Senescent hepatic stellate cells caused by deoxycholic acid modulates malignant behavior of hepatocellular carcinoma
Senescent hepatic stellate cells caused by deoxycholic acid modulates malignant behavior of hepatocellular carcinoma
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DOI：
10.1007/s00432-020-03374-9
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发表时间：
2020-09-01
影响因子：
3.6
通讯作者：
Tazuma, Susumu
中科院分区：
文献类型：
--
作者：
Phuong Thao Nguyen;Kanno, Keishi;Tazuma, Susumu
目的脱氧胆酸(DCA)是一种次级胆汁酸，在非酒精性脂肪性肝炎患者和实验性肝细胞癌动物的血清中有升高的报道，但其在肝癌恶性行为中的作用尚不清楚。本研究旨在探讨DCA对肝脏中非实质细胞的主要成分--肝星状细胞(HSCs)的影响及其对肝癌细胞的间接影响。方法体外培养人肝星状细胞系Lx2细胞，用DCA处理细胞。然后，将人肝癌细胞株Huh7细胞培养在DCA处理的Lx2的条件培养液中，观察其对恶性行为的后续影响。结果DCA导致Lx2细胞衰老，细胞增殖受阻于G0/1期，并诱导衰老相关分泌表型(SASP)因子的产生。为探讨肝星状细胞分泌SASP因子对DCA反应的影响，用诱导上皮间充质转化促进细胞迁移和侵袭的条件培养液处理肝癌细胞。这些变化在抗IL8或转化生长因子β的中和抗体的存在下被减弱。肝细胞癌手术标本的病理分析显示，在肝细胞癌周围的间质中检测到衰老的HSCs。结论DCA诱导的HSC衰老可能通过诱导SASP因子，尤其是IL8和TGF-β，在肝癌的恶性生物学行为中起重要作用。
Purpose Deoxycholic acid (DCA), a secondary bile acid, is reportedly increased in the serum of patients with nonalcoholic steatohepatitis and animals with experimentally induced hepatocellular carcinoma (HCC), but its contribution to malignant behaviors of HCC has not been precisely clarified. This study aimed to examine the effect of DCA on hepatic stellate cells (HSCs), a major component of nonparenchymal cells in the liver, and its subsequent indirect effect on HCC cells. Methods LX2 cells, a human HSC line, were treated with DCA in vitro. Then, HuH7 cells, a human hepatoma cell line, were incubated in conditioned media of DCA-treated LX2 to investigate the subsequent effect focusing on malignant behaviors. Results DCA resulted in cellular senescence in LX2 with the decreased cell proliferation via cell cycle arrest at G0/1 phase, together with the induction of senescence-associated secretory phenotype (SASP) factors. To investigate the influence of SASP factors secreted by HSCs in response to DCA, HCC cells were treated with conditioned media that promoted cell migration and invasion via induction of epithelial mesenchymal transition. These changes were attenuated in the presence of neutralizing antibody against IL8 or TGF beta. Pathological analysis of surgical specimens from HCC patients revealed that senescent HSCs were detected in the stroma surrounding HCC. Conclusion Our data suggest an important role of HSC senescence caused by DCA for the malignant biological behaviors of HCC via induction of SASP factors, particularly IL8 and TGF beta.