Search

The majority of patients are diagnosed when ovarian cancer (OC) has metastasized, making surgery and chemotherapy less effective. Thus, there is an urgent need to elucidate the mechanisms underlying metastasis and to further explore novel diagnostic biomarkers of OC metastasis. Here, we conducted a genome-wide CRISPR-Cas9 screen for anoikis resistance to identify key genes associated with OC metastasis. Further, bioinformatic analysis was performed using TCGA and GTEx datasets to explore the genes associated with OC progression and prognosis. After integrated analysis, the V-set and transmembrane domain-containing protein 2-like (VSTM2L) was identified as a crucial gene closely associated with OC metastasis, progression, and prognosis. Further validation using a patient-based cohort suggested that VSTM2L expression was significantly higher in metastatic lesions than in primary lesions. Subsequently, an in vitro assay showed that VSTM2L silencing increased SKOV3 cell death and hampered spheroid formation. Mechanistically, GSEA highlighted that epithelial-mesenchymal transition (EMT)-related pathways was positively associated with VSTM2L expression. Consistently, the validation based on the VSTM2L silence suggested the involvement of VSTM2L in EMT-related TGF-β and NF-κB signaling. Meanwhile, the addition of VSTM2L-containing medium did not provoke those signaling, indicating VSTM2L functions as an intracellular protein to activate TGF-β and NF-κB signaling. In summary, our study revealed that VSTM2L is a novel player involved in anoikis resistance and is a promising biomarker of OC metastasis and prognosis. • Genome-wide screening combined with bioinformatics identified VSTM2L as a promising biomarker for ovarian cancer. • VSTM2L regulates TGF-β and NF-κB signaling and promotes anoikis resistance. • VSTM2L functions as an intracellular protein to regulate EMT-related signaling. [ABSTRACT FROM AUTHOR]

Objective. To investigate the association between programmed death-ligand 1 (PD-L1) coupled with CD8+ tumor-infiltrating lymphocytes (TILS) and the clinicopathological features, along with prognosis of cervical squamous cell carcinoma (CSCC). Methods. 95 patients of CSCC received tumor resection at the Department of Pathology of the First Affiliated Hospital of University of Science and Technology of China (USTC) from 2015 to 2020. Full-automatic immunohistochemistry was applied to measure PD-L1 expression and CD8+ TILS density. Our literature deeply assessed the links between PD-L1 expression, clinicopathological features, and the influences of combination of PD-L1 and CD8+ TILS (PD-L1+/CD8+ TILS) on the prognosis of CSCC. Results. 64.21% of CSCC patients (61/95) expressed PD-L1, and PD-L1 expression was related to the Federation of Gynecology and Obstetrics (FIGO) stage, tumor size, invasion depth, differentiation degree, metastasis of lymph node, and vascular invasion (P < 0.05). Dramatic correlation between PD-L1 expression and CD8+ TILS density was illustrated in CSCC patients (r = − 0.461 , P < 0.001). Obvious differences in differentiation degree, FIGO stage, infiltration depth, and lymph node metastasis were shown between patients with PD-L1 coupled with high-density of CD8+ TILS and those with PD-L1 coupled with low-density of CD8+ TILS (P < 0.05). Patients with PD-L1 negative expression exhibited better prognosis compared with those with PD-L1 positive expression (P < 0.05). Patients with PD-L1 coupled with high-density of CD8+ TILS showed better prognostic status, while those with PD-L1 coupled with low-density of CD8+ TILS had worse prognostic condition (P < 0.05). Differentiation, metastasis of lymph node, and FIGO stage were substantive impact elements of a CSCC patient's overall survival (OS) by Cox multivariate analysis. Conclusions. CD8+ TILS density is related to PD-L1 expression in carcinoma. PD-L1/CD8+ TILS density can be regarded as evaluation for the prognosis of patients with CSCC, providing a new therapeutic target in clinical application. