加藤 琢哉

INTRODUCTION: REV7 functions in various biological processes, including the DNA damage response. REV7 expression has been linked to the prognosis and chemoresistance in several human cancers. This study investigated the significance of REV7 in gallbladder adenocarcinoma (GBAC). METHODS: REV7 expression was examined immunohistochemically in 77 resected GBAC specimens, and its association with clinicopathological features was analyzed. REV7-depleted GBAC cell lines were established, and the biological effects of REV7 depletion were evaluated. RESULTS: High REV7 expression in GBAC tissues correlated with increased cell proliferation, as assessed by Ki-67 labeling indices (p < 0.001), and was associated with a trend toward shorter overall survival (p = 0.070) and significantly shorter post-progression survival (p = 0.035). REV7-knockout and REV7-knockdown cell lines derived from NOZ and G415 GBAC cells (NOZ-KO and G415-KD, respectively) showed reduced proliferation and increased sensitivity to cisplatin, however, REV7 depletion did not affect cell migration and invasion. Reintroduction of REV7 into NOZ-KO cells restores chemoresistance. Furthermore, RNA sequencing analysis comparing wild-type NOZ and NOZ-KOs revealed that REV7 inactivation downregulates genes involved in the DNA damage response. CONCLUSION: REV7 may contribute to tumor progression and chemoresistance in GBAC and may serve as a prognostic biomarker and molecular target for GBAC management.

CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is upregulated in various human cancers and exhibits tumor-promoting effects. In this study, we investigated the role of CD109 in gallbladder adenocarcinoma (GBAC). CD109 expression in 77 resected GBAC samples was immunohistochemically evaluated. CD109 expression in tumor cells correlated with TNM stage, N factor, histological grade, lymphatic invasion, and perineural invasion and was associated with reduced disease-free survival (DFS) and overall survival (OS). Stromal CD109 expression was detected in several cases, similar to that of α-SMA and FAP, suggesting its presence in cancer-associated fibroblasts. Stromal expression was also correlated with TNM stage, N factor, perineural invasion, and reduced DFS. Combined analysis of CD109 expression in tumor and stromal cells further stratified patients by prognosis. CD109 overexpression in GBAC cell lines induced the expression of the epithelial-to-mesenchymal transition (EMT) markers. Analyses using a public database revealed the association between CD109 and EMT-related gene expression in biliary tract cancer cell lines. Moreover, CD109 depletion promoted enhanced transforming growth factor-β1/Smad3 signaling and attenuated epidermal growth factor/AKT signaling in GBAC cells in a cell type-dependent manner. Collectively, these findings suggest that CD109 may serve as a prognostic biomarker of tumor progression and outcome in GBAC.

Immune checkpoint inhibitor (ICI) therapy serves as a standard treatment for advanced or recurrent malignant melanoma. Tumour neoantigenicity is an important factor for the effectiveness of the ICI therapy. However, the absence of reliable biomarkers to predict ICI therapy efficacy remains an unresolved challenge. REV7 is a subunit of mutagenic DNA polymerase ζ and plays a role in generating genetic alterations following DNA damage. In this study, we examined REV7 as a potential predictive biomarker for ICI therapy in melanoma. Using RNA in situ hybridisation, we assessed REV7 expression in melanomas from 42 patients who received ICI therapy. Our analysis revealed that high REV7 expression correlated significantly with improved progression-free survival, durable clinical benefit and favourable clinical outcomes according to response evaluation criteria in solid tumours. These findings suggest that REV7 may be a potential predictive biomarker for ICI therapy response in melanoma.

REV7 is a multifunctional protein essential for promoting cellular tolerance to DNA damage. REV7 expression is associated with disease progression and prognosis in several human malignant tumors. This study aimed to evaluate the clinical and biological significance of REV7 in gastric adenocarcinoma (GAD). REV7 expression in 167 resected GADs was immunohistochemically assessed and examined the association with clinicopathological features. Positive expression of REV7 was significantly associated with tumor undifferentiation (p < 0.001), lymphatic invasion (p = 0.035), recurrence (p = 0.042), and mortality (p = 0.031). The Kaplan-Meier curves with log-rank tests revealed significantly poorer progression-free survival (p = 0.049), overall survival (p = 0.037), and post-progression survival (p = 0.038) in the REV7-positive group. Multivariate analysis using the Cox proportional hazard model identified REV7 as an independent prognostic factor for overall survival (p = 0.028). REV7-depleted GAD cell lines demonstrated enhanced sensitivity to cisplatin compared with control cells. Additionally, the expression levels of REV7 in residual tumors from surgical specimens of patients who received preoperative chemotherapy were higher than those in samples without chemotherapy (p = 0.029), suggesting that REV7-positive tumors are chemoresistant. These results indicate that REV7 is a predictive biomarker for the prognosis and chemosensitivity of GAD.

REV7 is a multifunctional protein involved in the DNA damage response, cell cycle regulation, gene expression, or primordial germ cell maintenance. REV7 expression in tumor cells is associated with clinical aggressive features and chemoresistance in several human malignancies, however, the clinicopathological significance of REV7 in lung adenocarcinoma (LUAD) has not been studied yet. In this study, we investigated the significance of REV7 expression in LUAD using clinical materials and cell lines. REV7 expression in 142 invasive LUADs were determined using immunohistochemistry, and the relationship between REV7 expression and clinicopathological features was analyzed. High levels of REV7 expression in tumor tissues were positively associated with progressive tumor behavior as assessed by Ki-67 labeling indexes (p < 0.001), maximum standardized uptake values on positron emission tomography (p = 0.005), pathological stage (p = 0.031), N factor (p = 0.048), recurrence (p = 0.038), and disease-specific death (p = 0.020). The REV7-high-expression group showed poorer relapse-free survival (RFS) (p = 0.025) and overall survival (OS) (p = 0.019) compared to the REV7-low-expression group, and REV7 was a significant prognostic factor for RFS and OS. CRISPR/Cas9-mediated REV7-knockout and siRNA-mediated REV7 knockdown were carried out using the LUAD cell lines A549 and H1975, respectively, and it was demonstrated that REV7 inactivation led to slower cell growth, attenuated activation of AKT signaling, and enhanced chemosensitivity compared with control cells. These results suggest that REV7 is a potential predictive biomarker for poor prognosis in invasive LUAD and a possible molecular target for LUAD management.