Bioinformatics analysis of CMTM family in pan-cancer and preliminary exploration of CMTM6 in bladder cancer.

BACKGROUND: The chemokine-like factor (CKLF)-like Marvel transmembrane structural domain (CMTM) family is widely expressed in the tumor and immune systems and is essential in human cancer progression. However, the multi-omic profile of CMTM family genes and their role in tumor patient prognosis and immune microenvironment have not been explored. METHODS: We collected data from 33 cancers and 33 non-cancers and then comprehensively analyzed the basal expression levels of CMTM family genes in normal human tissues as well as abnormal expression in diseases, genomic alterations, diagnostic and prognostic roles, subcellular localization, pathway enrichment, the immune microenvironment, associations with immune checkpoints, and drug sensitivities as well as to predict the immunotherapeutic response of patients to ICIs and targeting of small molecule drugs, the above results were validated by immunohistochemical staining, pathology sections and experiments. We also performed protein docking of immune checkpoints binding to CMTM6 and screening of small molecule drugs targeting CMTM6 based on mass spectrometry results and molecular docking techniques. Finally, we experimentally confirmed the role of CMTM6 in bladder cancer. RESULTS: We found differential expression and diagnostic biomarker value of the CMTMs family in diseases (cancer and non-cancer). CMTMs were also found to play a key role in pan-cancer with the tumor microenvironment. CMTMs were closely associated with common immune checkpoints, TMB and MSI, so we scored CMTMs based on CMTMs expression in patients undergoing ICI, and patients with lower scores had better survival and showed higher immunotherapy response after immunotherapy. Finally, molecular docking was used to identify small molecule inhibitors that could target CMTM6 and binding poses of CMTM6 to other immune checkpoint genes. Finally, it was determined experimentally that knockdown of CMTM6 gene expression inhibited the proliferation and invasion of bladder cancer cells. CONCLUSIONS: Our findings provide a valuable strategy to guide the diagnostic and therapeutic direction of CMTM family genes in disease.

An RRx-001 Analogue With Potent Anti-NLRP3 Inflammasome Activity but Without High-Energy Nitro Functional Groups.

NLRP3 inflammasome is involved in the pathology of multiple human inflammatory diseases but there are still no clinically available medications targeting the NLRP3 inflammasome. We have previously identified RRx-001 as a highly selective and potent NLRP3 inhibitor, however, it contains high-energy nitro functional groups and may cause potential processing problems and generates highly toxic oxidants. Here, we show that compound 149-01, an RRx-001 analogue without high-energy nitro functional groups, is a potent, specific and covalent NLRP3 inhibitor. Mechanistically, 149-01 binds directly to cysteine 409 of NLRP3 to block the NEK7-NLRP3 interaction, thereby preventing NLRP3 inflammasome complex assembly and activation. Furthermore, treatment with 149-01 effectively alleviate the severity of several inflammatory diseases in mice, including lipopolysaccharide (LPS)-induced systemic inflammation, monosodium urate crystals (MSU)-induced peritonitis and experimental autoimmune encephalomyelitis (EAE). Thus, our results indicate that 149-01 is a potential lead for developing therapeutic agent for NLRP3-related inflammatory diseases.

miR-1251-5p Overexpression Inhibits Proliferation, Migration, and Immune Escape in Clear Cell Renal Cell Carcinoma by Targeting NPTX2.

Background: miR-1251-5p was identified as a tumor suppressor in a variety of malignancies; however, its biological function in clear cell renal cell carcinoma (ccRCC) is unknown. Methods: The Cancer Genome Atlas (TCGA) database was used to download expression information, including miR-1251-5p, in 521 ccRCC tissues and 71 ordinary tissues, and bioinformatics was used to explore possible target mRNAs. The relationship between miR-1251-5p, target mRNA activity, and clinical factors was examined. To estimate the biological activity of miR-1251-5p and target mRNA in ccRCC cells, we used MTT, colony formation, enzyme-linked immunosorbent, and Transwell assays. We employed a dual-luciferase reporter assay and a western blot to examine the molecular mechanisms of miR-1251-5p in ccRCC cells. In addition, the expressions of miR-1251-5p and target mRNA were further verified in the GEO database. Results: Our findings revealed that miR-1251-5p binds with NPTX2's 3'-UTR. In TCGA and GEO datasets, miR-1251-5p activity is found to be lower in ccRCC tissues than that in nearby conventional tissues, although NPTX2 activity is higher. In ccRCC sufferers, miR-1251-5p and NPTX2 act as biomarkers that indicate a bad prognosis. Meanwhile, in miR-1251-5p tissues, NPTX2 expression and multiple clinical variables (survival status, grade, T staging, N staging, M staging, and clinical stage) had significant differences (p < 0.05). Structurally, miR-1251-5p inhibited proliferation, migration, and immune escape of ccRCC cells by targeting NPTX2. Conclusion: Our findings indicate that miR-1251-5p constrained ccRCC cell advancement, migration, and immune evasion via targeting NPTX2, providing novel insights into ccRCC target treatment.

Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity.

PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor survival. Although the intrinsic tumour-suppressor function of PTEN has been well established, evidence of its role in the tumour immune microenvironment is lacking. Here, we show that chemotherapy-induced antitumour immune responses and tumour suppression rely on myeloid-cell PTEN, which is essential for chemotherapy-induced activation of the NLRP3 inflammasome and antitumour immunity. PTEN directly interacts with and dephosphorylates NLRP3 to enable NLRP3-ASC interaction, inflammasome assembly and activation. Importantly, supplementation of IL-1ß restores chemotherapy sensitivity in mouse myeloid cells with a PTEN deficiency. Clinically, chemotherapy-induced IL-1ß production and antitumour immunity in patients with cancer is correlated with PTEN expression in myeloid cells, but not tumour cells. Our results demonstrate that myeloid PTEN can determine chemotherapy responsiveness by promoting NLRP3-dependent antitumour immunity and suggest that myeloid PTEN might be a potential biomarker to predict chemotherapy responses.