Dai Geyang, Sun Yue, Wei Rui, Xi Ling
Cancer Biology Research Center, Key Laboratory of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Curr Issues Mol Biol. 2023 Jul 22;45(7):6116-6139. doi: 10.3390/cimb45070386.
The podocan-like protein 1 (PODNL1), an important member of the small leucine-rich proteoglycans (SLRP) family, is a crucial component of the tumor microenvironment (TME). But its prognostic values and the role in the TME have not been systematically estimated in a pan-cancer setting. Targeting , a systematic exploration into the TCGA datasets, reconciling with the analyses of single-cell transcriptomes and immunotherapeutic cohorts in cancers, and validation by tissue microarray-based multiplex immunofluorescence staining was performed. PODNL1 was significantly correlated with the poor prognosis and immunotherapeutic responses in various cancers. In-depth demonstration of molecular mechanisms indicated that expressions were notably positively correlated with cancer-associated fibroblast (CAF) infiltration levels in 33 types of cancers. It also positively correlated with the pan-fibroblast TGF-β response signature score, and the hallmarks including TGF-β, TNF-α, inflammatory response, apical junction, epithelial-mesenchymal transition and hedgehog in pan-cancer. Furthermore, high expressions were positively related with the regulation of tumor-promoting TGF-β signaling through downregulating SMAD2/3:4 heterotrimer regulations transcription and up-regulating the pathway restricted SMAD protein phosphorylation. Single-cell transcriptome analyses and immunofluorescence validations indicated that was predominantly expressed in the cancer cells and CAFs in various cancers. Additionally, the heterogeneity of cancer genotype-phenotype cross-talking was also observed associated with . Our systematic study indicates that plays an important role in the complex regulation network of tumor progression, and lays a foundation for further exploration to develop as a valuable matrix-mediated biomarker for cancer immunotherapy and prognosis in a pan-cancer setting.
类足突蛋白1（PODNL1）是富含亮氨酸小分子蛋白聚糖（SLRP）家族的重要成员，是肿瘤微环境（TME）的关键组成部分。但其预后价值及在TME中的作用尚未在泛癌背景下进行系统评估。针对此，我们对TCGA数据集进行了系统探索，结合癌症单细胞转录组和免疫治疗队列分析，并通过基于组织芯片的多重免疫荧光染色进行验证。PODNL1在多种癌症中与不良预后和免疫治疗反应显著相关。分子机制的深入研究表明，其表达在33种癌症中与癌症相关成纤维细胞（CAF）浸润水平显著正相关。它还与泛成纤维细胞TGF-β反应特征评分以及泛癌中的TGF-β、TNF-α、炎症反应、顶端连接、上皮-间质转化和刺猬信号等特征正相关。此外，高表达通过下调SMAD2/3:4异源三聚体调控转录并上调途径限制的SMAD蛋白磷酸化，与促进肿瘤的TGF-β信号通路的调控正相关。单细胞转录组分析和免疫荧光验证表明，PODNL1在多种癌症的癌细胞和CAF中主要表达。此外，还观察到癌症基因型-表型相互作用的异质性与PODNL1有关。我们的系统研究表明，PODNL1在肿瘤进展的复杂调控网络中起重要作用，为进一步探索将其开发为泛癌背景下癌症免疫治疗和预后的有价值的基质介导生物标志物奠定了基础。
