Zhong Ming, Wang Xiaohua, Zhu Enyi, Gong Lian, Fei Lingyan, Zhao Liang, Wu Keping, Tang Chun, Zhang Lizhen, Wang Zhongli, Zheng Zhihua
Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, China.
Front Genet. 2022 Jun 29;13:905051. doi: 10.3389/fgene.2022.905051. eCollection 2022.
Clear cell renal cell carcinoma (ccRCC) is a common urinary system malignant tumor with a high incidence and recurrence rate. Pyroptosis is a kind of programmed cell death caused by inflammasomes. More and more evidence had confirmed that pyroptosis plays a very significant part in cancer, and it is controversial whether pyroptosis promotes or inhibits tumors. Consistently, its potential role in ccRCC treatment efficacy and prognosis remains unclear. In this study, we systematically investigated the role of pyroptosis in the ccRCC samples from The Cancer Genome Atlas (TCGA) database. Based on the differentially expressed pyroptosis-related genes (DEPRGs), we identified three pyroptosis subtypes with different clinical outcomes, immune signatures, and responses to immunotherapy. Gene set variation analysis (GSVA), Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that pyroptosis activation meant infiltration of more immune cells that is conducive to tumor progression. To further investigate the immunomodulatory effect of pyroptosis in ccRCC, we constructed a pyroptosis-score based on the common differential prognostic genes of the three pyroptosis subtypes. It was found that patients with high pyroptosis-score were in an unfavorable immune environment and the prognosis was worse. Gene set enrichment analysis suggested that immune-related biological processes were activated in the high pyroptosis-score group. Then, the least absolute shrinkage and selection operator (LASSO) Cox regression was implemented for constructing a prognostic model of eight pyroptosis-related long noncoding RNAs (PRlncRNAs) in the TCGA dataset, and the outcomes revealed that, compared with the low-risk group, the model-based high-risk group was intently associated with poor overall survival (OS). We further explored the relationship between high- and low-risk groups with tumor microenvironment (TME), immune infiltration, and drug therapy. Finally, we constructed and confirmed a robust and reliable PRlncRNA pairs prediction model of ccRCC, identified PRlncRNA, and verified it by experiments. Our findings suggested the potential role of pyroptosis in ccRCC, offering new insights into the prognosis of ccRCC and guiding effectual targeted therapy and immunotherapy.
透明细胞肾细胞癌（ccRCC）是一种常见的泌尿系统恶性肿瘤，发病率和复发率都很高。细胞焦亡是一种由炎性小体引起的程序性细胞死亡。越来越多的证据证实，细胞焦亡在癌症中起着非常重要的作用，而细胞焦亡是促进还是抑制肿瘤仍存在争议。同样，其在ccRCC治疗效果和预后中的潜在作用仍不清楚。在本研究中，我们系统地研究了细胞焦亡在来自癌症基因组图谱（TCGA）数据库的ccRCC样本中的作用。基于差异表达的细胞焦亡相关基因（DEPRG），我们鉴定出三种具有不同临床结果、免疫特征和免疫治疗反应的细胞焦亡亚型。基因集变异分析（GSVA）、基因本体（GO）分析和京都基因与基因组百科全书（KEGG）分析表明，细胞焦亡激活意味着更多免疫细胞浸润，这有利于肿瘤进展。为了进一步研究细胞焦亡在ccRCC中的免疫调节作用，我们基于三种细胞焦亡亚型的共同差异预后基因构建了一个细胞焦亡评分。发现细胞焦亡评分高的患者处于不利的免疫环境中，预后较差。基因集富集分析表明，免疫相关生物学过程在高细胞焦亡评分组中被激活。然后，实施最小绝对收缩和选择算子（LASSO）Cox回归，以构建TCGA数据集中八个细胞焦亡相关长链非编码RNA（PRlncRNA）的预后模型，结果显示，与低风险组相比，基于模型的高风险组与较差的总生存期（OS）密切相关。我们进一步探讨了高风险组和低风险组与肿瘤微环境（TME）、免疫浸润和药物治疗之间的关系。最后，我们构建并验证了一个强大且可靠的ccRCC的PRlncRNA对预测模型，鉴定了PRlncRNA，并通过实验进行了验证。我们的研究结果表明了细胞焦亡在ccRCC中的潜在作用，为ccRCC的预后提供了新的见解，并指导有效的靶向治疗和免疫治疗。
