<p>Membrane progesterone receptor α (mPRα)/ Progestin and adipoQ receptor family member 7(PAQR7), has been insufficiently studied in pan-cancer. This study analyzed its expression, diagnostic value, and correlations with clinical data, tumor stemness, genomic instability, prognosis, interacting molecules, RNA methylation phenotypes, and immune cell infiltration, immune-related genes, and immune checkpoints via multiple databases. It also evaluated mPRα’s effects on LUSC cell malignancy using cell counting kit-8 (CCK-8), colony formation, transwell, and flow cytometry, detected its expression in lung squamous cell carcinoma (LUSC) tissue microarray by immunohistochemistry (IHC) staining, and analyzed its overall survival (OS) correlation in LUSC via Kaplan-Meier curves. Results showed PAQR7 up-regulated and down-regulated in some cancers. It had diagnostic value in some cancers and correlated with clinical data, tumor stemness, genomic instability, and prognosis in some tumors. PAQR7 interacted with various molecules, focusing on hormone-mediated signaling pathways in biological process (BP), steroid binding in molecular function (MF), and chemical carcinogenesis-receptor activation in Kyoto Encyclopedia of Genes and Genomes (KEGG). PAQR7 was related to tumor angiogenesis, differentiation, and stemness. PAQR7 expression further showed associations with immune cell infiltration, related immune genes, and immune checkpoints. More importantly, validation experiments demonstrated that mPRα was aberrantly overexpressed in LUSC cells, and its knockdown impaired the malignant characteristics of LUSCs. In addition, higher mPRα protein expression was associated with a poor OS in LUSC patients. In conclusion, mPRα/PAQR7 was abnormally expressed in various cancers, and its high expression was associated with malignant phenotypes and poor prognosis in LUSC.</p>