Yang Qinyan, Liang Yuxin, Shi Ying, Shang Jin, Huang Xiaolun
Liver Transplantation Center and HBP Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
J Cancer Res Clin Oncol. 2023 Nov;149(17):15499-15510. doi: 10.1007/s00432-023-05309-6. Epub 2023 Aug 30.
Hepatocellular carcinoma (HCC), featured with high prevalence and poor prognosis, is the major cause of cancer-related deaths worldwide. As a subgroup of liver cancer cells capable of differentiation, tumorigenesis and self-renewal, liver cancer stem cells (LCSCs) serve as one of the reasons leading to HCC progression and therapeutic resistance. Therefore, in-depth exploration of novel molecular biomarkers related to LSCSs is of great necessity. In our study, we found that human AlkB homolog H5 (ALKBH5) expression was enriched in LCSCs, which could foster proliferation, invasion and migration of the HCC cells. Mechanically, ALKBH5 positively mediated the expression of SOX4 via demethylation, and SOX4 promoted SHH expression at the transcriptional level to activate sonic hedgehog (SHH) signaling pathway. Furthermore, exosomes derived from CD133 HCC cells could transmit ALKBH5 into THP-1 cells, which might be associated with M2 polarization of macrophages. In summary, the ALKBH5/SOX4 axis plays a significant role in exacerbating LCSC properties via activating SHH signaling pathway, and ALKBH5 could be a critical effector related to macrophage M2 polarization. These findings might provide a promising new biomarker for HCC diagnosis and treatment.
肝细胞癌（HCC）发病率高且预后差，是全球癌症相关死亡的主要原因。作为具有分化、肿瘤发生和自我更新能力的肝癌细胞亚群，肝癌干细胞（LCSCs）是导致HCC进展和治疗耐药的原因之一。因此，深入探索与LCSCs相关的新型分子生物标志物非常必要。在我们的研究中，我们发现人烷基化修复蛋白H5（ALKBH5）在LCSCs中表达富集，它可促进HCC细胞的增殖、侵袭和迁移。机制上，ALKBH5通过去甲基化正向介导SOX4的表达，且SOX4在转录水平促进SHH表达以激活音猬因子（SHH）信号通路。此外，来自CD133 HCC细胞的外泌体可将ALKBH5传递至THP-1细胞，这可能与巨噬细胞的M2极化有关。总之，ALKBH5/SOX4轴通过激活SHH信号通路在加剧LCSC特性方面发挥重要作用，且ALKBH5可能是与巨噬细胞M2极化相关的关键效应因子。这些发现可能为HCC的诊断和治疗提供一种有前景的新生物标志物。
