Long noncoding RNA H19 derived miR-675 regulates cell proliferation by down-regulating E2F-1 in human pancreatic ductal adenocarcinoma

Abstract

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.

lncRNA GAS5 Reverses EMT and Tumor Stem Cell-Mediated Gemcitabine Resistance and Metastasis by Targeting miR-221/SOCS3 in Pancreatic Cancer

“…Numerous studies have shown that lncRNAs play an important role in the regulation of cancer progression. In PC, several lncRNAs have been identified as either oncogenes, such as lncRNA H19, lncRNA NNT-AS1, and lncRNA SNHG15, 32 , 33 , 34 or as tumor-suppressive lncRNAs, such as lncRNA MEG3 and lncRNA GAS5. 35 , 36 The function of GAS5 in PC has not been investigated.…”

Long non-coding RNA H19 contributes to apoptosis of hippocampal neurons by inhibiting let-7b in a rat model of temporal lobe epilepsy

“…The mechanisms of downstream regulation of H19 are complicated and H19 may play differential roles depending on tissue type and/or developmental stage of different pathological conditions 13 . The previous studies reveal that H19 enhances tumorigenesis, metastasis, and invasion of different kinds of tumor cells through encoding miRNA-675, such as pancreatic ductal adenocarcinoma 40 , breast cancer 41 , 42 , gastric cancer 43 , and glioma 19 . However, the present results with no changes of miR-675 after SE suggest that H19 might not act by encoding miR-675 during epileptogenesis in TLE.…”

LncRNA H19/miR‐194/PFTK1 axis modulates the cell proliferation and migration of pancreatic cancer

“…In addition, lncRNA deregulation constitutes an important aspect of the metastatic process . Of lncRNAs that have been reported to be related to pancreatic cancer, H19 serves as an oncogene by promoting cancer cell proliferation and metastasis through interacting with miRNAs . Importantly, H19 can activate Wnt‐signaling pathway to increase the metastasis of bladder cancer .…”