PTBP1 promotes hepatocellular carcinoma progression by regulating the skipping of exon 9 in NUMB pre-mRNA

Aberrant alternative splicing is one of the important causes of cancer. Polypyrimidine tract binding protein 1 (PTBP1) has been found to be involved in splicing regulation in a variety of tumors. Here, we observed significant up-regulation of PTBP1 in primary hepatocellular carcinoma (HCC) tissues. High levels of PTBP1 expression were associated with poor prognosis and increased metastatic potential in HCC. In vitro studies demonstrated that elevated PTBP1 promoted both migration and invasion by HCC cells. In contrast, knockdown of PTBP1 significantly inhibited the migration and invasion of HCC cells in vitro. Further, up-regulation of PTBP1 markedly accumulated the expression of oncogenic isoform of NUMB, NUMB-PRR(L). We observed two isoforms of NUMB, NUMB-PRR(L) and NUMB-PRR(S) exhibit opposite function in HCC cells, which partially explain PTBP1 plays the tumor promoting roles in a NUMB splicing-dependent manner. In summary, our study indicates that PTBP1 may serve as an oncogene in HCC patients by regulating the alternative splicing of NUMB exon 9 and could potentially serve as a prognostic indicator.