Allele imbalance in the transcriptome of human hepatocellular carcinoma: stress-induced gene plays a role

Abstract

The two alleles of a gene are usually expressed equally in a normal cell, however, high incidence of allele-specific imbalance is frequently observed in cancer cells. Chromosomal regions with recurrent allele-specific imbalance usually harbor risk alleles and critical genes associated with cancer susceptibility and progression. With the development of large scale transcriptome sequencing technology, systematic analysis of the allele imbalance in the cancer transcriptome could be achieved at the single nucleotide resolution. In the April 2014 issue of Gastroenterology, we reported that the allele-specific imbalance of Oxidative Stress Induced Growth Inhibitor 1 (OSGIN1) can significantly contribute to the progression of HCC. OSGIN1 is a stress-induced pro-apoptotic protein. By validating the sequencing results in a cohort of HCC patients, we found the variant 438H form of OSGIN1 was specifically overrepresented in the tumor tissues. Functional studies indicated that OSGIN1 has strong tumor suppressive function in HCC both in vitro and in vivo. The pro-apoptotic function of the variant form of OSGIN1 was found to be less potent than the wild-type form, and the functional defects might be due to its poor efficiency to localize to the mitochondria. Clinical pathological analysis further revealed that the expression and genotype of OSGIN1 are closely associated with the prognosis of HCC patients. Taken together, our study linked the stress-induced genes with allele imbalance in HCC transcriptome, and proposed OSGIN1 to be an important tumor suppressor gene in the progression of HCC. Further characterization of OSGIN1 might help predict the prognosis of HCC patients and their responses to chemotherapeutic drugs.