尽管近年来免疫疗法显示出疗效，但肝癌仍是最致命的癌症之一，主要是由于该病的异质性。因此，有必要不断探索新的治疗方法。化学诱导的细胞分化是一种有前途的方法，它能够持续重塑基因表达谱并改变细胞命运。

受干细胞和重编程领域进展的启发，本文报道一种小分子混合物(SMC)，包括:SB431542 (TGF????抑制剂)，CHIR99021 (GSK3????抑制剂)、BIX01294 (H3K9甲基转移酶/G9a抑制剂)、全反式维甲酸(ATRA)均可诱导肝脏分化癌细胞，包括细胞系、原代癌细胞、癌干细胞和药物抗性细胞。

治疗后的细胞失去恶性特征，反而恢复肝细胞表型。当在体内应用时，SMC在肿瘤内诱导大范围的组织坏死或纤维化，而剩余的组织开始表达肝核因子4???? (HNF4????)，肝核标记物。SMC还会导致原位异种移植模型中的肿瘤消失和动物寿命延长。SMC强大的分化诱导作用是通过调节Akt/mTOR/HIF1????信号和代谢重编程，以及抑制Snail和增强HNF4????表达来实现的。化学诱导分化有可能在不考虑异质性的情况下有效治疗肝癌

ABSTRACT

Despite the efficacy demonstrated by immunotherapy recently, liver cancer still remains one of the deadliest cancers, mainly due to heterogeneity of this disease. Continuous exploration of new therapeutics is therefore necessary.Chemical-induced cell differentiation can serve as a promising approach, with its ability to consistently remodel gene expression profile and alter cell fate. Inspired by advances in stem cell and reprogramming field, here it is reported that a small molecule cocktail (SMC) consisted of: SB431542 (TGF???? inhibitor),CHIR99021 (GSK3???? inhibitor), BIX01294 (H3K9 methyltransferase/G9a inhibitor), and all-trans retinoic acid (ATRA), can induce differentiation of liver cancer cells including cell lines, primary cancer cells, cancer stem cells, and drug resistant cells. Treated cells lose malignant characteristics and regain hepatocyte phenotype instead. When applied in vivo, SMC induces wide range of tissue necrosis or fibrosis within the tumors, while remaining tissues begin to express hepatic nuclear factor 4???? (HNF4????), the hepatic nuclear

marker. SMC also leads to tumor abrogation in orthotopic xenograft models and life span extension of animals. The powerful differentiation induction of SMC is exerted through modulation of Akt/mTOR/HIF1???? signaling and metabolic reprogramming, as well as suppressing Snail and enhancing HNF4???? expression. Together, these results highlight that chemical-induced differentiation has the potential to effectively treat liver cancer disregard of heterogeneity

原文链接

https://pubmed.ncbi.nlm.nih.gov/35343115/

百度浏览   来源 : 医微客   

版权声明：本网站所有注明来源“医微客”的文字、图片和音视频资料，版权均属于医微客所有，非经授权，任何媒体、网站或个人不得转载，授权转载时须注明来源：”医微客”。本网所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，转载仅作观点分享，版权归原作者所有。不希望被转载的媒体或个人可与我们联系，我们将立即进行删除处理。 本站拥有对此声明的最终解释权。