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the leading causes of cancer mortality in the world. P2X7 receptor (P2X7R), encoded by the P2rx7 gene, is a trimeric ion channel activated by extracellular Adenosine triphosphate and is widely expressed in various types of tissues and tumors to regulate inflammation, cell proliferation, or death. The discovery of new biomarkers and understanding the role of P2X7R in CRC are therefore critical to improving the prognosis and treatment of CRC. P2X7R expression was analyzed in CRC tumor samples and normal colorectal tissues from 97 patients and various colon cancer cell lines. The correlation of tumor antigens, survival periods, and P2X7R expression were documented. P2X7RHigh and P2X7RLow populations were observed in CRC patients. P2X7RHigh patients had relatively shorter survival periods, higher levels of serum carcinoembryonic antigen, and greater numbers of advanced tumors. In addition, P2X7R expression had a significant up-regulation in metastatic CRC and metastatic CRC cell lines, which indicates that P2X7R expression is positively associated with metastasis. P2X7R expression might be a potential biomarker for prognosis and metastasis of CRC. [ABSTRACT FROM AUTHOR]

Steroid receptor coactivator 1 (Src-1) and Twist1 are aberrantly upregulated in a variety of tumors and play an important role in tumor progression. However, the exact role of Src-1 and Twist1 in nasopharyngeal carcinoma (NPC) is uncertain. In this study, we investigated the possible prognostic value and biological effect of Src-1 and Twist1 in NPC. Src-1 and Twist1 expression was detected in a cohort of NPC patients (n = 134) by qRT-PCR. Kaplan-Meier survival analysis was used comparing overall survival (OS) and progression-free survival (PFS). Multivariate analysis was performed using the Cox proportional hazard regression model. Biologic effect of Src-1 and Twist1 in NPC cell lines was evaluated by western blot, colony formation assay, soft agar assay, scratch wound healing assay, transwell invasion assay and tumor xenografts growth. We have found that Src-1 and Twist1 were aberrantly upregulated in human NPC tissues, and associated with advanced tumor stage, distant metastasis and unfavorable prognosis. Knockdown of Src-1 or Twist1 in human NPC cell line CNE-1 suppressed colony formation, anchorage-independent growth, cell migration, invasion and tumor xenografts growth, while enforced expression of Src-1 or Twist1 in human NPC cell line HNE-2 promotes anchorage-independent growth, cell migration and invasion. In addition, Src-1 and Twist1 could suppress E-cadherin expression and increase Vimentin expression, thus suggested that Src-1 and Twist1 enhanced the malignant behaviors of NPC cells via inducing epithelial-mesenchymal transition (EMT). Our data indicated that Src-1 and Twist1 could be possible prognostic biomarkers and potential therapy targets for patients with NPC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common malignancy tumors with insidious onset, rapid development and metastasis, and poor prognosis. Therefore, it is necessary to understand molecular mechanisms of HCC and identify clinically useful biomarkers for it. This study aimed to investigate the role of retinoblastoma binding protein 5 (RBBP5) in HCC. The expression level of RBBP5 was examined by immunohistochemistry and western blot. The effect of RBBP5 on cell cycle, proliferation, apoptosis, and drug sensitivity was analyzed. RBBP5 was significantly upregulated in HCC tissues and cells. High RBBP5 expression was significantly associated with elevated level of AFP, advanced TNM stage, high Ki-67 expression, larger tumor size, and poor prognosis. Knockdown of RBBP5 significantly inhibited proliferation of HCC cells through cell cycle arrest. In addition, inhibition of RBBP5 increased the sensitivity of HCC cells to doxorubicin. In conclusion, our findings suggest that RBBP5 plays an important role in the progression of HCC and may serve as a novel biomarker and potential therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

