Oncogenic microRNA-4534 regulates PTEN pathway in prostate cancer.
Oncogenic microRNA-4534 regulates PTEN pathway in prostate cancer.
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DOI：
10.18632/oncotarget.12031
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发表时间：
2016-10-18
期刊：
影响因子：
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通讯作者：
Majid S
中科院分区：
文献类型：
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作者：
Nip H;Dar AA;Saini S;Colden M;Varahram S;Chowdhary H;Yamamura S;Mitsui Y;Tanaka Y;Kato T;Hashimoto Y;Shiina M;Kulkarni P;Dasgupta P;Imai-Sumida M;Tabatabai ZL;Greene K;Deng G;Dahiya R;Majid S
前列腺癌的发生涉及几种信号通路的改变，最突出的是PI 3 K/AKT通路。该途径是组成性活性的，并驱动前列腺癌（PCa）进展为晚期转移性疾病。PTEN是一种重要的肿瘤和转移抑制基因，通过PI 3 K/Akt途径负性调节细胞存活、增殖、迁移和血管生成。PTEN在许多癌症中突变、下调/功能失调，并且其失调与PCa的不良预后相关。在这里，我们证明了microRNA-4534（miR-4534）在PCa中过表达，并表明与PCa组织/细胞相比，miR-4534在正常组织和细胞系中高甲基化。miR-4534部分通过下调肿瘤抑制基因PTEN发挥其致癌作用。在PCa中，miR-4534的敲低损害细胞增殖、迁移/侵袭并诱导G 0/G1细胞周期停滞和凋亡。在异种移植小鼠模型中证实了miR-4534的抑制及其对肿瘤生长的影响。我们在非癌RWPE 1细胞中进行了平行实验，通过过表达miR-4534，然后进行功能测定。miR-4534的过表达在该非癌细胞系中诱导了促癌特征。统计分析显示，miR-4534具有独立区分恶性组织与正常组织的潜力，并且与较差的总体和PSA无复发生存率正相关。总之，我们的结果表明，PCa中miR-4534的缺失部分通过诱导PTEN诱导肿瘤抑制表型。这些结果对于识别和定义新的PTEN调节因子如microRNA在前列腺肿瘤发生中的作用具有重要意义。了解异常过表达的miR-4534及其对PTEN的下调将为PCa治疗提供机制见解和治疗靶点。
Prostate carcinogenesis involves alterations in several signaling pathways, the most prominent being the PI3K/AKT pathway. This pathway is constitutively active and drives prostate cancer (PCa) progression to advanced metastatic disease. PTEN, a critical tumor and metastasis suppressor gene negatively regulates cell survival, proliferation, migration and angiogenesis via the PI3K/Akt pathway. PTEN is mutated, downregulated/dysfunctional in many cancers and its dysregulation correlates with poor prognosis in PCa. Here, we demonstrate that microRNA-4534 (miR-4534) is overexpressed in PCa and show that miR-4534 is hypermethylated in normal tissues and cell lines compared to PCa tissues/cells. miR-4534 exerts its oncogenic effects partly by downregulating the tumor suppressor PTEN gene. Knockdown of miR-4534 impaired cell proliferation, migration/invasion and induced G0/G1 cell cycle arrest and apoptosis in PCa. Suppression of miR-4534 and its effects on tumor growth was confirmed in a xenograft mouse model. We performed parallel experiments in non-cancer RWPE1 cells by overexpessing miR-4534 followed by functional assays. Overexpression of miR-4534 induced pro-cancerous characteristics in this non-cancer cell line. Statistical analyses revealed that miR-4534 has potential to independently distinguish malignant from normal tissues and positively correlated with poor overall and PSA recurrence free survival. Taken together, our results show that depletion of miR-4534 in PCa induces a tumor suppressor phenotype partly through induction of PTEN. These results have important implications for identifying and defining the role of new PTEN regulators such as microRNAs in prostate tumorigenesis. Understanding aberrantly overexpressed miR-4534 and its downregulation of PTEN will provide mechanistic insight and therapeutic targets for PCa therapy.