The role of monoglyceride lipase gene in promoting proliferation, metastasis, and free fatty acid accumulation in uveal melanoma cells.

Uveal melanoma is a malignant tumor originating from melanocytes in the eye's uvea, often detected during routine ophthalmic examinations due to its typically asymptomatic nature. Despite effective local treatments, up to 50% of patients develop hematogenous metastases, highlighting the need for better prognostic markers and therapeutic targets. In this study, we developed an innovative Metastasis-Related Gene Signature (MERGS) score to classify patients from various cohorts. By establishing this scoring method, we discovered underlying mechanisms responsible for significant differences between samples with high and low MERGS scores. We identified a set of ten genes to construct MERGS, which showed a high predictive accuracy for patient survival. Further, Monoglyceride Lipase (MGLL) emerged as the most important gene in distinguishing uveal melanoma metastasis. Functional studies demonstrated that knocking down MGLL significantly inhibited proliferation, invasion, and migration of uveal melanoma cells in vitro and in vivo, while overexpression of MGLL enhanced these malignant behaviors. Additionally, MGLL modulated free fatty acid (FFA) levels within these cells. Our findings reveal MGLL as a crucial player in uveal melanoma progression and propose it as a novel therapeutic target, potentially leading to improved management and outcomes for patients with this disease.

Xu Y ，Zhong J ，Liu Z ，Li D ... -  《Human Cell》

Monoacylglycerol lipase regulates macrophage polarization and cancer progression in uveal melanoma and pan-cancer.

Although lipid metabolism has been proven to play a key role in the development of cancer, its significance in uveal melanoma (UM) has not yet been elucidated in the available literature. To identify the expression patterns of lipid metabolism in 80 UM patients from the TCGA database, 47 genes involved in lipid metabolism were analyzed. Consensus clustering revealed two distinct molecular groups. ESTIMATE, TIMER, and ssGSEA analyses were done to identify the differences between the two subgroups in tumor microenvironment (TME) and immune state. Using Cox regression and Lasso regression analysis, a risk model based on differentially expressed genes (DEGs) was developed. To validate the expression of monoacylglycerol lipase (MGLL) and immune infiltration in diverse malignancies, a pan-cancer cohort from the UCSC database was utilized. Next, a single-cell sequencing analysis on UM patients from the GEO data was used to characterize the lipid metabolism in TME and the role of MGLL in UM. Finally, in vitro investigations were utilized to study the involvement of MGLL in UM. Two molecular subgroups of UM patients have considerably varied survival rates. The majority of DEGs between the two subgroups were associated with immune-related pathways. Low immune scores, high tumor purity, a low number of immune infiltrating cells, and a comparatively low immunological state were associated with a more favorable prognosis. An examination of GO and KEGG data demonstrated that the risk model based on genes involved with lipid metabolism can accurately predict survival in patients with UM. It has been demonstrated that MGLL, a crucial gene in this paradigm, promotes the proliferation, invasion, and migration of UM cells. In addition, we discovered that MGLL is strongly expressed in macrophages, specifically M2 macrophages, which may play a function in the M2 polarization of macrophages and M2 macrophage activation in cancer cells. This study demonstrates that the risk model based on lipid metabolism may be useful for predicting the prognosis of patients with UM. By promoting macrophage M2 polarization, MGLL contributes to the evolution of malignancy in UM, suggesting that it may be a therapeutic target for UM.

Tan Y ，Pan J ，Deng Z ，Chen T ，Xia J ，Liu Z ，Zou C ，Qin B ... -  《Frontiers in Immunology》

MiR-155 Promotes Uveal Melanoma Cell Proliferation and Invasion by Regulating NDFIP1 Expression.

Peng J ，Liu H ，Liu C 《-》

Suppression of long noncoding RNA MALAT1 inhibits the development of uveal melanoma via microRNA-608-mediated inhibition of HOXC4.

Wu S ，Chen H ，Zuo L ，Jiang H ，Yan H ... -  《-》

Crizotinib, a c-Met inhibitor, prevents metastasis in a metastatic uveal melanoma model.

Uveal melanoma is the most common primary intraocular malignant tumor in adults and half of the primary tumors will develop fatal metastatic disease to the liver and the lung. Crizotinib, an inhibitor of c-Met, anaplastic lymphoma kinase (ALK), and ROS1, inhibited the phosphorylation of the c-Met receptor but not of ALK or ROS1 in uveal melanoma cells and tumor tissue. Consequently, migration of uveal melanoma cells was suppressed in vitro at a concentration associated with the specific inhibition of c-Met phosphorylation. This effect on cell migration could be recapitulated with siRNA specific to c-Met but not to ALK or ROS1. Therefore, we developed a uveal melanoma metastatic mouse model with EGFP-luciferase-labeled uveal melanoma cells transplanted by retro-orbital injections to test the effect of crizotinib on metastasis. In this model, there was development of melanoma within the eye and also metastases to the liver and lung at 7 weeks after the initial transplantation. When mice were treated with crizotinib starting 1 week after the transplantation, we observed a significant reduction in the development of metastases as compared with untreated control sets. These results indicate that the inhibition of c-Met activity alone may be sufficient to strongly inhibit metastasis of uveal melanoma from forming, suggesting crizotinib as a potential adjuvant therapy for patients with primary uveal melanoma who are at high risk for the development of metastatic disease.

Surriga O ，Rajasekhar VK ，Ambrosini G ，Dogan Y ，Huang R ，Schwartz GK ... -  《-》