhance the sensitivity of DDP-resistant GC cells to chemotherapy and regulate their biological function by targeted inhibition of CCL22.

Uropathogenic Escherichia coli (UPEC), a leading cause of urinary tract infections, is associated with prostate and bladder cancers. Cytotoxic necrotizing factor 1 (CNF1) is a key UPEC toxin; however, its role in bladder cancer is unknown. In the present study, we found CNF1 induced bladder cancer cells to secrete vascular endothelial growth factor (VEGF) through activating Ras homolog family member C (RhoC), leading to subsequent angiogenesis in the bladder cancer microenvironment. We then investigated that CNF1-mediated RhoC activation modulated the stabilization of hypoxia-inducible factor 1α (HIF1α) to upregulate the VEGF. We demonstrated in vitro that active RhoC increased heat shock factor 1 (HSF1) phosphorylation, which induced the heat shock protein 90α (HSP90α) expression, leading to stabilization of HIF1α. Active RhoC elevated HSP90α, HIF1α, VEGF expression, and angiogenesis in the human bladder cancer xenografts. In addition, HSP90α, HIF1α, and VEGF expression were also found positively correlated with the human bladder cancer development. These results provide a potential mechanism through which UPEC contributes to bladder cancer progression, and may provide potential therapeutic targets for bladder cancer.

Since December, 2019, a 2019 novel coronavirus disease (COVID-19) infected by the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) emerged in Wuhan, Hubei province, and the epidemic situation has continued to spread globally. The epidemic spread of COVID-19 has brought great challenges to the clinical practice of thoracic oncology. Outpatient clinics need to strengthen the differential diagnosis of initial symptoms, pulmonary ground-glass opacity (GGO), consolidation, interstitial and/or interlobular septal thickening, and crazy paving appearance. In the routine of oncology, the differential diagnosis of adverse events from COVID-19 is also significant, including radiation pneumonitis, checkpoint inhibitor pneumonitis (CIP), neutropenic fever, and so on. During the epidemic, indications of transbronchial biopsy (TBB) and CT-guided percutaneous thoracic biopsy are strictly controlled. For patients who are planning to undergo biopsy operation, screening to exclude the possibility of COVID-19 should be carried out. For confirmed or suspected patients, three-level protection should be performed during the operation. Disinfection and isolation measures should be strictly carried out during the operation. At last, more attention to the protection of cancer patients and give priority to the treatment of infected cancer patients.

Polypyrimidine tract-binding protein 1 (PTBP1) plays an essential role in splicing and is expressed in almost all cell types in humans, unlike the other proteins of the PTBP family. PTBP1 mediates several cellular processes in certain types of cells, including the growth and differentiation of neuronal cells and activation of immune cells. Its function is regulated by various molecules, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and RNA-binding proteins. PTBP1 plays roles in various diseases, particularly in some cancers, including colorectal cancer, renal cell cancer, breast cancer, and glioma. In cancers, it acts mainly as a regulator of glycolysis, apoptosis, proliferation, tumorigenesis, invasion, and migration. The role of PTBP1 in cancer has become a popular research topic in recent years, and this research has contributed greatly to the formulation of a useful therapeutic strategy for cancer. In this review, we summarize recent findings related to PTBP1 and discuss how it regulates the development of cancer cells.

Identification of cancer driver modules or pathways is a key step in understanding cancer pathogenesis and exploring patient-specific treatments. Numerous studies have shown that some genes with low mutation frequency are also important for the cancer progression, while previous research have focused on identifying high-frequency mutation genes. In this study, we propose a new framework with a new metric to identify driver modules with low-frequency mutation genes, called iCDModule. Inspired by the gravity model, we integrate the coverage and mutual exclusivity in mutation information, define a new metric between gene pairs, called mutation impact distance, to help identifying potential driver genes sets, including those have extremely low mutation rates but play an important role in functional networks. A genetic network is constructed by combining the defined mutation impact distance and then the driver module identification problem is formalized as the maximum clique solution problem, and an improved ant colony optimization algorithm is used to solve it. iCDModule is applied to TCGA breast cancer, glioblastoma, ovarian cancer to test performance. Experiments show that it can accurately identify known cancer driver modules and pathways, and also detect driver modules containing low-frequency mutation genes. iCDModule is significantly better than other existing methods in identifying driver modules.

A pH/GSH-responsive SO2 generation nanoplatform (BODS NPs) is established to achieve lysosomal escape and GSH depletion in tumor cells. O2˙- as the main ROS during SO2-mediated gas therapy can be accumulated through Cu/Zn-SOD enzymatic activity suppression and mitochondrial biogenesis, further exacerbating the oxidative stress and resulting in cell apoptosis.

