IRGM promotes melanoma cell survival through autophagy and is a promising prognostic biomarker for clinical application

Abstract

Previously, we showed that mouse immunity-related guanosine triphosphatase (GTPase) family M protein 1 (Irgm1) promotes malignant melanoma progression by inducing cellular autophagy flux and metastasis. Human IRGM, a truncated protein functionally distinct from its mouse counterpart, has several splice isoforms. In this study, we analyzed the association of IRGM and human melanoma clinical prognosis and investigated the function of IRGM in human melanoma cells. Data from the training cohort (n = 144) showed that overexpression of IRGM is proportional to melanoma genesis and clinical stages in human tissue chips. A validation cohort (n = 78) further confirmed that IRGM is an independent risk factor promoting melanoma progression and is associated with poor survival of patients. Among IRGM isoforms, we found that IRGMb is responsible for such correlation. In addition, IRGM promoted melanoma cell survival through autophagy, both in vitro and in vivo . We further showed that the blockade of translocation of high-mobility group box 1 (HMGB1) from the nucleus to cytoplasm inhibits IRGM1-mediated cellular autophagy and reduces cell survival. IRGM functions as a positive regulator of melanoma progression through autophagy and may serve as a promising prognostic marker and therapeutic target.

Immunity-related GTPase IRGM at the intersection of autophagy, inflammation, and tumorigenesis

“…In addition, IRGMb was shown to increase melanoma cell survival via increasing autophagic flux, in an HMGB1dependant manner [16]. This study also established IRGMb as a notable independent risk factor for melanoma progression [16]. Given that generation of alternatively spliced isoforms is frequently associated with drug resistance in cancer therapy, further studies are required to determine the role of IRGM isoforms in diverse tumours.…”

“…In gastric cancer, mRNA and protein levels of IRGM were shown to be significantly upregulated in the peripheral blood of cancer patients compared to healthy controls, and these levels were higher in stage IV than in stage I cancer patients [33]. Furthermore, there were significant differences in IRGM expression in patients presenting with melanoma, wherein the highest expression occurred in metastatic tumours, followed by primary tumours, and finally, benign adjacent nevus tissue [16]. A similar pattern was observed according to disease stage, where patients in stages III-IV of melanoma showed significantly higher expression of IRGM mRNA and protein levels, compared to patients in stages I and II [16].…”

“…Isoforms IRGMa and IRGMc also exert the same effect at high concentrations, albeit with different kinetic profiles [15]. Tian et al [16] demonstrated that concentrations of IRGMb, IRGMc, and IRGMd were higher in cancerous tissue compared to paracancerous tissue in melanoma patients, while IRGMa concentrations were relatively lower. In addition, IRGMb was shown to increase melanoma cell survival via increasing autophagic flux, in an HMGB1dependant manner [16].…”

“…Tian et al [16] demonstrated that concentrations of IRGMb, IRGMc, and IRGMd were higher in cancerous tissue compared to paracancerous tissue in melanoma patients, while IRGMa concentrations were relatively lower. In addition, IRGMb was shown to increase melanoma cell survival via increasing autophagic flux, in an HMGB1dependant manner [16]. This study also established IRGMb as a notable independent risk factor for melanoma progression [16].…”

“…IRGM appears to be a fulcrum between immunity and tumorigenesis. Studies on melanoma [16,30], hepatocellular carcinoma [31], glioma [32], and gastric cancer [33] have shown that IRGM can promote carcinogenesis. In human glioma cell lines, overexpression of IRGM was linked to increased cell colony formation, cell proliferation, and Akt activation [32].…”