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Thermosensation is vital for the survival, propagation, and adaption of all organisms, but its mechanism is not fully understood yet. Here, we find that TMC6, a membrane protein of unknown function, is highly expressed in dorsal root ganglion (DRG) neurons and functions as a Gαq-coupled G protein-coupled receptor (GPCR)-like receptor to sense noxious heat. TMC6-deficient mice display a substantial impairment in noxious heat sensation while maintaining normal perception of cold, warmth, touch, and mechanical pain. Further studies show that TMC6 interacts with Gαq via its intracellular C-terminal region spanning Ser780 to Pro810. Specifically disrupting such interaction using polypeptide in DRG neurons, genetically ablating Gαq, or pharmacologically blocking Gαq-coupled GPCR signaling can replicate the phenotype of TMC6 deficient mice regarding noxious heat sensation. Noxious heat stimulation triggers intracellular calcium release from the endoplasmic reticulum (ER) of TMC6- but not control vector-transfected HEK293T cell, which can be significantly inhibited by blocking PLC or IP3R. Consistently, noxious heat-induced intracellular Ca2+ release from ER and action potentials of DRG neurons largely reduced when ablating TMC6 or blocking Gαq/PLC/IP3R signaling pathway as well. In summary, our findings indicate that TMC6 can directly function as a Gαq-coupled GPCR-like receptor sensing noxious heat.
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Background: Adenocarcinoma of the rete testis (AORT) is an extremely rare and aggressive tumor with a poor prognosis. Its etiology and pathological characteristics have not been extensively studied, making accurate diagnosis and appropriate management challenging. AORT, an invasive testicular tumor with a mortality rate of 46%, treatment typically involves radical orchiectomy, retroperitoneal pelvic lymph node dissection (RPLND), adjuvant chemotherapy, and/or ongoing monitoring, but the response to conventional radiation and chemotherapy is limited. At present, no effective targeted therapy for AORT has been found. Case description: In this case report, we present the clinical scenario of a 50-year-old male patient initially diagnosed with a right testicular hydrocele, who subsequently underwent eversion of the parietal tunica vaginalis. Postoperative pathological analysis revealed metastatic clear cell renal cell carcinoma (ccRCC). PET/CT demonstrated findings suggestive of left renal upper pole carcinoma with involvement of the right scrotum, para-aortic region, bilateral iliac vessels, bilateral inguinal region, and multiple metastases. Sunitinib, a tyrosine kinase inhibitor, is commonly employed in the treatment of ccRCC. The patient underwent treatment with sunitinib for a duration of 20 months, resulting in the inactivation of multiple metastases. Following this, a radical orchiectomy was performed, and the postoperative pathology confirmed the presence of AORT. This article provides a comprehensive account of the patient's medical history, diagnostic process, treatment modalities, and subsequent follow-up observations. Conclusions: This case report highlights the successful use of targeted therapy with sunitinib in a patient with AORT. The patient showed a positive response to targeted therapy. This study not only provides a novel foundation for the treatment of AORT, but also offers valuable insights for future treatment strategies in managing this particular form of testicular cancer.
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Background: The cluster of differentiation 48 (CD48) is a member of the signaling lymphocyte activation molecule family, constitutively expressed on most hematopoietic cells. CD48 was reported to affect immune regulation in certain tumors, thereby influencing tumor development and prognosis, but its impact on the prognosis and immune infiltration in pan-cancer remains unclear. Material and Methods: We systematically analyzed the raw data from The Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER), and Tumor Immune Dysfunction and Exclusion (TIDE) databases. Initially, we investigated the differences in CD48 expression between pan-cancer and adjacent normal tissues. Then, the correlation analysis of CD48 with tumor mutational burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), and immune-related genes was evaluated. Moreover, bioinformatics tools: ESTIMATE and gene set enrichment analysis (GSEA) were used for tumor immunology analysis in pan-cancer. We performed validation studies including quantitative real-time PCR (qPCR) and Western blotting. Results: Differential analysis revealed that CD48 was significantly altered in pan-cancer as compared with normal tissues. Meanwhile, the survival analysis demonstrated that CD48 strongly correlated with overall survival (OS), disease-free interval (DFI), progression-free interval (PFI), and disease-specific survival (DSS), indicating its crucial role in the tumor patients' prognosis. CD48 expression was also associated with TMB and MSI levels in 17 and 14 types of pan-cancers, respectively. Moreover, CD48 was linked to immune infiltrating cells and stromal components in the TME. Conclusion: Concludingly, patients with pan-cancer may benefit from evaluating CD48 as a prognostic and immunotherapy response biomarker.