JCI：顾建新研究组发现核糖体蛋白能够促进肝细胞癌的化疗耐药及生长

近日，由上海复旦大学顾建新教授所在的研究组发现，核糖体蛋白RACK1能够促进了肝细胞癌（HCC）的生长及化疗耐药。相关研究成果于6月1日发表在The Journal of Clinical Investigation上。

众所周知，翻译的起始与细胞周期进程及细胞生长相偶联，然而，过多的核糖体的合成及翻译起始通常都导致了肿瘤的转化及存活。

肝细胞癌(HCC)是世界上最常见的恶性癌症之一，对化疗药物通常都表现出高的耐受性。RACK1是激活的蛋白激酶C1的受体。在这项研究里，研究人员发现RACK1在正常肝脏中高表达，并在肝细胞癌中频繁的被上调。他们发现，RACK1的异常表达促进了肝细胞癌的化疗抗性及生长，而这些作用主要依赖于RACK1的核糖体定位。

进一步研究发现，核糖体RACK1通过偶联PKCβII促进了真核起始因子4E(eIF4E)的磷酸化，导致了与生长及生存有关的蛋白因子的优先翻译。而抑制PKCβII或者是消耗eIF4E则破坏了由RACK1介导的肝细胞癌的化疗抗性。

总的来说，该研究表明了RACK1很可能是与肝细胞癌的生长及存活有关的内源性因子。为此，研究人员表示，靶向RACK1很可能会成为一种有效的的策略来治疗肝细胞癌。

doi: 10.1172/JCI58488
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Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma

Yuanyuan Ruan, Linlin Sun, Yuqing Hao, Lijing Wang, Jiejie Xu, Wen Zhang, Jianhui Xie, Liang Guo, Lei Zhou, Xiaojing Yun, Hongguang Zhu, Aiguo Shen and Jianxin Gu.

Coordinated translation initiation is coupled with cell cycle progression and cell growth, whereas excessive ribosome biogenesis and translation initiation often lead to tumor transformation and survival. Hepatocellular carcinoma (HCC) is among the most common and aggressive cancers worldwide and generally displays inherently high resistance to chemotherapeutic drugs.We found that RACK1, the receptor for activated C-kinase 1, was highly expressed in normal liver and frequently upregulated in HCC. Aberrant expression of RACK1 contributed to in vitro chemoresistance as well as in vivo tumor growth of HCC.These effects depended on ribosome localization of RACK1. Ribosomal RACK1 coupled with PKCβII to promote the phosphorylation of eukaryotic initiation factor 4E (eIF4E), which led to preferential translation of the potent factors involved in growth and survival. Inhibition of PKCβII or depletion of eIF4E abolished RACK1-mediated chemotherapy resistance of HCC in vitro.Our results imply that RACK1 may function as an internal factor involved in the growth and survival of HCC and suggest that targeting RACK1 may be an efficacious strategy for HCC treatment.