近日,，來自中山大學(xué)腫瘤防治中心的康鐵邦教授及其團(tuán)隊(duì)發(fā)現(xiàn)，在肝細(xì)胞癌中,，CHK1靶向脾酪氨酸激酶能夠促進(jìn)其水解,，則靶向CHK1/SYK(L)通路能成為一個(gè)很有潛力的HCC治療策略。
肝細(xì)胞癌(HCC)是目前最流行的惡性腫瘤之一,，能夠頑強(qiáng)抵抗化療或放療,。因此，確定HCC新的治療靶點(diǎn)更是迫在眉睫,。
在這項(xiàng)研究里,，他們發(fā)現(xiàn)，HCC患者的細(xì)胞周期檢測(cè)點(diǎn)激酶1(CHK1)被頻繁的過表達(dá),，而且這與不良預(yù)后結(jié)果一致,。進(jìn)一步研究發(fā)現(xiàn)，CHK1抑制劑GÖ6976能夠使HCC細(xì)胞對(duì)順鉑（一種廣譜抗癌藥物）敏感,，這表明CHK1可能具有促癌功能,。
他們發(fā)現(xiàn)，CHK1磷酸化了腫瘤抑制因子-脾酪氨酸激酶(L)(SYK[L]),，其磷酸化位點(diǎn)為Ser295,。此外,，CHK1磷酸化SYK[L]以后，促進(jìn)了SYK[L]隨后的蛋白酶體降解,。
而且,，在HCC細(xì)胞系，SYK(L)的非磷酸化突變體能夠更有效的抑制細(xì)胞增生,、集落形成,、細(xì)胞遷移及腫瘤生長(zhǎng)。
重要的是,，在HCC患者,，他們發(fā)現(xiàn)CHK1與SYK(L)的表達(dá)水平之間表現(xiàn)出很強(qiáng)的反相關(guān)關(guān)系。（生物谷Deepblue編譯）
doi: 10.1172/JCI61380
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CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma
Jian Hong, Kaishun Hu, Yunfei Yuan, Yi Sang, Qiangui Bu, Guihua Chen, Longjun Yang, Binkui Li, Pinzhu Huang, Dongtai Chen, Yi Liang, Ruhua Zhang, Jingxuan Pan, Yi-Xin Zeng and Tiebang Kang.
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies resistant to current chemotherapies or radiotherapies, which makes it urgent to identify new therapeutic targets for HCC.In this study, we found that checkpoint kinase 1 (CHK1) was frequently overexpressed and correlated with poor clinical outcome in patients with HCC. We further showed that the CHK1 inhibitor GÖ6976 was capable of sensitizing HCC cells to cisplatin, indicating that CHK1 may have oncogenic function in HCC.We found that CHK1 phosphorylated the tumor suppressor spleen tyrosine kinase (L)(SYK[L]) and identified the phosphorylation site at Ser295. Furthermore, CHK1 phosphorylation of SYK(L) promoted its subsequent proteasomal degradation.Expression of a nonphosphorylated mutant of SYK(L) was more efficient at suppressing proliferation, colony formation, mobility, and tumor growth in HCC lines.Importantly, a strong inverse correlation between the expression levels of CHK1 and SYK(L) was observed in patients with HCC.Collectively, our data demonstrate that SYK(L) is a substrate of CHK1 in tumor cells and suggest that targeting the CHK1/SYK(L) pathway may be a promising strategy for treating HCC.
