CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma.
CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma.
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CD24通过激活肝细胞癌自噬调节索拉非尼耐药
DOI：
10.1038/s41419-018-0681-z
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发表时间：
2018-05-29
影响因子：
9
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Lu S;Yao Y;Xu G;Zhou C;Zhang Y;Sun J;Jiang R;Shao Q;Chen Y
肝细胞癌是世界上最常见的实体癌之一。索拉非尼被认为是治疗晚期肝细胞癌的一种方法。然而，由于耐药性的发展，索拉非尼的临床疗效已严重受损，其确切的耐药机制仍很大程度上仍不清楚。在这里，我们发现细胞表面分子CD24在肿瘤组织和对索拉非尼耐药的肝癌细胞系中过表达。此外，CD24表达水平与索拉非尼耐药呈正相关。在对索拉非尼耐药的肝癌细胞系中，CD24缺失导致对索拉非尼的敏感性显著增加。此外，我们发现CD24相关的索拉非尼耐药伴随着自噬的激活，并且可以通过药物抑制剂或必要的自噬基因敲除来抑制自噬。在进一步的研究中，我们发现CD24的过表达还会导致PP2A蛋白产量的增加，并诱导mTOR/AKT途径的失活，从而增强自噬水平。这些结果表明CD24通过激活肝细胞癌中的自噬来调节索拉非尼的耐药性。这是首次报道CD24、自噬和索拉非尼耐药之间的关系。综上所述，自噬调节与CD24靶向治疗相结合是一种很有前途的肝癌治疗策略。
Hepatocellular carcinoma is one of most common solid cancers worldwide. Sorafenib is indicated as a treatment for advanced hepatocellular carcinoma (HCC). However, the clinical efficacy of sorafenib has been severely compromised by the development of drug resistance, and the precise mechanisms of drug resistance remain largely unknown. Here we found that a cell surface molecule, CD24, is overexpressed in tumor tissues and sorafenib-resistant hepatocellular carcinoma cell lines. Moreover, there is a positive correlation between CD24 expression levels and sorafenib resistance. In sorafenib-resistant HCC cell lines, depletion of CD24 caused a notable increase of sorafenib sensitivity. In addition, we found that CD24-related sorafenib resistance was accompanied by the activation of autophagy and can be blocked by the inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown. In further research, we found that CD24 overexpression also leads to an increase in PP2A protein production and induces the deactivation of the mTOR/AKT pathway, which enhances the level of autophagy. These results demonstrate that CD24 regulates sorafenib resistance via activating autophagy in HCC. This is the first report to describe the relationships among CD24, autophagy, and sorafenib resistance. In conclusion, the combination of autophagy modulation and CD24 targeted therapy is a promising therapeutic strategy in the treatment of HCC.
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影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
--
作者：
Majores M;Schindler A;Fuchs A;Stein J;Heukamp L;Altevogt P;Kristiansen G
通讯作者：
Kristiansen G
影响因子：
11.2
作者：
Baumann, P;Cremers, N;Sleeman, JP
通讯作者：
Sleeman, JP
影响因子：
45.3
作者：
Johnson, Philip J.;Berhane, Sarah;Toyoda, Hidenori
通讯作者：
Toyoda, Hidenori
影响因子：
3.3
作者：
Fujita, Naonobu;Hayashi-Nishino, Mitsuko;Yoshimori, Tamotsu
通讯作者：
Yoshimori, Tamotsu