Variant 1 of KIAA0101, overexpressed in hepatocellular carcinoma, prevents doxorubicin-induced apoptosis by inhibiting p53 activation

Abstract

KIAA0101 overexpression was detected in numerous malignant solid tumors and involved in tumor progression; however, the correlation between KIAA0101 expression level and human hepatocellular carcinoma (HCC) was controversial. Our data revealed abnormal expression of the KIAA0101 transcript variant 1 (KIAA0101 tv1) at both messenger RNA and protein levels in HCC tissues and cell lines assessed by semiquantitative reverse‐transcription polymerase chain reaction (RT‐PCR), virtual northern blot, western blot, and immunohistochemical analysis, especially in stage 3‐4 HCCs. NIH3T3 cells transfected with KIAA0101 tv1 induced colony formation in vitro and tumor xenorafts in vivo, implying the oncogenic potential of KIAA0101 tv1. Semiquantitative RT‐PCR, real‐time quantitative RT‐PCR, and western blot analysis demonstrated that doxorubicin (Adriamycin, ADR) treatment down‐regulated expression of the KIAA0101 tv1, whereas it increased the acetylation of the p53 protein. Additionally, KIAA0101 tv1 prevented cells from apoptosis caused by ADR through suppressing the acetylation of p53 at Lys382. Immunoprecipitation analysis and mammalian two‐hybrid assay indicated that KIAA0101 tv1 bound to the transactivation region (1‐42 amino acids) of p53 and strongly inhibits its transcriptional activity. Taken together, our data suggest that KIAA0101 tv1 played an important role in the late stage of metastatic HCC and prevented apoptosis after chemotherapeutic drug treatment through inhibiting the transcriptional activity of the p53 gene. Conclusion: KIAA0101 tv1 may function as a regulator, promoting cell survival in HCC through regulating the function of p53. Suppression of the KIAA0101 tv1 function is likely to be a promising strategy to develop novel cancer therapeutic drugs. (HEPATOLOGY 2012;56:1760–1769)

NS5ATP9 Suppresses Activation of Human Hepatic Stellate Cells, Possibly via Inhibition of Smad3/Phosphorylated-Smad3 Expression

“…Moreover, we proved that NS5ATP9 prevented LX-2 cells from proliferation and migration, and promoted apoptosis, which differs entirely from its proliferative and anti-apoptotic activities in most types of tumor cells [10,14,28,29], but is consistent with that in others, including HCC [30,31]. The promotion/suppression effects of NS5ATP9 on HSC apoptosis/proliferation may be one of the ways to protect HSCs from maintaining the activation status.…”

“…transactivated by the hepatitis C virus (HCV) NS5A protein via the suppression subtractive hybridization technique by our group [8]. NS5ATP9 expression was significantly altered in numerous malignant tumors, including pancreatic cancer, colorectal adenoma and adenocarcinoma, nonsmall cell lung cancer, anaplastic thyroid carcinoma, and liver cancer [9][10][11][12][13]. NS5ATP9 is also involved in the regulation of DNA repair, apoptosis, cellular signaling pathway, cell cycle progression, and cell proliferation [11,14,15].…”

Expression of KIAA0101 protein is associated with poor survival of esophageal cancer patients and resistance to cisplatin treatment in vitro

“…Indeed, a previous study showed that overexpression of KIAA0101 greatly decreased the effect of cisplatin plus doxorubicin in hepatocellular carcinoma. 24 Although we did not further explore the underlying molecular mechanisms, this result may provide a novel insight into KIAA0101 for the selection of optimal chemotherapy for EC patients. A further study will pursue such underlying mechanism for effective control of EC.…”

Disentangling polydispersity in the PCNA−p15PAF complex, a disordered, transient and multivalent macromolecular assembly

“…p15 functions by interacting with PCNA (30–32), and its overexpression correlates with poor prognosis in several types of cancer (33–36). The study used complementary biophysical techniques to determine the structural details of the PCNA–p15 recognition and the flexibility of the non-interacting regions of p15 (27).…”