BIRC6 promotes hepatocellular carcinogenesis: Interaction of BIRC6 with p53 facilitating p53 degradation

Abstract

The genes that encode inhibitor of apoptosis proteins (IAPs) are frequently overexpressed in human cancers. However, the expression pattern and clinical significance of BIRC6, a member of IAPs, in hepatocellular carcinoma (HCC) remains unclear. Here we investigated the role of BIRC6 in hepatocellular carcinogenesis. We used immunoblot and immunochemical analyses to determine the levels of BIRC6 in 7 hepatoma cell lines and 160 HCC specimens. We evaluated the proognostic value of BIRC6 expression and its association with clinical parameters. A lentivirus-mediated silencing method was used to knockdown BIRC6, and the biological consequences of BIRC6 silencing in three hepatoma cell lines were investigated in vitro and in vivo. We found that BIRC6 overexpression was significantly correlated with serum ALT level and HCC vascular invasion. Patients with positive BIRC6 expression in tumor tissue had a poor survival and a high rate of recurrence. BIRC6 knockdown remarkably suppressed cell proliferation, caused G1/S arrest and sensitized hepatoma cells to sorafenib-induced apoptosis in hepatoma cells, which was partly reversed by RNA interference targeting p53. The mechanistic study revealed that BIRC6 interacted with p53 and facilitated its degradation. The in vivo study showed that BIRC6 knockdown inhibited xenograft tumor growth and increased the sensitivity of tumor cells to sorafenib in nude mice. Taken together, these findings demonstate that BIRC6 overexpression in HCC specimens is indicative of poor prognosis and that its interaction with p53 facilitates the degradation of p53, leading to carcinogenesis and an anti-apoptotic status.

Downregulation of miR-129-2 by promoter hypermethylation regulates breast cancer cell proliferation and apoptosis

“…We predicted several potential target candidates for miR-129-2-3p. Among them, BCL2L2 provoked our interesting due to its oncogenic role in many solid tumors (31)(32)(33). Luciferase report assay confirmed that miR-129-2-3p directly targeted BCL2L2 3'UTR for degradation.…”

CAPS1 Negatively Regulates Hepatocellular Carcinoma Development through Alteration of Exocytosis-Associated Tumor Microenvironment

“…The semiquantitative scoring system was based on both the staining intensity (0, negative; 1, weak; 2, intermediate; 3, strong) and the percentage of positive cells (0, 0% positive cells; 1, ≤25% positive cells; 2, 26%–50% positive cells; 3, >50% positive cells). The final score of each sample was obtained by multiplying the scores of staining intensity and percentage of positive cells [25]. We chose five randomized microscopic views of 400-fold magnification of each slide to score and get a composite score.…”

“…Briefly, cells were incubated with CCK-8 for 1 h. Cell proliferation rate was assessed by measuring the absorbance at 450 nm with the Universal Microplate Reader (BIO-TEK Instruments, Minneapolis, MN, USA). Anchorage-independent growth ability was measured using the colony forming assay and soft agar colony formation assay, as previously [25]. The colonies with diameter >0.1 mm were counted and colony forming efficiency was calculated (Percentage of colonies = Number of colonies formed/Number of cells inoculated × 100%).…”

BIRC6 (Baculoviral IAP repeat-containing 6)

“…On the other hand, BIRC6 also inhibits apoptosis via negatively regulating p53 protein levels by facilitating its degradation via ubiquitination (Ren et al, 2005;Tang et al, 2014). BIRC6 and treatment resistance.…”