High expression of PTBP1 promote invasion of colorectal cancer by alternative splicing of cortactin

// Zhi-na Wang 1, * , Dan Liu 1, 2, * , Bin Yin 3 , Wen-yi Ju 3 , Hui-zhong Qiu 4 , Yi Xiao 4 , Yuan-jia Chen 1 , Xiao-zhong Peng 3 and Chong-mei Lu 1 1 Department of Gastroenteology and Hepatology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China 2 Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China 3 National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 4 Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China * These authors have contributed equally to this work Correspondence to: Chong-mei Lu, email: lcm5788@163.com Xiao-zhong Peng, email: pengxiaozhong@pumc.edu.cn Keywords: polypyrimidine tract-binding protein 1, cortactin, colorectal cancer, splicing, invasion Received: June 13, 2016     Accepted: January 23, 2017     Published: March 03, 2017 ABSTRACT Polypyrimidine tract-binding protein 1 (PTBP1) involving in almost all steps of mRNA regulation including alternative splicing metabolism during tumorigenesis due to its RNA-binding activity. Initially, we found that high expressed PTBP1 and poor prognosis was interrelated in colorectal cancer (CRC) patients with stages II and III CRC, which widely different in prognosis and treatment, by immunohistochemistry. PTBP1 was also upregulated in colon cancer cell lines. In our study, knockdown of PTBP1 by siRNA transfection decreased cell proliferation and invasion in vitro . Denovirus shRNA knockdown of PTBP1 inhibited colorectal cancer growth in vivo . Furthermore, PTBP1 regulates alternative splicing of many target genes involving in tumorgenesis in colon cancer cells. We confirmed that the splicing of cortactin exon 11 which was only contained in cortactin isoform-a, as a PTBP1 target. Knockdown of PTBP1 decreased the expression of cortactin isoform-a by exclusion of exon 11. Also the mRNA levels of PTBP1 and cortactin isoform-a were cooperatively expressed in colorectal cancer tissues. Knocking down cortactin isoform-a significantly decreased cell migration and invasion in colorectal cancer cells. Overexpression of cortactin isoform-a could rescue PTBP1-knockdown effect of cell motility. In summary the study revealed that PTBP1 facilitates colorectal cancer migration and invasion activities by inclusion of cortactin exon 11.