Increased APOBEC3B mRNA levels are associated with a hypermutator phenotype and poor prognosis in ER-positive breast cancer patients. In addition, a 29.5 kb deletion polymorphism of APOBEC3B, resulting in an APOBEC3A-B hybrid transcript, has been associated with an increased breast cancer risk and the hypermutator phenotype. Here we evaluated whether the APOBEC3B deletion polymorphism also associates with clinical outcome of breast cancer. Copy number analysis was performed by quantitative PCR (qPCR) in primary tumors of 1,756 Dutch breast cancer patients. The APOBEC3B deletion was found in 187 patients of whom 16 carried a two-copy deletion and 171 carried a one-copy deletion. The prognostic value of the APOBEC3B deletion for the natural course of the disease was evaluated among 1,076 lymph-node negative (LNN) patients who did not receive adjuvant systemic treatment. No association was found between APOBEC3B copy number values and the length of metastasis-free survival (MFS; hazard ratio (HR) = 1.00, 95% confidence interval (CI) = 0.90–1.11, P = 0.96). Subgroup analysis by ER status also did not reveal an association between APOBEC3B copy number values and the length of MFS. The predictive value of the APOBEC3B deletion was assessed among 329 ER-positive breast cancer patients who received tamoxifen as the first-line therapy for recurrent disease and 226 breast cancer patients who received first-line chemotherapy for recurrent disease. No association between APOBEC3B copy number values and the overall response rate (ORR) to either tamoxifen (odds ratio (OR) = 0.88, 95% CI = 0.69–1.13, P = 0.31) or chemotherapy (OR = 0.97, 95% CI = 0.71–1.33, P = 0.87) was found. Thus, in contrast to APOBEC3B mRNA levels, the APOBEC3B deletion polymorphism has neither a prognostic nor a predictive value for breast cancer patients. Although a correlation exists between APOBEC3B copy number and mRNA expression, it is relatively weak. This suggests that other mechanisms exist that may affect and therefore determine the prognostic value of APOBEC3B mRNA levels. [ABSTRACT FROM AUTHOR]

Background: Tumor progression and distant metastasis are the main causes of deaths in colorectal cancer (CRC) patients, and the molecular mechanisms in CRC metastasis have not been completely discovered. Methods: We identified differentially expressed genes (DEGs) and lncRNAs (DELs) of CRC from The Cancer Genome Atlas (TCGA) database. Then we conducted the weighted gene co-expression network analysis (WGCNA) to investigate co-expression modules related with CRC metastasis. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, DEG-DEL co-expression network and survival analyses of significant modules were also conducted. Finally, the expressions of selected biomarkers were validated in cell lines by quantitative real-time PCR (qRT-PCR). Results: 2032 DEGs and 487 DELs were involved the construction of WGCNA network, and greenyellow, turquoise and brown module were identified to have more significant correlation with CRC metastasis. GO and KEGG pathway analysis of these three modules have proven that the functions of DEGs were closely involved in many important processes in cancer pathogenesis. Through the DEG-DEL co-expression network, 12 DEGs and 2 DELs were considered as hub nodes. Besides, survival analysis showed that 30 DEGs were associated with the overall survival of CRC. Then 10 candidate biomarkers were chosen for validation and the expression of CA2, CHP2, SULT1B1, MOGAT2 and C1orf115 were significantly decreased in CRC cell lines when compared to normal human colonic epithelial cells, which were consistent with the results of differential expression analysis. Especially, low expression of SULT1B1, MOGAT2 and C1orf115 were closely correlated with poorer survival of CRC. Conclusion: This study identified 5 genes as new biomarkers affecting the metastasis of CRC. Besides, SULT1B1, MOGAT2 and C1orf115 might be implicated in the prognosis of CRC patients. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most common bone malignancy, and is particularly prevalent in children and adolescents. OS is an aggressive tumor with a tendency to metastasize and invade to para-carcinoma tissues. The primary treatment for this tumor is a combination of surgery and chemotherapy. However, the prognosis remains poor due to chemoresistance and early metastasis. Osteopontin (OPN), a multifunctional secreted protein, has emerged as an important potential biomarker for diagnosing and treating cancer. The overexpression of OPN has been found in numerous malignant tumors, including breast, lung, gastric and ovarian cancer, as well as melanoma. Recent studies have suggested that OPN may provide an important function in the diagnosis and treatment of OS. The present review summarizes current knowledge and progress in understanding the potential role of OPN as a biomarker in OS. [ABSTRACT FROM AUTHOR]

