Overexpression of ZNF460 predicts worse survival and promotes metastasis through JAK2/STAT3 signaling pathway in patient with colon cancer.

Zinc finger proteins (ZNFs) are a class of protein containing zinc finger domains, and they play an important role in tumor progression. However, as a member of the ZNFs family, the effect of ZNF460 in colon cancer remains unclear. In this study, we found that the expression of ZNF460 protein were markedly increased in clinical colon cancer tissues compared with para-cancer non-cancerous tissues by tissue immunohistochemistry (IHC) and western blot (WB). We also confirmed this result at the mRNA and protein levels of ZNF460 through bioinformatics analysis. In addition, high expression of ZNF460 was correlated with increased depth of invasion (P<0.05), increased lymph node metastasis (P<0.05), distant metastasis (P<0.05) and high blood serum CA19-9 level (P<0.05). High expression of ZNF460 predicted poor overall survival (OS) and recurrence free survival (RFS) in patients with colon cancer. Moreover, multivariate analyses revealed that ZNF460 was an independent prognostic factor in both OS (hazard ratio [HR]: 1.636; 95% confidence interval [CI], 1.028-2.603; P = 0.038) and RFS (HR: 2.215; 95% CI: 1.227-3.997; P = 0.008). The knockdown of ZNF460 suppressed the invasion and metastasis of colon cancer cells in vitro. Mechanistically, we revealed that ZNF460 promotes the activation of the JAK2/STAT3 signaling pathway in colon cancer cells. Taken together, overexpression of ZNF460 predicted worse survival and promoted metastasis through JAK2/STAT3 signaling pathway in patient with colon cancer, and could be a novel therapeutic target in colon cancer.

Down-regulation of UBC9 increases the sensitivity of hepatocellular carcinoma to doxorubicin.

UBC9 is an E2-conjugating enzyme that is required for SUMOylation and has been implicated in regulating several critical cellular pathways. UBC9 is overexpressed in certain tumors, such as lung adenocarcinoma, ovarian carcinoma and melanoma, which implies that it has special clinical significance. However, the role of UBC9 in Hepatocellular carcinoma (HCC) drug responsiveness is not clear. In this study, we investigated the clinicopathological significance of UBC9 in HCC and investigated the mechanism of UBC9-mediated chemosensitivity to doxorubicin (DOX) in hepatocellular carcinoma cells. We found that relative to adjacent normal tissues, UBC9 was markedly overexpressed in HCC, which closely correlated with tumor size, tumor microsatellite formation, and tumor encapsulation. Our results also showed that down-regulation of UBC9 by shRNA reduced the expression of Bcl-2 and Bcl-xl and increased the expression of cleaved-Caspase3, which is a proapoptotic protein. These changes were associated with reduced apoptosis in response to DOX. Furthermore, we observed a mechanism involving modulation of the P38 and ERK1/2 signaling pathways. Together, our results indicate that down-regulation of UBC9 sensitizes cells to anticancer drugs, is possibly associated with the regulation of ERK1/2 and P38 activation and interacts with the intrinsic apoptosis pathway. Thus, knockdown of UBC9 may have a tumor suppressor effect and UBC9 could be a potential target for the treatment of HCC cancer.

Downregulation of UBC9 promotes apoptosis of activated human LX-2 hepatic stellate cells by suppressing the canonical NF-κB signaling pathway.

UBC9, the only known E2-conjugating enzyme involved in SUMOylation, is a key regulator in fibrosis. However, the roles of UBC9 in liver fibrosis remain unclear. Therefore, in this study, we investigated the roles of UBC9 in HSC apoptosis and liver fibrogenesis. Our results showed that the UBC9 levels in activated LX-2 cells, HepG2 and SMMC-7721 were increased compared with LO2, and the expression of UBC9 in activated LX-2 cells, HepG2 and SMMC-7721 were no significant differences. The expression of UBC9 was effectively down-regulated by the UBC9-shRNA plasmid, and this effect was accompanied by the attenuated expression of the myofibroblast markers smooth muscle actin (α-SMA) and Collagen I. Downregulation of UBC9 also promotes activated HSCs apoptosis by up-regulating cell apoptosis-related proteins. Further, knockdown of UBC9 in activated HSCs inhibited cell viability and caused cell cycle arrest in the G2 phase. Moreover, knockdown of UBC9 suppressed the activation of NF-κB signaling pathways. In conclusion, these results demonstrated that down-regulation of UBC9 expression induced activated LX-2 cell apoptosis and promoted cells to return to a quiescent state by inhibiting the NF-κB signaling pathway. These results provide novel mechanistic insights for the anti-fibrotic effect of UBC9.