J Cancer 2018; 9(2):389-399. doi:10.7150/jca.21347
Long noncoding RNA H19 derived miR-675 regulates cell proliferation by down-regulating E2F-1 in human pancreatic ductal adenocarcinoma
1. Department of General Surgery, Peking University First Hospital, Beijing 100034, People's Republic of China;
2. Department of Surgical Oncology, Peking University Ninth School of Clinical Medicine (Beijing Shijitan Hospital, Capital Medical University), Beijing 100038, People's Republic of China;
3. Clinic of General, Visceral and Transplantation Surgery, University of Ulm, Ulm 89081, Germany.
* Contributed equally
Ma L, Tian X, Guo H, Zhang Z, Du C, Wang F, Xie X, Gao H, Zhuang Y, Kornmann M, Gao H, Yang Y. Long noncoding RNA H19 derived miR-675 regulates cell proliferation by down-regulating E2F-1 in human pancreatic ductal adenocarcinoma. J Cancer 2018; 9(2):389-399. doi:10.7150/jca.21347. Available from http://www.jcancer.org/v09p0389.htm
The long noncoding RNA (lncRNA) H19 has been proven to be overexpressed in human pancreatic ductal adenocarcinoma (PDAC). H19-induced PDAC cell proliferation is cell cycle-dependent by modulating E2F-1. However, the mechanism of how H19 regulates E2F-1 remains unclear. In this study, we investigated the expression of miR-675 in PDAC tumours and cells, the biological function of miR-675 in PDAC cell proliferation and the possible relationship among H19, miR-675 and E2F-1. As a transcript of the first exon of H19, the level of miR-675 was negatively correlated with H19 expression in microdissected PDAC tissues (r=-0.0646, P=0.001). The serum miR-675 expression was significantly down-regulated in patients with PDAC compared to those in healthy individuals. Moreover, an evaluation of five PDAC cases showed that there was a remarkable increase of serum miR-675 levels after resection of the primary tumours. Ectopic overexpression of miR-675 in AsPC-1 and PANC-1 cells decreased cell viability, the colony-forming ability and the percentage of cells in S phase; contrarily, miR-675 knockdown resulted in enhanced cell proliferation. Furthermore, the suppressed cell proliferation caused by H19 knockdown could be rescued by inhibiting miR-675 expression. Additionally, intratumoural injection of either miR-675 agomir or antagomir could significantly affect tumour growth in vivo. Both the bioinformatic prediction and luciferase activity assay confirmed that E2F-1 was a direct target of miR-675. And the decrease of E2F-1 protein expression caused by siH19 could be partially reversed by miR-675 knockdown. We concluded that there might be a H19/miR-675/E2F-1 regulatory loop in cell cycle modulation. Serum miR-675 might serve as a potential biomarker for not only early diagnosis but also outcome prediction in PDAC.
Keywords: long noncoding RNA H19, miR-675, E2F-1, pancreatic ductal adenocarcinoma, cell proliferation, cell cycle.