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Variant 1 of KIAA0101, overexpressed in hepatocellular carcinoma, prevents doxorubicin‐induced apoptosis by inhibiting p53 activation
Author(s) -
Liu Lijuan,
Chen Xiaobei,
Xie Shuixiang,
Zhang Chuanjie,
Qiu Zhenpeng,
Zhu Fan
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25834
Subject(s) - biology , western blot , cancer research , hccs , apoptosis , hepatocellular carcinoma , transfection , blot , transactivation , messenger rna , microbiology and biotechnology , gene , gene expression , biochemistry
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. (H EPATOLOGY 2012;56:1760–1769)