Exosome CTLA-4 Regulates PTEN/CD44 Signal Pathway in Spleen Deficiency Internal Environment to Promote Invasion and Metastasis of Hepatocellular Carcinoma.
Exosome CTLA-4 Regulates PTEN/CD44 Signal Pathway in Spleen Deficiency Internal Environment to Promote Invasion and Metastasis of Hepatocellular Carcinoma.
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外泌体CTLA-4调控脾虚内环境PTEN/CD44信号通路促进肝癌侵袭转移
DOI：
10.3389/fphar.2021.757194
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发表时间：
2021
影响因子：
5.6
通讯作者：
Yu L
中科院分区：
文献类型：
--
作者：
Wang Y;Li P;Mao S;Mo Z;Cao Z;Luo J;Zhou M;Liu X;Zhang S;Yu L
肝细胞癌（HCC）是最常见的原发肿瘤之一，其发病机制复杂，难以筛查。目前尚无有效的治疗方法。在中医中，有很大比例的HCC患者被诊断为脾虚（SD）证，并给予补益中药治疗，具有显著的临床疗效。然而，SD在HCC中的作用和分子机制尚不清楚。本研究将40只小鼠随机分为4组：对照组、SD组、HCC组和SD-HCC组。采用利血平诱导和原位移植建立SD肝癌模型。通过细胞增殖、细胞凋亡、细胞划痕和transwell实验研究SD对肝癌细胞增殖、凋亡、侵袭和转移的影响。我们发现，与HCC组相比，SD-HCC组外泌体中细胞毒性T淋巴细胞抗原4 （CTLA-4）、程序性细胞死亡蛋白1 （PD-1）、磷酸酶和紧张素同源物（PTEN）以及AKT（也称为蛋白激酶B或PKB）的蛋白表达上调。此外，SD-HCC组外泌体的转移和自我更新比HCC组更具侵袭性，这可以通过添加CTLA-4抑制剂部分逆转。进一步研究表明，在SD内环境中，CTLA-4通过调控PTEN/CD44通路促进肿瘤侵袭转移。综上所述，我们的研究结果表明，在内环境SD过程中，外泌体CTLA-4调节PTEN/CD44信号通路，促进肝癌的增殖、自我更新和转移。
Hepatocellular carcinoma (HCC) is one of the most common primary cancers, and its pathogenesis is complicated and difficult to screen. Currently, there is no effective treatment. In traditional Chinese medicine, a large proportion of patients with HCC have been diagnosed with spleen deficiency (SD) syndrome and treated with tonifying traditional Chinese medicine, which has significant clinical efficacy. However, the role and molecular mechanism of SD in HCC remain unclear. In this study, 40 mice were randomly divided into four groups: control, SD, HCC, and SD-HCC groups. The liver cancer model of SD was established by reserpine induction and orthotopic transplantation. The effects of SD on the proliferation, apoptosis, invasion, and metastasis of HCC cells were studied by cell proliferation, cell apoptosis, cell scratch, and transwell assay. We found that compared with the HCC group, the protein expressions of cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), phosphatase and tensin homolog (PTEN), and AKT (also known as protein kinase B or PKB) in the exosomes of the SD-HCC group were upregulated. In addition, the metastases and self-renewal of exosomes in the SD-HCC group were more aggressive than those in the HCC group, which could be partially reversed with the addition of CTLA-4 inhibitors. Further studies showed that in the internal environment of SD, CTLA-4 promoted tumor invasion and metastasis by regulating the PTEN/CD44 pathway. In conclusion, our findings suggest that during SD in the internal environment, exosome CTLA-4 regulates the PTEN/CD44 signal pathway to promote the proliferation, self-renewal, and metastasis of liver cancer.
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影响因子：
16.2
作者：
Feng, Rui-Mei;Zong, Yi-Nan;Xu, Rui-Hua
通讯作者：
Xu, Rui-Hua
影响因子：
8.8
作者：
Cogdill AP;Andrews MC;Wargo JA
通讯作者：
Wargo JA
影响因子：
4.4
作者：
Goenka, Radhika;Xu, Zhenghai;Akamatsu, Yoshiko
通讯作者：
Akamatsu, Yoshiko
影响因子：
--
作者：
Mo Z;Cao Z;Yu L;Wang Y;Li P;Lin Y;Zhang S
通讯作者：
Zhang S
影响因子：
9.7
作者：
Cao Dai Phung;Thanh Tung Pham;Kim, Jong Oh
通讯作者：
Kim, Jong Oh