Myeloid cell-expressed MNDA enhances M2 polarization to facilitate the metastasis of hepatocellular carcinoma

Abstract

Abstract Background The molecular subtypes of hepatocellular carcinoma (HCC) with the worst prognosis are characterized by immune disorders dominated by myeloid cell infiltration, but how to accurately screen these patients for accurate diagnosis and treatment is not clear. In this study, based on HCC proteomic data from two independent centers, we found that Myeloid cell nuclear differentiation antigen (MNDA) could be used as a marker of myeloid lymphocyte especially M2 myeloid cell infiltration, and further analyzed the mechanism and potential clinical value of MNDA in promoting poor prognosis of HCC. Methods We investigated the proteomic molecular subtype of HCC and discovered a significant elevation of the myeloid cell nuclear differentiation antigen (MNDA) in the most aggressive subtype. The association between MNDA and the prognosis of HCC was examined using multi-omics data. Gene expression analysis, multiple immunofluorescence and western blot were used for detecting the localization of MNDA in HCC. Cellular co-culture experiments were conducted for exploring the functions of MNDA in vitro while intravenous injections were used in in vivo study. To elucidate its oncogenic mechanisms, we used RNA-seq combined with mass spectrometry analysis and cellular experiments to identify the related signaling pathway. Results MNDA demonstrated significantly elevated expression in the most aggressive subtype of HCC and exhibited a positively correlation with M2 infiltration and HCC metastasis. Moreover, MNDA also functioned as an independent prognostic predictor and has a good synergistic effect with existing prognostic clinical indicators (such as AFP, tumor size, MVI, etc.). We also found that MNDA was primarily expressed in tumor M2 macrophages and contributed to the enhancement of M2 macrophage polarization by upregulating the expression of the enhancers of M2 polarization. Furthermore, MNDA knockdown inhibited the secretion of M2 macrophage-derived pro-metastasis proteins via the exosome pathway to suppress HCC metastasis both in vivo and in vitro. Conclusions MNDA exerts a protumor role by promoting M2 macrophages polarization and HCC metastasis, and can serve as a potential biomarker and therapeutic target for HCC.