Ferroptosis-related gene HIC1 in the prediction of the prognosis and immunotherapeutic efficacy with immunological activity

Abstract

BackgroundHypermethylated in Cancer 1 (HIC1) was originally confirmed as a tumor suppressor and has been found to be hypermethylated in human cancers. Although growing evidence has supported the critical roles of HIC1 in cancer initiation and development, its roles in tumor immune microenvironment and immunotherapy are still unclear, and no comprehensive pan-cancer analysis of HIC1 has been conducted.MethodsHIC1 expression in pan-cancer, and differential HIC1 expression between tumor and normal samples were investigated. Immunohistochemistry (IHC) was employed to validate HIC1 expression in different cancers by our clinical cohorts, including lung cancer, sarcoma (SARC), breast cancer, and kidney renal clear cell carcinoma (KIRC). The prognostic value of HIC1 was illustrated by Kaplan-Meier curves and univariate Cox analysis, followed by the genetic alteration analysis of HIC1 in pan-cancer. Gene Set Enrichment Analysis (GSEA) was conducted to illustrate the signaling pathways and biological functions of HIC1. The correlations between HIC1 and tumor mutation burden (TMB), microsatellite instability (MSI), and the immunotherapy efficacy of PD-1/PD-L1 inhibitors were analyzed by Spearman correlation analysis. Drug sensitivity analysis of HIC1 was performed by extracting data from the CellMiner™ database.ResultsHIC1 expression was abnormally expressed in most cancers, and remarkable associations between HIC1 expression and prognostic outcomes of patients in pan-cancer were detected. HIC1 was significantly correlated with T cells, macrophages, and mast cell infiltration in different cancers. Moreover, GSEA revealed that HIC1 was significantly involved in immune-related biological functions and signaling pathways. There was a close relationship of HIC1 with TMB and MSI in different cancers. Furthermore, the most exciting finding was that HIC1 expression was significantly correlated with the response to PD-1/PD-L1 inhibitors in cancer treatment. We also found that HIC1 was significantly correlated with the sensitivity of several anti-cancer drugs, such as axitinib, batracylin, and nelarabine. Finally, our clinical cohorts further validated the expression pattern of HIC1 in cancers.ConclusionsOur investigation provided an integrative understanding of the clinicopathological significance and functional roles of HIC1 in pan-cancer. Our findings suggested that HIC1 can function as a potential biomarker for predicting the prognosis, immunotherapy efficacy, and drug sensitivity with immunological activity in cancers.

Ferroptosis in lung cancer: dual role, multi-level regulation, and new therapeutic strategies

“…The amalgamation of immunotherapy with GAPDH-targeted ferroptosis induction in LUAD could unveil a novel therapeutic avenue ( 59 ). Furthermore, Hyper-methylated In Cancer 1 (HIC1) in cancers can not only predict the prognosis (including lung cancer) but also predict the effects of immunotherapy and drug sensitivity, marking HIC1 as a potential biomarker with immune activity ( 82 ).…”

Revolutionizing breast cancer treatment: Harnessing the related mechanisms and drugs for regulated cell death (Review)

“…Notably, HIC1 expression varies across different clinical stages of breast cancer. Furthermore, HIC1 significantly participates in immune-related biological functions and signaling pathways, with its expression being directly associated with the response to PD-1/PD-L1 inhibitors in cancer therapy ( 174 ). Beyond enhancing the chemotherapeutic efficacy (as aforementioned), ferroptosis can also potentiate radiotherapy in breast cancer.…”

SPP1 could be an immunological and prognostic biomarker: From pan‐cancer comprehensive analysis to osteosarcoma validation

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