PKM2-regulated STAT3 promotes esophageal squamous cell carcinoma progression via TGF-1-induced EMT
PKM2-regulated STAT3 promotes esophageal squamous cell carcinoma progression via TGF-1-induced EMT
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DOI：
10.1002/jcb.28434
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发表时间：
2019-07-01
影响因子：
4
通讯作者：
Lu, Xiaomei
中科院分区：
文献类型：
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作者：
Ma, Rong;Liu, Qing;Lu, Xiaomei
最近的研究表明，丙酮酸激酶同工酶M2 （PKM2）在肿瘤进展中的多效性作用。然而，PKM2影响食管鳞状细胞癌（ESCC）转移和转化生长因子1 （TGF-1）诱导的上皮-间质转化（EMT）的确切机制仍有待确定。在本研究中，我们观察到PKM2在ESCC组织中的上调与淋巴结转移和不良预后显著相关。肿瘤组织中PKM2高表达往往与pSTAT3Tyr705高表达和E-cadherin低表达相吻合。此外，除了EMT标记物（Snail、E-cadherin和vimentin）和pSTAT3(Tyr705)/STAT3比值的表达模式外，PKM2表达的改变还与ESCC细胞的增殖、迁移和侵袭显著相关。STAT3过表达显著减弱PKM2敲低对细胞增殖和运动的影响，以及pSTAT3 （Tyr705）和EMT标记物的表达。稳定的短发卡RNA （shRNA）介导的PKM2沉默可以逆转TGF-1治疗的效果，特别是PKM2上调、STAT3 Tyr705位点磷酸化、EMT、迁移和侵袭增加。我们提出PKM2通过tgf -1诱导的EMT，通过STAT3的磷酸化调节细胞增殖、迁移和侵袭。我们的研究结果共同提供了PKM2促肿瘤作用的机制见解，支持其预后价值和PKM2抑制剂作为ESCC潜在抗肿瘤药物的治疗效用。
Recent studies have demonstrated pleiotropic roles of pyruvate kinase isoenzyme type M2 (PKM2) in tumor progression. However, the precise mechanisms underlying the effects of PKM2 on esophageal squamous cell carcinoma (ESCC) metastasis and transforming growth factor 1 (TGF-1)-induced epithelial-mesenchymal transition (EMT) remain to be established. In this study, we observed upregulation of PKM2 in ESCC tissues that was markedly associated with lymph node metastasis and poor prognosis. High PKM2 expression in tumor tissues frequently coincided with the high pSTAT3Tyr705 expression and low E-cadherin expression. Furthermore, altered PKM2 expression was significantly associated with proliferation, migration, and invasion of ESCC cells, in addition to expression patterns of EMT markers (Snail, E-cadherin, and vimentin) and pSTAT3(Tyr705)/STAT3 ratio. Overexpression of STAT3 significantly attenuated the effects of PKM2 knockdown on cell proliferation and motility as well as expression of pSTAT3 (Tyr705) and EMT markers. Consistently, stable short hairpin RNA (shRNA)-mediated silencing of PKM2 reversed the effects of TGF-1 treatment, specifically, upregulation of PKM2, phosphorylation of STAT3 at Tyr705, and increased EMT, migration, and invasion. We propose that PKM2 regulates cell proliferation, migration, and invasion via phosphorylation of STAT3 through TGF-1-induced EMT. Our findings collectively provide mechanistic insights into the tumor-promoting role of PKM2, supporting its prognostic value and the therapeutic utility of PKM2 inhibitors as potential antitumor agents in ESCC.