Department of Colorectal Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Front Immunol. 2022 May 26;13:864244. doi: 10.3389/fimmu.2022.864244. eCollection 2022.
Pancreatic adenocarcinoma (PAAD) is a treatment-refractory cancer with poor prognosis. Accumulating evidence suggests that squalene epoxidase (SQLE) plays a pivotal role in the development and progression of several cancer types in humans. However, the function and underlying mechanism of SQLE in PAAD remain unclear.
SQLE expression data were downloaded from The Cancer Genome Atlas and the Genotype-Tissue Expression database. SQLE alterations were demonstrated based on the cBioPortal database. The upstream miRNAs regulating SQLE expression were predicted using starBase. The function of miRNA was validated by Western blotting and cell proliferation assay. The relationship between SQLE expression and biomarkers of the tumor immune microenvironment (TME) was analyzed using the TIMER and TISIDB databases. The correlation between SQLE and immunotherapy outcomes was assessed using Tumor Immune Dysfunction and Exclusion. The log-rank test was performed to compare prognosis between the high and low SQLE groups.
We demonstrated a potential oncogenic role of SQLE. SQLE expression was upregulated in PAAD, and it predicted poor disease-free survival (DFS) and overall survival (OS) in patients with PAAD. "Amplification" was the dominant type of SQLE alteration. In addition, this alteration was closely associated with the OS, disease-specific survival, DFS, and progression-free survival of patients with PAAD. Subsequently, hsa-miR-363-3p was recognized as a critical microRNA regulating SQLE expression and thereby influencing PAAD patient outcome. experiments suggested that miR-363-3p could knock down the expression of SQLE and inhibit the proliferation of PANC-1. SQLE was significantly associated with tumor immune cell infiltration, immune checkpoints (including PD-1 and CTLA-4), and biomarkers of the TME. KEGG and GO analyses indicated that cholesterol metabolism-associated RNA functions are implicated in the mechanisms of SQLE. SQLE was inversely associated with cytotoxic lymphocytes and predicted immunotherapy outcomes.
Collectively, our results indicate that cholesterol metabolism-related overexpression of SQLE is strongly correlated with tumor immune infiltration and immunotherapy outcomes in patients with PAAD.
胰腺导管腺癌（PAAD）是一种治疗难治性癌症，预后不良。越来越多的证据表明，角鲨烯环氧化酶（SQLE）在人类多种癌症的发生和发展中起着关键作用。然而，SQLE 在 PAAD 中的功能和潜在机制尚不清楚。
从癌症基因组图谱（TCGA）和基因-组织表达数据库中下载 SQLE 表达数据。基于 cBioPortal 数据库展示 SQLE 改变。使用 starBase 预测调节 SQLE 表达的上游 miRNA。通过 Western blot 和细胞增殖实验验证 miRNA 的功能。使用 TIMER 和 TISIDB 数据库分析 SQLE 表达与肿瘤免疫微环境（TME）生物标志物的关系。使用 Tumor Immune Dysfunction and Exclusion 评估 SQLE 与免疫治疗结果的相关性。使用对数秩检验比较高 SQLE 组和低 SQLE 组之间的预后。
我们证明了 SQLE 的潜在致癌作用。在 PAAD 中，SQLE 表达上调，并且预测 PAAD 患者无病生存（DFS）和总生存（OS）不良。“扩增”是 SQLE 改变的主要类型。此外，这种改变与 PAAD 患者的 OS、疾病特异性生存、DFS 和无进展生存密切相关。随后，hsa-miR-363-3p 被认为是一种关键的 miRNA，可调节 SQLE 表达，从而影响 PAAD 患者的预后。实验表明，miR-363-3p 可以下调 SQLE 的表达并抑制 PANC-1 的增殖。SQLE 与肿瘤免疫细胞浸润、免疫检查点（包括 PD-1 和 CTLA-4）和 TME 生物标志物显著相关。KEGG 和 GO 分析表明，胆固醇代谢相关 RNA 功能与 SQLE 的机制有关。SQLE 与细胞毒性淋巴细胞呈负相关，并预测免疫治疗结果。
总的来说，我们的研究结果表明，胆固醇代谢相关的 SQLE 过表达与 PAAD 患者的肿瘤免疫浸润和免疫治疗结果密切相关。
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