Expression of chromobox homolog 7 (CBX7) is associated with poor prognosis in ovarian clear cell adenocarcinomaviaTRAIL-induced apoptotic pathway regulation

Abstract

JapanOvarian cancer is the most lethal gynecologic malignancy, and clear cell adenocarcinoma of the ovary (OCCA), in particular, has a relatively poor prognosis among the ovarian cancer subtypes because of its high chemoresistance. Chromobox (CBX) 7 is a polycomb repressive complex 1 component that prolongs the lifespan of normal human cells by downregulating the INK4a/ARF expression which promotes cell-cycle progression. However, recent reports studying the relationship between CBX7 expression and patient survival have differed regarding the tumor cell origins, and the precise role of CBX7 in human carcinomas remains obscure. In this study, we analyzed CBX7 expression by immunohistochemistry in 81 OCCA patients and evaluated its association with their clinical outcomes. Both the overall and progression-free survival rates of the CBX7-positive patients were significantly shorter than those of the CBX7-negative patients (p < 0.05). CBX7 knockdown experiments using two OCCA cell lines, TOV21G and KOC-7C, revealed that cell viability was significantly reduced compared to the control cells (p < 0.001). Expression microarray analysis revealed that apoptosis-related genes, particularly tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were significantly upregulated in CBX7 knockdown cells (p < 0.01). We further confirmed that CBX7 knockdown resulted in TRAIL-induced apoptosis in the OCCA cells. Thus, in this study, we showed for the first time that CBX7 was associated with a decreased OCCA prognosis. We also successfully demonstrated that the TRAIL pathway is a novel target for CBX7 expression modulation in these cells, and therapeutic agents utilizing the TRAIL pathway may be particularly effective for targeted OCCA therapy.

Cbx7 is epigenetically silenced in glioblastoma and inhibits cell migration by targeting YAP/TAZ-dependent transcription

“…There exists a nice correlation between the loss of expression of Cbx7 and the aggressiveness of various cancers3334. This observation is further substantiated by the fact that Cbx7 is either undetectable or very lowly expressed in most of the human cancers with a few exceptions10353637. However, the role of Cbx7 in human malignancies still remains ambiguous, owing to the fact that there are reports which portray Cbx7 as an oncogene as well as some of them depict its role as a tumour suppressor.…”

Expression of ANRIL–Polycomb Complexes–CDKN2A/B/ARF Genes in Breast Tumors: Identification of a Two-Gene (EZH2/CBX7) Signature with Independent Prognostic Value

“…Conversely, in our series of breast tumors, we showed marked CBX7 underexpression and a nonexpected high positive link between ANRIL overexpression and CDKN2A/CDKNB/ARF overexpression, and more particularly with p14/ARF. Although these results seem to be contradictory, it can be hypothesized that CBX7 can exhibit both oncosuppressive and oncogenic functions, depending on type of cancer, microenvironment, and presence of interacting proteins (32)(33)(34)(35). CBX7 underexpression was strongly correlated with high SBR histologic grade, negative ERa and PR status, and EMT and breast cancer stem cell markers.…”

Context-dependent actions of Polycomb repressors in cancer

“…Elevated levels of CBX7 have also been observed in prostate cancer and ovarian clear cell carcinoma, where CBX7 represses CDKN2A and suppress apoptosis. 123,126,127 , and prevents aberrant differentiation by repressing lineage-specification genes. In addition, it represses the genes encoding the paralogs BMI1, CBX2, CBX4 and CBX8.…”