KIF2C: a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma.
KIF2C: a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma.
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KIF2C：Wnt/β-连环蛋白和 mTORC1 信号在肝细胞癌发病机制中的新联系
DOI：
10.1007/s13238-020-00766-y
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发表时间：
2021-10
期刊：
影响因子：
21.1
通讯作者：
Xie D
中科院分区：
文献类型：
--
作者：
Wei S;Dai M;Zhang C;Teng K;Wang F;Li H;Sun W;Feng Z;Kang T;Guan X;Xu R;Cai M;Xie D
肝细胞癌（HCC）是最常见的原发性肝脏恶性肿瘤，也是全球癌症相关死亡的第四大原因。HCC对许多标准癌症治疗是难治的，并且预后通常很差，这突出了迫切需要识别侵袭性生物标志物和未来治疗的潜在靶点。据报道，驱动蛋白家族成员2C（KIF 2C）在几种人类肿瘤中高度表达。然而，KIF 2C在肿瘤发展和进展中的作用的分子机制尚未研究。在这项研究中，我们发现KIF 2C表达在HCC中显著上调，并且KIF 2C上调与不良预后相关。利用获得和丧失功能的实验，我们发现KIF 2C在体外和体内均促进HCC细胞的增殖、迁移、侵袭和转移。从机制上讲，我们确定了TBC 1D 7作为KIF 2C的结合伴侣，这种相互作用破坏了TSC复合物的形成，导致雷帕霉素复合物1（mTORC 1）信号转导的哺乳动物靶标的增强。此外，我们发现KIF 2C是Wnt/β-catenin通路的直接靶点，并且在介导Wnt/β-catenin和mTORC 1信号传导之间的串扰中起关键作用。因此，我们的研究结果建立了Wnt/β-catenin和mTORC 1信号之间的联系，这突出了KIF 2C作为HCC治疗靶点的潜力。
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide. HCC is refractory to many standard cancer treatments and the prognosis is often poor, highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments. Kinesin family member 2C (KIF2C) is reported to be highly expressed in several human tumors. Nevertheless, the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated. In this study, we found that KIF2C expression was significantly upregulated in HCC, and that KIF2C up-regulation was associated with a poor prognosis. Utilizing both gain and loss of function assays, we showed that KIF2C promoted HCC cell proliferation, migration, invasion, and metastasis bothin vitroandin vivo. Mechanistically, we identified TBC1D7 as a binding partner of KIF2C, and this interaction disrupts the formation of the TSC complex, resulting in the enhancement of mammalian target of rapamycin complex1 (mTORC1) signal transduction. Additionally, we found that KIF2C is a direct target of the Wnt/β-catenin pathway, and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORC1 signaling. Thus, the results of our study establish a link between Wnt/β-catenin and mTORC1 signaling, which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
24.5
作者：
Chen J;Rajasekaran M;Xia H;Zhang X;Kong SN;Sekar K;Seshachalam VP;Deivasigamani A;Goh BK;Ooi LL;Hong W;Hui KM
通讯作者：
Hui KM
影响因子：
2.7
作者：
Hedgepeth, CM;Conrad, LJ;Klein, PS
通讯作者：
Klein, PS
影响因子：
3.6
作者：
Gan, Huizhu;Lin, Lin;Sun, Butong
通讯作者：
Sun, Butong
影响因子：
64.8
作者：
Hsieh, Andrew C.;Liu, Yi;Edlind, Merritt P.;Ingolia, Nicholas T.;Janes, Matthew R.;Sher, Annie;Shi, Evan Y.;Stumpf, Craig R.;Christensen, Carly;Bonham, Michael J.;Wang, Shunyou;Ren, Pingda;Martin, Michael;Jessen, Katti;Feldman, Morris E.;Weissman, Jonathan S.;Shokat, Kevan M.;Rommel, Christian;Ruggero, Davide
通讯作者：
Ruggero, Davide