Yilun Wang

Introduction. Hepatocellular carcinoma (HCC) is a primary cause of liver cancer, accounting for over 90% of liver cancers and ranking fourth in worldwide cancer deaths.¹ HCC is commonly associated with chronic liver conditions, including hepatitis B/C and alcoholic cirrhosis.¹ HCC has evidence of immune alterations with elevated levels of immune checkpoint (immunosuppressive) proteins PD-1 and PD-L1, for which novel PD-1 inhibitors like pembrolizumab have been developed.^2,3 However, these new therapies have only modest response rate and average survival of 12.9 months post-treatment, indicating a need for more research.⁴ HCC cells have increased levels of GOLM1, a Golgi transmembrane protein involved in endosomal transport.⁴ Elevated GOLM1 expression is associated with immunosuppression, increased tumor progression and size, and poorer patient prognoses, suggesting GOLM1 has potential as a prognostic biomarker and therapeutic target.⁴ Methods. To explore GOLM1’s mechanisms of pathogenesis, immunoaffinity purification was used to identify interactions between GOLM1, EGFR, and PD-L1 in various HCC cells lines (Hep3B, PLC, MHCC-97H).⁴ Liu et al. used immunoblotting analyses on MHCC-97H cell lines to reveal another GOLM1 pathogenic signaling pathway involving matrix metalloproteinase (MMP-7).⁵ Finally, the potential of microRNA’s in controlling GOLM1 expression was explored. Gai et al. used CCK8 proliferation analysis to assess miR-145’s in-vitro effects on MHCC97H GOLM1+ cells and patient samples to analyze correlations between miR-145 expression and HCC prognosis.⁶ Zhang et al. performed invasion assays on miR-382-transfected normal human cells (L02) and HCC cells to compare miR-382’s in-vitro effects as well as mouse xenografts to explore miR-382’s effects on HCC tumors.⁷ Results. GOLM1 overexpression in Hep3B cells increased phosphorylation of EGFR which activated a signaling pathway, leading to PD-L1 overexpression, immunosuppression, and HCC immune escape.⁴ Inhibition of this pathway was associated with improved prognoses and patient survival.⁴ GOLM1 expression also directly correlated with expression of MMP-7, which allowed HCC cells to degrade extracellular matrix and expand from their primary tumor site.⁵ miR-145 and miR-382 both showed suppressive function on GOLM1 expression in-vivo and in-vitro with associated improvements in tumor size and patient survival.^6,7 This shows great promise for these miRNAs as targets to suppress GOLM1 levels.^6,7 Conclusions. GOLM1 is involved in multiple HCC tumorigenic pathways, including immunosuppression and metastasis.^4,5 Due to its central role and the limited efficacy of current HCC therapies, GOLM1 is a strong candidate for immunotherapy and further research.⁴ miRNA’s 145 and 382 show tumor-suppressive activity through downregulation of GOLM1 and are candidates for drug targeting and future investigations.^6,7

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3. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. The Lancet Oncology. 2018;19(7):940-952. doi:10.1016/S1470-2045(18)30351-6
4. Yan J, Zhou B, Guo L, et al. GOLM1 upregulates expression of PD-L1 through EGFR/STAT3 pathway in hepatocellular carcinoma. Am J Cancer Res. 2020;10(11):3705-3720.
5. Liu Y, Zhou S, Shi J, et al. c-Myc transactivates GP73 and promotes metastasis of hepatocellular carcinoma cells through GP73-mediated MMP-7 trafficking in a mildly hypoxic microenvironment. Oncogenesis. 2019;8(10). doi:10.1038/s41389-019-0166-7
6. Gai X, Tang B, Liu F, et al. mTOR/miR-145-regulated exosomal GOLM1 promotes hepatocellular carcinoma through augmented GSK-3β/MMPs. Journal of Genetics and Genomics. 2019;46(5):235-245. doi:10.1016/j.jgg.2019.03.013
7. Zhang S, Ge W, Zou G, et al. MiR-382 targets GOLM1 to inhibit metastasis of hepatocellular carcinoma and its down-regulation predicts a poor survival. Am J Cancer Res. 2018;8(1):120-131.