miR-137 Modulates a Tumor Suppressor Network-Inducing Senescence in Pancreatic Cancer Cells
miR-137 Modulates a Tumor Suppressor Network-Inducing Senescence in Pancreatic Cancer Cells
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DOI：
10.1016/j.celrep.2016.01.068
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发表时间：
2016-03-01
期刊：
影响因子：
8.8
通讯作者：
Richard, Stephane
中科院分区：
文献类型：
--
作者：
Neault, Mathieu;Mallette, Frederick A.;Richard, Stephane
激活 K-Ras 突变经常发生在胰腺癌中，并且与胰腺癌的发展有关。癌症引发事件，例如致癌 Ras 激活，会导致细胞衰老（一种肿瘤抑制反应）的诱导。在衰老过程中，KDM4A 赖氨酸脱甲基酶水平降低有助于 p53 激活，然而 KDM4A 下调的机制尚不清楚。我们发现，miR-137 在 Ras 诱导的衰老过程中靶向 KDM4A mRNA，并激活 p53 和视网膜母细胞瘤 (pRb) 肿瘤抑制途径。恢复 KDM4A 表达有助于绕过 miR-137 诱导的衰老，并用 miRNA 海绵受损的 Ras 诱导的衰老抑制内源性 miR-137。人类胰腺肿瘤中 miR-137 水平显着降低，这与之前揭示这种癌症类型衰老反应缺陷的研究一致。 miR-137表达的恢复抑制了胰腺癌细胞的增殖并促进了衰老。这些结果表明，调节 miR-137 的水平可能对于触发胰腺癌中的肿瘤抑制网络很重要。
Activating K-Ras mutations occurs frequently in pancreatic cancers and is implicated in their development. Cancer-initiating events, such as oncogenic Ras activation, lead to the induction of cellular senescence, a tumor suppressor response. During senescence, the decreased levels of KDM4A lysine demethylase contribute to p53 activation, however, the mechanism by which KDM4A is downregulated is unknown. We show that miR-137 targets KDM4A mRNA during Ras-induced senescence and activates both p53 and retinoblastoma (pRb) tumor suppressor pathways. Restoring the KDM4A expression contributed to bypass of miR-137-induced senescence and inhibition of endogenous miR-137 with an miRNA sponge-compromised Ras-induced senescence. miR-137 levels are significantly reduced in human pancreatic tumors, consistent with previous studies revealing a defective senescence response in this cancer type. Restoration of miR-137 expression inhibited proliferation and promoted senescence of pancreatic cancer cells. These results suggest that modulating levels of miR-137 may be important for triggering tumor suppressor networks in pancreatic cancer.