Pancreatic Cancer

H19[LncRNA]

let-7a[miRNA]

Hmga2[mRNA]

Panc-1,Sw1990, Aspc-1, Bxpc-3, Cfpac-1

Homo sapiens (human)

Tumour Biol 2014 Sep 35, 9163-9 doi:10.1007/s13277-014-2185-5 PMID:24920070

H19 promotes pancreatic cancer metastasis by derepressing let-7’s suppression on its target HMGA2-mediated EMT

siRNA transfection;qRT-PCR;Western blot

We found that the expression level of H19 was significantly upregulated in most PDAC tissues, intriguingly, when tumor tissues were stratified based on clinical progression, we found that H19 levels were remark- ably increased in primary tumors that subsequently metasta- sized compared with those in nonmetastatic PDAC tissues, which suggested that H19 might play a role in PDAC metas- tasis. Secondly, H19 function was investigated in siRNA- mediated knockdown studies and we demonstrated that H19 enhanced PDAC cell migration and invasion. Thirdly, given that H19 exerted pro-oncogenic activities in PDAC, whereas let-7 exhibited a well-known tumor suppressor in PDAC [33–35], and that H19 acted as a molecular sponge to bind with let-7 and inhibited its function in muscle differentiation as previously reported [16], we postulate that H19/let-7 reguation may also contribute to PDAC metastasis. To confirm this speculation, we want to explore whether H19 inhibited let-7 function and affected its target gene. Since oncogenic HMGA2 was reported as the let-7 wellkown target and was dysregulated in many types of tumor, including PDAC [22, 36], additionally, HMGA2 is proved to be a key factor in- volved in the epithelia-mesenchymal transition (EMT), which is vital for tumor invasion and metastasis [24, 37–44]. We detected the expression level of HMGA2 as well as EMT markers after treated PDAC cells with H19-siRNA, and we proved that H19 indeed inhibit endogenous let-7 function, leading to derepression of HMGA2 which mediated EMT. Last but not least, we proved that downregulation of let-7 could significantly restore the impaired migration and inva- sion induced byH19-siRNA, which indicated that let-7 played pivotal roles, at least partially in H19-induced PDAC metastasis.