Background: The treatment efficacy of transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) varies widely between individuals. The aim of this study was to identify subtype landscapes and responser related to TACE, and further clarify the regulatory effect and corresponding mechanism of NDRG1 on HCC tumorgenesis and metastasis. Methods: The principal component analysis (PCA) algorithm was used to construct a TACE response scoring (TRscore) system. The random forest algorithm was applied to identify the TACE response-related core gene NDRG1 of HCC, and its role in the prognosis of HCC was explored. The role of NDRG1 in the progression and metastasis of HCC and functional mechanism were confirmed using several experimental methods. Results: Based on the GSE14520 and GSE104580 cohorts, we identified 2 TACE response-related molecular subtypes for HCC with significant differences in clinical features, and the TACE prognosis of Cluster A was significantly better than that of Cluster B (p < 0.0001). We then established the TRscore system and found that the low TRscore group showed a higher probability of survival and a lower rate of recurrence than the high TRscore group (p < 0.05) in both the HCC and TACE-treated HCC cohorts within the GSE14520 cohort. NDRG1 was determined to be the the hub gene associated with the TACE response of HCC and its high expression suggested a poor prognosis. Furthermore, The suppression of NDRG1 konckdown in tumorgenesis and metastasis of HCC was clarified in both vivo and vitro, which was importantly achieved through inducing ferroptosis in HCC cells, especially contributing to RLS3-induced ferroptosis. Conclusion: The constructed TACE response-related molecular subtypes and TRscores can specifically and accurately predict TACE prognosis for HCC. In addition, the TACE response-related hub gene NDRG1 may act as a guardian against ferroptosis to drive tumorgenesis and metastasis in HCC, which laid a new foundation for the development of new potential targeted therapy strategies to improve disease prognosis in HCC patients. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to determine the diagnostic performance of conventional magnetic resonance imaging (MRI) in assessing the distance between the tumor and the internal os, stromal infiltration, lymph node metastasis, and parametrial invasion in patients with cervical cancer.Methods: A systematic English-language literature search of conventional MRI in the evaluation of human cervical cancer was performed in the PubMed, Cochrane Library, Embase, and Web of Science databases from 1995 to 2018. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and positive and negative likelihood ratios (PLR and NLR) of all studies were calculated. The results were then plotted in a hierarchical summary receiver operating characteristic (HSROC) plot, and meta-regression and subgroup analyses of the parametrial invasion were also performed.Results: The pooled sensitivity, specificity, DOR, PLR, and NLR were 86%, 97%, 167.91, 24.74, and 0.15, respectively, in evaluating the internal os involvement (6 studies, 454 patients); 87%, 91%, 73.41, 10.22, and 0.14, respectively, in evaluating the stromal infiltration (11 studies, 672 patients); 51%, 89%, 8.63, 4.72, and 0.55, respectively, in evaluating the lymph node metastasis (15 studies, 997 patients); and 75%, 92%, 34.01, 9.38, and 0.28, respectively, in evaluating the parametrial invasion (19 studies, 1748 patients). The meta-regression of the parametrial invasion showed that the application of contrast enhancement was a significant factor affected the heterogeneity (p = 0.039).Conclusions: Conventional MRI can accurately evaluate the distance between the tumor and the internal os, as well as stromal infiltration, and performs well in diagnosing the parametrial invasion. However, this method exhibited a limited ability in diagnosing the lymph node metastasis.Key Points: • MRI can help clinicians to accurately assess the distance between the tumor and the internal os, stromal infiltration, and parametrial invasion in patients with uterine cervical neoplasms. • MRI exhibits a limited ability in diagnosing the lymph node metastasis. • Management of patients with uterine cervical neoplasms becomes more appropriate. [ABSTRACT FROM AUTHOR]

