Reduced expression of the H19 long non-coding RNA inhibits pancreatic cancer metastasis
Reduced expression of the H19 long non-coding RNA inhibits pancreatic cancer metastasis
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DOI：
10.1038/s41374-018-0048-1
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发表时间：
2018-06-01
影响因子：
5
通讯作者：
Ishiwata, Toshiyuki
中科院分区：
文献类型：
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作者：
Yoshimura, Hisashi;Matsuda, Yoko;Ishiwata, Toshiyuki
H19是一种癌胎儿RNA，在发育中的胚胎以及膀胱癌、乳腺癌、胃癌、胰腺癌、肝细胞癌和前列腺癌中表达。最近的研究表明，H19增强了癌症的侵袭和转移；然而，它在癌症中的作用仍然存在争议。在目前的研究中，H19表现出第二大的增长(82.4倍)，并代表了在11个基因中唯一的非蛋白质编码基因，这些基因在肺转移的胰腺癌细胞中与其亲代细胞相比在小鼠转移模型中升高了10倍以上。随后，我们利用体外和体内技术进一步阐明了H19在胰腺癌生长和转移中的作用。原位杂交显示H19在23例浸润性导管癌中表达(17%)，且H19的表达与组织学分级呈正相关(P<；0.0001)。H19在PANC-1胰腺癌细胞中的过表达诱导了更高的运动能力，而用shRNA和siRNA抑制H19的结果相反，但细胞的生长速度没有受到影响。静脉注射H19shRNA载体转染的PANC-1细胞可显著抑制免疫缺陷小鼠的肝和肺转移。这些发现表明，H19在胰腺癌转移中起重要作用，抑制H19有望成为胰腺癌治疗的新靶点。
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-metastasisderived 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.