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Abstract：
Hypermethylated 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.
HIC1 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.
HIC1 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.
Our 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.
HIC1 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.
HIC1 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.
Our 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.
摘要：
癌症1中的高甲基化(HIC1)最初被确认为肿瘤抑制因子,并且已经发现在人类癌症中高甲基化。尽管越来越多的证据支持HIC1在癌症发生和发展中的关键作用，其在肿瘤免疫微环境和免疫治疗中的作用尚不清楚，并且没有对HIC1进行全面的泛癌症分析。
■HIC1在泛癌症中的表达，研究了肿瘤和正常样品之间的差异HIC1表达。我们的临床队列采用免疫组织化学（IHC）来验证HIC1在不同癌症中的表达，包括肺癌,肉瘤(SARC),乳腺癌,肾透明细胞癌（KIRC）。Kaplan-Meier曲线和单因素Cox分析显示HIC1的预后价值,其次是泛癌中HIC1的遗传改变分析。进行基因集富集分析(GSEA)以说明HIC1的信号传导途径和生物学功能。HIC1与肿瘤突变负荷(TMB)的相关性微卫星不稳定性（MSI），采用Spearman相关性分析PD-1/PD-L1抑制剂的免疫治疗效果。通过从CellMiner™数据库提取数据进行HIC1的药物敏感性分析。
■HIC1表达在大多数癌症中异常表达，并检测到HIC1表达与泛癌症患者预后结果之间的显著关联。HIC1与T细胞显著相关,巨噬细胞，和肥大细胞浸润在不同的癌症。此外，GSEA显示HIC1显著参与免疫相关的生物学功能和信号通路。在不同的癌症中，HIC1与TMB和MSI密切相关。此外，最令人兴奋的发现是HIC1表达与癌症治疗中PD-1/PD-L1抑制剂的应答显著相关.我们还发现HIC1与几种抗癌药物的敏感性显著相关,比如阿西替尼，batracylin,和奈拉滨。最后,我们的临床队列进一步验证了HIC1在癌症中的表达模式.
■我们的研究提供了对HIC1在泛癌症中的临床病理意义和功能作用的综合理解。我们的研究结果表明，HIC1可以作为预测预后的潜在生物标志物。免疫治疗疗效，以及在癌症中具有免疫活性的药物敏感性。
■HIC1在泛癌症中的表达，研究了肿瘤和正常样品之间的差异HIC1表达。我们的临床队列采用免疫组织化学（IHC）来验证HIC1在不同癌症中的表达，包括肺癌,肉瘤(SARC),乳腺癌,肾透明细胞癌（KIRC）。Kaplan-Meier曲线和单因素Cox分析显示HIC1的预后价值,其次是泛癌中HIC1的遗传改变分析。进行基因集富集分析(GSEA)以说明HIC1的信号传导途径和生物学功能。HIC1与肿瘤突变负荷(TMB)的相关性微卫星不稳定性（MSI），采用Spearman相关性分析PD-1/PD-L1抑制剂的免疫治疗效果。通过从CellMiner™数据库提取数据进行HIC1的药物敏感性分析。
■HIC1表达在大多数癌症中异常表达，并检测到HIC1表达与泛癌症患者预后结果之间的显著关联。HIC1与T细胞显著相关,巨噬细胞，和肥大细胞浸润在不同的癌症。此外，GSEA显示HIC1显著参与免疫相关的生物学功能和信号通路。在不同的癌症中，HIC1与TMB和MSI密切相关。此外，最令人兴奋的发现是HIC1表达与癌症治疗中PD-1/PD-L1抑制剂的应答显著相关.我们还发现HIC1与几种抗癌药物的敏感性显著相关,比如阿西替尼，batracylin,和奈拉滨。最后,我们的临床队列进一步验证了HIC1在癌症中的表达模式.
■我们的研究提供了对HIC1在泛癌症中的临床病理意义和功能作用的综合理解。我们的研究结果表明，HIC1可以作为预测预后的潜在生物标志物。免疫治疗疗效，以及在癌症中具有免疫活性的药物敏感性。
