Dept of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
Dept of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
Biochem Biophys Res Commun. 2024 Nov 12;733:150709. doi: 10.1016/j.bbrc.2024.150709. Epub 2024 Sep 18.
SLC16A3/monocarboxylate transporter 4 (MCT4) regulates intracellular lactate transport and is highly expressed in many tumors, indicating poor prognosis. It may be related to inducing hypoxia, apoptosis and other mechanisms, but the study of MCT4 in HCC is far from complete. In this study, we first analyzed the expression of SLC16A3 in HCC tumor and non-tumor tissue samples based on TCGA data and immunohistochemistry. Subsequently, the effects of SLC16A3 expression on cell proliferation and invasion were analyzed using hepatocellular carcinoma (HCC) lines, and Western blot (WB) analysis was performed to explore the changes in pathway proteins and ferroptosis proteins. Finally, the drug sensitivity was tested by CCK8 kit. We found that SLC16A3 was significantly upregulated in tumor tissues, and was significantly correlated with TNM stage, histological grade, and macrovascular invasion. TCGA data and WB analysis showed that the high expression of SLC16A3 induced hypoxia, and knockdown could reverse hypoxia and inhibit ERK phosphorylation, thus limiting the malignant behavior of HCC cells. Moreover, knockdown of SLC16A3 significantly increased the level of lipid peroxidation and reactive oxygen species (ROS), while the expressions of GPX4, DHODH and SLC7A11 were inhibited. The expression of SLC16A3 affected the sensitivity of HCC cells to chemotherapy and targeted drugs, and RNA sequencing data suggested that the expression level influenced tumor microenvironment and response to immunotherapy. So, we draw a conclude that SLC16A3 is associated with poor prognosis of HCC. Inhibition of SLC16A3 expression is a potential therapeutic target for HCC.
SLC16A3/单羧酸转运蛋白 4（MCT4）调节细胞内乳酸转运，在许多肿瘤中高表达，提示预后不良。它可能与诱导缺氧、凋亡等机制有关，但 MCT4 在 HCC 中的研究还远未完成。在这项研究中，我们首先基于 TCGA 数据和免疫组织化学分析了 SLC16A3 在 HCC 肿瘤和非肿瘤组织样本中的表达。随后，使用肝细胞癌（HCC）细胞系分析了 SLC16A3 表达对细胞增殖和侵袭的影响，并进行了 Western blot（WB）分析，以探讨通路蛋白和铁死亡蛋白的变化。最后，通过 CCK8 试剂盒测试了药物敏感性。我们发现 SLC16A3 在肿瘤组织中显著上调，并且与 TNM 分期、组织学分级和大血管侵犯显著相关。TCGA 数据和 WB 分析表明，SLC16A3 的高表达诱导了缺氧，而敲低可以逆转缺氧并抑制 ERK 磷酸化，从而限制了 HCC 细胞的恶性行为。此外，敲低 SLC16A3 显著增加了脂质过氧化和活性氧（ROS）的水平，同时抑制了 GPX4、DHODH 和 SLC7A11 的表达。SLC16A3 的表达影响 HCC 细胞对化疗和靶向药物的敏感性，RNA 测序数据表明表达水平影响肿瘤微环境和对免疫疗法的反应。因此，我们得出结论，SLC16A3 与 HCC 的不良预后有关。抑制 SLC16A3 表达可能是 HCC 的潜在治疗靶点。
