Reduced expression of the H19 long non-coding RNA inhibits pancreatic cancer metastasis

Abstract

H19 is an oncofetal RNA expressed in the developing embryo as well as in bladder, breast, gastric, pancreatic, hepatocellular, and prostate cancers. Recent studies have shown that H19 enhances cancer invasion and metastasis; however, its roles in cancer remain controversial. In the current study, H19 exhibited the second largest increase (82.4-fold) and represented the only non-protein coding gene among 11 genes identified that were elevated over 10-fold in lung-metastasis-derived pancreatic cancer cells compared with their parental cells using a mouse metastatic model. Subsequently, we further clarified the roles of H19 in pancreatic cancer growth and metastasis using in vitro and in vivo techniques. In situ hybridization showed that H19 was detected in 23 of 139 invasive ductal carcinomas (17%), and that H19 expression positively correlated with higher histological grades (P < 0.0001). Overexpression of H19 in PANC-1 pancreatic cancer cells induced higher motilities, whereas H19 inhibition using shRNA and siRNA showed opposite results; however, cell growth rates were not impacted. Intravenous injection of H19 shRNA vector-transfected PANC-1 cells yielded marked inhibition of metastasis in the liver and lungs of immunodeficient mice. These findings suggest that H19 has important roles in pancreatic cancer metastasis, and that inhibition of H19 represents a novel candidate for pancreatic cancer therapy.

Gene modules and non-coding RNAs involved in pancreatic tumorigenesis through acinar ductal metaplasia

“…Another tumor suppressor Meg3, predicted to interact with Hist1h2bn in our study, was found to be involved in pancreatic cancer [61]. H19, identi ed as oncogenic lncRNA, played a role in pancreatic cancer invasion and metastasis [59]. In line with previous ndings, we found H19 as the top lncRNA in crosstalk with ADM, PanIN and PDAC.…”

“…Consistently, one of our strongest candidates, Gas5, was recently shown to regulate pancreatic cancer metastasis via PTEN [22]. MiR-143, reported to be suppressed in colorectal neoplasia [59], was predicted to regulate ADM-PanIN-PDAC via targeting ACTR10. MiR-193b, validated as a tumor suppressor in various cancer types, was found to regulate CLIP3 and interact with oncogenic lncRNA (MIR31HG) in our network [60].…”

H19 gene polymorphisms and Wilms tumor risk in Chinese children: a four-center case-control study

“…So far, 10 polymorphisms in H19 have been identi ed as predisposing factors to various cancer types, among which the rs217727 has been most frequently studied, followed by rs2839698 [45]. H19 plays an essential role in the tumor progression of breast cancer [15], bladder cancer [46], gastric cancer [17], and other tumors [20,47,48], other than that, mutations in the H19 gene coding sequence are also closely related to tumors, despite unknown regulatory mechanisms [12,49]. The following evidence suggests that SNPs may affect the expression and function of the H19 gene.…”

The multifaceted roles of long noncoding RNAs in pancreatic cancer: an update on what we know

“…The observed inhibition of PDAC proliferation suggested that the H19/miR-194/PFTK1 axis in the WNT signaling pathway contributes to PC proliferation and migration [58]. In vivo experiments showed that the stable knockdown of H19 significantly suppressed the lung and liver metastatic potential of xenografts [8]. These findings imply that H19 plays an important role in proliferation and metastasis in PC.…”

“…Although several genes and pathways have been found to participate in the occurrence and progression of PC, the underlying mechanisms are still unclear. Therefore, it is extremely important to investigate novel and effective regulatory models for the further treatment of PC [8].…”