Increased angiogenesis in the liver plays a critical role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism underlying increased angiogenesis in HCC is not well understood. Current study was designed to identify the potential angiogenic effect of RNA-binding motif 4 (RBM4)through a small-scale overexpression screening, followed by comparison of the expression level of RBM4 in cancer and adjacent tissues in multiple malignancies to explore the relationship between RBM4 and CD31 protein expression level and related clinical indicators, and understand the role of RBM4 in the hepatocellular carcinoma. To understand the specific mechanism of RBM4 in detail, transcriptome sequencing, mass spectrometry and multiple molecular cytological studies were performed. These cellular level results were verified by experiments in animal models of nude mice. The increased expression of RBM4 in cancer tissues, suggested its use as a prognostic biomarker. The RBM4 expression was found to be strongly correlated with tumor microvessel density. Mechanistically, RBM4 mediated its effects via interaction with HNRNP-M through the latter's WDR15 domain, which then stabilized RelA/p65 mRNA. Consequently, RBM4 induced the activation of the NF-kB signaling pathway, upregulating the expression of proangiogenic factor VEGF-A. The results confirmed the mechanism by which RBM4 promotes angiogenesis in hepatocellular carcinoma suggesting RBM4 as a crucial promoter of angiogenesis in HCC, helping understand regulation of NF-kB signaling in HCC. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The prognostic significance of claudin 4 (CLDN4) in patients with gastric cancer (GC) is controversial. This meta-analysis aims to assess the correlation between CLDN4 expression and clinicopathological characteristics and assess the prognostic significance of CLDN4 in GC. Methods: We searched the PubMed and Embase databases. We performed the meta-analysis with odds ratio (OR), hazard ratio (HR), and 95% confidence interval (CI) as effect values. Results: Fourteen studies containing 2,106 patients with GC were analyzed. The overall analysis showed that CLDN4 expression was associated with increasing pT category, tumor size, and lymph node metastasis in patients with GC (pT3-T4 vs pT1-T2: OR =1.56, 95% CI =1.13-2.16; P<0.01; large tumor size vs small tumor size: OR =1.64, 95% CI =1.15-2.34; P<0.01; positive lymph node metastasis vs negative lymph node metastasis: OR =1.49, 95% CI =1.12-1.97; P<0.01). CLDN4 expression was associated with histological differentiation (differentiated type vs undifferentiated type: OR =2.90, 95% CI =1.32-6.37; P=0.01; Lauren intestinal type vs diffuse type: OR =3.51,95% CI =1.48-8.28; P<0.01). CLDN4 expression was also strongly associated with sex and age. This meta-analysis found no significant association between CLDN4 expression and prognosis for overall survival in patients with GC (HR =0.74, 95% CI =0.43-1.27; P=0.28). Conclusion: Present study indicates that aberrant CLDN4 expression plays an important role in the clinicopathological characteristics of GC. [ABSTRACT FROM AUTHOR]

Based on previous findings regarding the angiogenic activities and prognostic roles of metastasis-associated protein 1 (MTA1) in early-stage non-small cell lung cancer, the clinicopathological and prognostic significance of MTA1 protein expression, and its correlation with angiogenesis in lung invasive adenocarcinoma, were further assessed in the present study, according to the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. High protein expression levels of MTA1 were commonly observed in patients with lung invasive adenocarcinoma, and were significantly correlated with tumor size (P=0.030), lymph node metastasis (P=0.021) and microvessel density (P=0.015). Survival analysis demonstrated that patients with high protein expression levels of MTA1 exhibited significantly shorter five-year disease-free and overall survival than those patients whose protein expression levels of MTA1 were low (24.5% vs. 48.7%, P=0.001, and 34.7% vs. 59.2%, P=0.005, respectively). In addition, Cox regression multivariate analysis demonstrated that high protein expression levels of MTA1 significantly correlated with unfavorable five-year disease-free survival (P=0.024). These findings indicate that MTA1 protein expression may possess clinical potential as an indicator of progressive phenotype. Therefore, MTA1 is a promising prognostic predictor to identify subgroups of patients with high risk of relapse, and a potentially novel therapeutic target for antiangiogenesis in patients with lung invasive adenocarcinoma. [ABSTRACT FROM AUTHOR]

Abstract: The membrane mucin MUC4 is aberrantly expressed in multiple cancers and is of clinical significance to diagnosis and prognosis in pancreatic cancer. However, the role of MUC4 in angiogenesis and the potential association among these malignant capabilities have not been explored. In this study, we investigated the collective signaling mechanisms associated with MUC4-induced growth, metastasis and angiogenesis in pancreatic cancer. Knockdown of MUC4 in two pancreatic cancer cell lines led to downregulation of lysosomal degradation of E-cadherin by Src kinase through downregulation of pFAK and pSrc pathway. The downregulation of lysosomal degradation of E-cadherin in turn induced the formation of E-cadherin/β-catenin complex and membrane translocation of β-catenin, resulting in the downregulation of Wnt/β-catenin signaling pathway. Thus, the Wnt/β-catenin target genes c-Myc, Cyclin D1, CD44 and VEGF were down-regulated and their malignant functions proliferation, metastasis and angiogenesis were reduced. Taken together, MUC4-induced nuclear translocation of β-catenin is a novel mechanism for growth, metastasis and angiogenesis of pancreatic cancer. [Copyright &y& Elsevier]

Although the correlation between glypican-5 (GPC5) and lung cancer is well known, the effect of GPC5 expression on non-small cell lung cancer (NSCLC) survival remains to be determined. In the present study, GPC5 expression in A549, H3255, and SPC-A1 NSCLC cell lines was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. GPC5 mRNA and protein expression levels were found to be higher in A549 and H3255 cells compared with SPC-A1 cells. The role of GPC5 in NSCLC cell migration was evaluated in vitro by shRNA-mediated knockdown or the overexpression of GPC5 through scratch and transwell assays. The mean migration rates of cancer cells transfected with pRNAT-shRNA-GPC5-1 were reduced compared with the controls in A549 (P<0.001) and H3255 (P=0.001), while the migration rate of SPC-A1 with GPC5 overexpression was higher than that of the control (P=0.001). The downregulation of GPC5 impeded the transmigration of A549 and H3255 while the upregulation of GPC5 expression promoted the transmembrane invasion of SPC-A1. Furthermore, a panel of formalin-fixed paraffin-embedded NSCLC tissues from 127 patients undergoing curative resection (stages I, II and III) between January, 2003 and December, 2008 were obtained in order to investigate the correlation between GPC5 expression and clinicopathological factors using immunohistochemical methods. The results demonstrated that high GPC5 expression levels in NSCLC were associated with respiratory symptoms in lung cancer diagnosis, poor differentiation, vascular invasion, regional lymph node metastasis and a higher TNM stage. Using the Kaplan-Meier method, NSCLC patients with high levels of GPC5 expression demonstrated a significantly shorter overall survival time compared with those with low GPC5 expression levels (median postsurgical survival time: 14.0 months vs. 59.0 months, P=0.001). GPC5 expression was also identified as an independent prognostic factor by Cox regression analysis [adjusted hazard ratio: 2.18; 95% confidence interval (CI): 1.35-3.52; P=0.001]. This study suggested that increased levels of GPC5 expression are a poor prognostic marker for NSCLC. [ABSTRACT FROM AUTHOR]