Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China.
Medical School, Southeast University, Nanjing, 210000, China.
Oncol Res. 2024 May 23;32(6):1063-1078. doi: 10.32604/or.2024.047078. eCollection 2024.
Hepatocellular carcinoma (HCC) is a malignancy known for its unfavorable prognosis. The dysregulation of the tumor microenvironment (TME) can affect the sensitivity to immunotherapy or chemotherapy, leading to treatment failure. The elucidation of PHLDA2's involvement in HCC is imperative, and the clinical value of PHLDA2 is also underestimated. Here, bioinformatics analysis was performed in multiple cohorts to explore the phenotype and mechanism through which PHLDA2 may affect the progression of HCC. Then, the expression and function of PHLDA2 were examined via the qRT-PCR, Western Blot, and MTT assays. Our findings indicate a substantial upregulation of PHLDA2 in HCC, correlated with a poorer prognosis. The methylation levels of PHLDA2 were found to be lower in HCC tissues compared to normal liver tissues. Besides, noteworthy associations were observed between PHLDA2 expression and immune infiltration in HCC. In addition, PHLDA2 upregulation is closely associated with stemness features and immunotherapy or chemotherapy resistance in HCC. experiments showed that sorafenib or cisplatin significantly up-regulated PHLDA2 mRNA levels, and PHLDA2 knockdown markedly decreased the sensitivity of HCC cells to chemotherapy drugs. Meanwhile, we found that TGF-β induced the expression of PHLDA2 . The GSEA and experiment indicated that PHLDA2 may promote the HCC progression via activating the AKT signaling pathway. Our study revealed the novel role of PHLDA2 as an independent prognostic factor, which plays an essential role in TME remodeling and treatment resistance in HCC.
肝细胞癌 (HCC) 是一种预后不良的恶性肿瘤。肿瘤微环境 (TME) 的失调会影响免疫治疗或化疗的敏感性，导致治疗失败。阐明 PHLDA2 在 HCC 中的作用至关重要，同时也低估了 PHLDA2 的临床价值。在这里，我们通过多队列的生物信息学分析来探讨 PHLDA2 影响 HCC 进展的表型和机制。然后，通过 qRT-PCR、Western Blot 和 MTT 实验检测 PHLDA2 的表达和功能。我们的研究结果表明，PHLDA2 在 HCC 中显著上调，与预后不良相关。与正常肝组织相比，PHLDA2 在 HCC 组织中的甲基化水平较低。此外，还观察到 PHLDA2 表达与 HCC 中的免疫浸润之间存在显著相关性。此外，PHLDA2 的上调与 HCC 中的干性特征以及免疫治疗或化疗耐药性密切相关。实验表明，索拉非尼或顺铂显著上调 PHLDA2 mRNA 水平，而 PHLDA2 敲低显著降低 HCC 细胞对化疗药物的敏感性。同时，我们发现 TGF-β 诱导 PHLDA2 的表达。GSEA 和实验表明，PHLDA2 可能通过激活 AKT 信号通路促进 HCC 的进展。我们的研究揭示了 PHLDA2 作为一个独立的预后因素的新作用，它在 HCC 的肿瘤微环境重塑和治疗耐药性中起着重要作用。
