4.5 Article

Small Leucine-Rich Proteoglycan PODNL1 Identified as a Potential Tumor Matrix-Mediated Biomarker for Prognosis and Immunotherapy in a Pan-Cancer Setting

Journal

CURRENT ISSUES IN MOLECULAR BIOLOGY
Volume 45, Issue 7, Pages 6116-6139

Publisher

MDPI
DOI: 10.3390/cimb45070386

Keywords

podocan-like protein 1 (PODNL1); pan-cancer; small leucine-rich proteoglycans (SLRPs); extracellular matrix (ECM); matrix-mediated biomarker; immunotherapy

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PODNL1, a member of SLRP family, plays a crucial role in the tumor microenvironment and has significant correlations with prognosis and immunotherapeutic responses in various cancers. It is closely associated with cancer-associated fibroblast infiltration levels and participates in the complex regulation network of tumor progression, indicating its potential as a biomarker for cancer treatment and prognosis.
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 PODNL1, 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 PODNL1 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-& beta; response signature score, and the hallmarks including TGF-& beta;, TNF-& alpha;, inflammatory response, apical junction, epithelial-mesenchymal transition and hedgehog in pan-cancer. Furthermore, high PODNL1 expressions were positively related with the regulation of tumor-promoting TGF-& beta; 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 PODNL1 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 PODNL1. Our systematic study indicates that PODNL1 plays an important role in the complex regulation network of tumor progression, and lays a foundation for further exploration to develop PODNL1 as a valuable matrix-mediated biomarker for cancer immunotherapy and prognosis in a pan-cancer setting.

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