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Although less common, melanoma is the deadliest form of skin cancer largely due to its highly metastatic nature. Currently, there are limited treatment options for metastatic melanoma and many of them could cause serious side effects. A better understanding of the molecular mechanisms underlying the complex disease pathophysiology of metastatic melanoma may lead to the identification of novel therapeutic targets and facilitate the development of targeted therapeutics. In this study, we investigated the role of leucine-rich α-2-glycoprotein 1 (LRG1) in melanoma development and progression. We first established the association between LRG1 and melanoma in both human patient biopsies and mouse melanoma cell lines and revealed a significant induction of LRG1 expression in metastatic melanoma cells. We then showed no change in tumour cell growth, proliferation, and angiogenesis in the absence of the host Lrg1. On the other hand, there was reduced melanoma cell metastasis to the lungs in Lrg1-deficient mice. This observation was supported by the promoting effect of LRG1 in melanoma cell migration, invasion, and adhesion. Mechanistically, LRG1 mediates melanoma cell invasiveness in an EGFR/STAT3-dependent manner. Taken together, our studies provided compelling evidence that LRG1 is required for melanoma metastasis but not growth. Targeting LRG1 may offer an alternative strategy to control malignant melanoma. Ministry of Education (MOE) National Medical Research Council (NMRC) Published version This project was supported by the MOE Academic Research Fund Tier 2 (MOE2014-T2-1- 036) to X.W. and W.W., the Duke-NUS Start-Up Grant to X.W. and the Singapore National Medical Research Council DYNAMO NMRC/OFLCG/001/2017 and TAPP NMRC/OFLCG/004/2018 to X.W., and the Lee Kong Chian School of Medicine, Nanyang Technological University Singapore Start-up Grant to W.W.

Introduction. LIM Homeobox 6 (LHX6) encodes a LIM homeodomain transcription factor, contributes to tissue development and morphogenesis, and is mostly expressed in medial ganglionic eminence and odontogenic mesenchyme. However, it has been reported to play a role in cancer progression. This narrative review summarizes literatures that emphasize the molecular regulation of LHX6 in tumorigenesis. Methods. In our systematic review, the PubMed database was used for the literature search using the combination of words that included “LHX6” and “cancer”. Relevant studies, including in vitro, in vivo experiments, and clinical studies, were analyzed in this review. Results. We found evidences that LHX6 might be important in the inhibition of tumor cell proliferation, growth, invasion, and metastasis through the suppression of Wnt/β-catenin signaling pathway. Moreover, LHX6 is observed to be downregulated in certain types of cancer due to hypermethylation, thus hindering its tumor suppressing ability. In addition, hypermethylation can also be used to determine the stage of cancer development. Conclusion. The downregulation of LHX6 expression might be responsible in promoting cancer progression. Future studies are necessary to investigate the potential of LHX6 as a novel cancer biomarker as well as its therapeutic implications towards certain types of cancer.