PIM2 promotes hepatocellular carcinoma tumorigenesis and progression through activating NF-κB signaling pathway
PIM2 promotes hepatocellular carcinoma tumorigenesis and progression through activating NF-κB signaling pathway
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PIM2通过激活NF-κB信号通路促进肝癌发生和进展
DOI：
10.1038/s41419-020-2700-0
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发表时间：
2020-07-02
影响因子：
9
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
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作者：
Tang, Xuming;Cao, Tingting;Guan, Xin-Yuan
炎症因子和癌基因的激活在肝细胞癌（HCC）的发生、发展中起着重要作用。然而，这两者之间的相互作用还没有得到很好的研究。在本研究中，我们发现受TNF α调节的Pim-2原癌基因丝氨酸/苏氨酸激酶（PIM-2）在HCC中高表达，并与预后不良（P = 0.007）和肿瘤复发（P = 0.014）相关。功能研究表明，PM 2可以增强细胞增殖、细胞运动、血管生成、化疗耐药性以及体内致瘤性和肝癌转移的能力。机制研究表明，PIM 2可通过上调RIPK 2的磷酸化水平激活NF-κ B B信号通路。有趣的是，TNF α处理可以诱导PIM 2的表达，并且PIM 2的过表达可以反过来上调HCC细胞中TNF α的表达。更重要的是，我们发现PIM 2的表达水平随着肝硬化的进展而增加，PIM激酶抑制剂AZD 1208可以有效地降低HCC细胞在体外和体内的致瘤能力。总的来说，我们的研究揭示了炎症因子和原癌基因之间的相互作用，有助于肿瘤的发生和发展的HCC，和PIM激酶抑制可能作为治疗HCC的治疗靶点。
Inflammatory factors and activation of oncogenes both played critical roles in the development and progression of human hepatocellular carcinoma (HCC). However, the interplay between these two has not been well studied. In this study, we found that regulated by TNF alpha, Pim-2 proto-oncogene, serine/threonine kinase (PIM2) was highly expressed in HCC and correlated with poor prognosis (P = 0.007) as well as tumor recurrence (P = 0.014). Functional studies showed that PIM2 could enhance abilities of cell proliferation, cell motility, angiogenesis, chemo-resistance, and in vivo tumorigenicity and HCC metastasis. Mechanistic studies revealed that PIM2 could activate NF-kappa B signaling pathway through upregulating phosphorylation level of RIPK2. Interestingly, TNF alpha treatment could induce the expression of PIM2, and overexpression of PIM2 could in turn upregulate the expression of TNF alpha in HCC cells. More importantly, we found the expression level of PIM2 increased with the progression of liver cirrhosis, and PIM kinase inhibitor AZD1208 treatment could effectively attenuate HCC cells' tumorigenic ability both in vitro and in vivo. Collectively, our study revealed the interaction between an inflammatory factor and a proto-oncogene that contributed to tumorigenesis and progression of HCC, and PIM kinase inhibition may serve as a therapeutic target in the treatment of HCC.