Background Studies have indicated that ATG3 could mediate the effects of other tumor-related regulators in carcinogenesis. However, the expression, role, and mechanism of ATG3 itself in cancers are rarely revealed. Thus, we explored the expression, function, and mechanism of ATG3 in colon cancer. Materials and methods The expression of ATG3 was detected in colon cancer tissues and cell lines, as well as in adjacent tumor tissues and normal colon epithelial cells. The effects of ATG3 alteration on proliferation and invasion were further analyzed. The expression and role of miR-431-5p, a potential negative regulator of ATG3, were also studied. Eventually, the role of autophagy in ATG3 related effects in colon cancer was checked. Results ATG3 is upregulated in colon cancer tissues and cells demonstrated by qPCR and IHC. ATG3 knockdown significantly suppressed proliferation and invasion of colon cancer cells indicated by plate clone formation and Transwell invasion assays. The expression of miR-431-5p is downregulated and negatively correlates with ATG3 in colon cancer. Furthermore, luciferase report system, plate clone formation and Transwell invasion assays demonstrated that miR-431-5p could prohibit cell proliferation and invasion via directly targeting ATG3 in colon cancer. Eventually, Western blot, plate clone formation and Transwell invasion assays proved that autophagy block could antagonize the promotive functions of ATG3 on proliferation and invasion in cancer suggesting autophagy activation accounts for the promotive role of ATG3 on proliferation and invasion in colon cancer. Conclusion Collectively, ATG3 upregulation, caused by downregulated miR-435-5p, promotes proliferation and invasion via an autophagy-dependent manner in colon cancer suggesting that miR-431-5p/ATG3/autophagy may be a potential therapeutic target in colon cancer.

BACKGROUND Colon cancer is the third most commonly diagnosed cancer with high morbidity and mortality. Calmodulin-binding transcription activator 2 (CAMTA2) belongs to the calmodulin-binding transcription activator protein family. The functional role of CAMTA2 in colon cancer development remains unclear. Our research found out that CAMTA2 was high-level expressed in colon cancer, and the upregulated CAMTA2 expression was markedly correlated with poor survival. Functional experiments showed that knockdown of CAMTA2 repressed colon cancer cell proliferation/migration in vitro and attenuated proliferation in vivo. In additional, CAMTA2 expression was controlled by miR-28-5p via posttranscriptional regulation and miR-28-5p expression was reversely correlated with CAMTA2 expression in colon cancer. Moreover, enforced miR-28-5p expression downregulated the expression of CAMTA2 significantly and the restoration of CAMTA2 expression abolished the inhibitory effect of miR-28-5p on colon cancer cell proliferation and metastasis. Mechanistically, overexpression of miR-28-5p suppressed Wnt/β-catenin signaling and the inhibitory could be partly abolished by overexpression of CAMTA2. In summary, our findings reveal that miR-28-5p/CAMTA2 axis plays a critical role in human colon cancer, which might be a promising diagnosis and therapeutic target for colon cancer treatment.

Gastric cancer continues to be a common cancer in the world with high incidence and mortality. Accumulating evidence has implicated long noncoding RNAs (lncRNAs) in gastric cancer progression. Here, this study identified the potential role of a novel lncRNA, LINC00629 in gastric cancer and to elucidate the underlying mechanism. Initially, microarray-based gene expression profiling of gastric cancer was employed to identify differentially expressed genes. Next, the expression of LINC00629, microRNA-196b-5p (miR-196b-5p) and aquaporin 4 (AQP4) in clinical gastric cancer tissues was determined and the cell line presenting with the lowest LINC00629 expression was selected. The interaction among LINC00629, miR-196b-5p, and AQP4 was identified. Expression of LINC00629, miR-196b-5p, and AQP4 in gastric cancer cells were altered and then biological behaviors of gastric cancer cells were assessed by 5-ethynyl-2'-deoxyuridine and Transwell assays. Tumor formation in vivo was evaluated in nude mice. In gastric cancer, expression of LINC00629 and AQP4 was downregulated, and expression of miR-196b-5p was upregulated. Proliferation, invasion, and migration of gastric cancer cells were reduced after overexpression of LINC00629. LINC00629 competitively bound to miR-196b-5p, while AQP4 was a target of miR-196b-5p. Either downregulating miR-196b-5p or upregulating AQP4 could restrain the development of gastric cancer in vitro. LINC00629 overexpression repressed the growth of transplanted tumors in vivo. Taken together, LINC00629 competitively bound to miR-196b-5p to upregulate AQP4 expression, thereby inhibiting gastric cancer progression. Therefore, understanding of this mechanism may help to improve gastric cancer treatment.

Myoferlin, a protein of the ferlin family, has seven C2 domains and exhibits activity in some cells, including myoblasts and endothelial cells. Recently, myoferlin was identified as a promising target and biomarker in non‐small‐cell lung cancer, breast cancer, pancreatic adenocarcinoma, hepatocellular carcinoma, colon cancer, melanoma, oropharyngeal squamous cell carcinoma, head and neck squamous cell carcinoma, clear cell renal cell carcinoma and endometrioid carcinoma. This evidence indicated that myoferlin was involved in the proliferation, invasion and migration of tumour cells, the mechanism of which mainly included promoting angiogenesis, vasculogenic mimicry, energy metabolism reprogramming, epithelial‐mesenchymal transition and modulating exosomes. The roles of myoferlin in both normal cells and cancer cells are of great significance to provide novel and efficient methods of tumour treatment. In this review, we summarize recent studies and findings of myoferlin and suggest that myoferlin is a novel potential candidate for clinical diagnosis and targeted cancer therapy.