Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China.
Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Room L10-56, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong, China.
J Exp Clin Cancer Res. 2022 Jun 28;41(1):211. doi: 10.1186/s13046-022-02424-z.
Tumor cells exhibited phenotypic and molecular characteristics similar to their lineage progenitor cells. Liver developmental signaling pathways are showed to be associated with HCC development and oncogenesis. The similarities of expression profiling between liver progenitors (LPs) and HCC suggest that understanding the molecular mechanism during liver development could provide insights into HCC.
To profile the dynamic gene expression during liver development, cells from an in vitro liver differentiation model and two paired hepatocellular carcinoma (HCC) samples were analyzed using deep RNA sequencing. The expression levels of selected genes were analyzed by qRT-PCR. Moreover, the role of a key transcription factor, pituitary homeobox 2 (PITX2), was characterized via in vitro and vivo functional assays. Furthermore, molecular mechanism studies were performed to unveil how PITX2C regulate the key developmental factors in LPs, thereby increasing the stemness of HCC.
PITX2 was found to exhibit a similar expression pattern to specific markers of LPs. PITX2 consists of three isoforms (PITX2A/B/C). The expression of PITX2 is associated with tumor size and overall survival rate, whereas only PITX2C expression is associated with AFP and differentiation in clinical patients. PITX2A/B/C has distinct functions in HCC tumorigenicity. PITX2C promotes HCC metastasis, self-renewal and chemoresistance. Molecular mechanism studies showed that PITX2C could up-regulate RALYL which could enhance HCC stemness via the TGF-β pathway. Furthermore, ChIP assays confirmed the role of PITX2C in regulating key developmental factors in LP.
PITX2C is a newly discovered transcription factor involved in hepatic differentiation and could increase HCC stemness by upregulating key transcriptional factors related to liver development.
肿瘤细胞表现出与其谱系祖细胞相似的表型和分子特征。肝发育信号通路与 HCC 的发生和癌变有关。肝祖细胞 (LP) 和 HCC 之间表达谱的相似性表明，了解肝发育过程中的分子机制可能为 HCC 提供新的见解。
为了分析肝发育过程中的动态基因表达，使用深度 RNA 测序分析了体外肝分化模型和两个配对肝癌 (HCC) 样本中的细胞。通过 qRT-PCR 分析了选定基因的表达水平。此外，通过体外和体内功能测定来表征关键转录因子垂体同源盒 2 (PITX2) 的作用。此外，进行了分子机制研究，以揭示 PITX2C 如何调节 LP 中的关键发育因子，从而增加 HCC 的干性。
发现 PITX2 与 LP 的特定标志物表现出相似的表达模式。PITX2 由三个异构体 (PITX2A/B/C) 组成。PITX2 的表达与肿瘤大小和总生存率相关，而只有 PITX2C 的表达与 AFP 和临床患者的分化相关。PITX2A/B/C 在 HCC 致瘤性中具有不同的功能。PITX2C 促进 HCC 转移、自我更新和化疗耐药性。分子机制研究表明，PITX2C 可以上调 RALYL，通过 TGF-β 途径增强 HCC 的干性。此外，ChIP 测定证实了 PITX2C 在调节 LP 中关键发育因子中的作用。
PITX2C 是一种新发现的参与肝分化的转录因子，可通过上调与肝发育相关的关键转录因子来增加 HCC 的干性。
