Molecular Perspective of GPNMB in the Progression of End-Stage Liver Disease

Rumgay H, Arnold M, Ferlay J, Lesi O, Cabasag CJ, Vignat J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022;77(6):1598–606.

Article  PubMed  PubMed Central  Google Scholar 

GLOBOCAN. Worldwide cancer data [Internet]. https://www.wcrf.org/preventing-cancer/cancer-statistics/worldwide-cancer-data/

World Health Organization. Cancer [Internet]. 2022. https://www.who.int/news-room/fact-sheets/detail/cancer

Saloni Dattani V, Samborska H, Ritchie MR. Cancer [Internet]. our world in data. 2024. https://ourworldindata.org/cancer

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.

PubMed  Google Scholar 

SEER. SEER Cancer Statistics Factsheets: Liver and Intrahepatic Bile Duct Cancer. National Cancer Institute [Internet]. 2014. http://www.seer.cancer.gov/statfacts/html/livibd.html

Aasarey R, Yadav K, Kashyap BK, Prabha S, Kumar P, Kumar A et al. Role of immunological cells in hepatocellular carcinoma disease and associated pathways. ACS Pharmacol \& Transl Sci [Internet]. 2023;6(12):1801–16. https://doi.org/10.1021/acsptsci.3c00216

Chen Y, Wang W, Morgan MP, Robson T, Annett S. Obesity, non-alcoholic fatty liver disease and hepatocellular carcinoma: current status and therapeutic targets. Front Endocrinol (Lausanne). 2023;14(June):1–23.

Google Scholar 

Younossi ZM, Henry L. Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma. JHEP Reports [Internet]. 2021;3(4):100305. https://doi.org/10.1016/j.jhepr.2021.100305

Chew V. Stress-mediated brain-liver connection induces metabolic dysfunction. J Hepatol [Internet]. 2026. https://doi.org/10.1016/j.jhep.2025.11.002

Ampuero J. General overview about the current management of nonalcoholic fatty liver disease. Clin Drug Investig [Internet]. 2022;42(s1):39–45. https://doi.org/10.1007/s40261-022-01142-w

Llovet JM, Willoughby CE, Singal AG, Greten TF, Heikenwälder M, El-Serag HB et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat Rev Gastroenterol Hepatol [Internet]. 2023;20(8):487–503. https://doi.org/10.1038/s41575-023-00754-7

Weterman MA, Ajubi N, van Dinter IM, Degen WG, van Muijen GN, Ruitter DJ, et al. nmb, a novel gene, is expressed in low-metastatic human melanoma cell lines and xenografts. Int J cancer. 1995;60(1):73–81.

Article  CAS  PubMed  Google Scholar 

Saade M, Souza GA, De, Scavone C, Kinoshita PF. The Role of GPNMB in In fl ammation. 2021;12(May):1–10.

Shikano S, Bonkobara M, Zukas PK, Ariizumi K. Molecular cloning of a dendritic cell-associated transmembrane, protein DC-HIL. That promotes RGD-dependent adhesion of endothelial cells through recognition of heparan sulfate proteoglycans *. J Biol Chem [Internet]. 2001;276(11):8125–34. https://doi.org/10.1074/jbc.M008539200

Bandari PS, Qian J, Yehia G, Joshi DD, Maloof PB, Potian J et al. Hematopoietic growth factor inducible neurokinin-1 type: a transmembrane protein that is similar to neurokinin 1 interacts with substance P. Regul Pept [Internet]. 2003;111(1):169–78. https://www.sciencedirect.com/science/article/pii/S0167011502002884

Rose AAN, Annis MG, Dong Z, Pepin F, Hallett M, Park M et al. ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties. PLoS ONE. 2010;5(8).

Abdelmagid SM, Barbe MF, Rico MC, Salihoglu S, Arango-Hisijara I, Selim AH, et al. Osteoactivin, an anabolic factor that regulates osteoblast differentiation and function. Exp Cell Res. 2008;314(13):2334–51.

Article  CAS  PubMed  Google Scholar 

Kuan C-T, Wakiya K, Dowell JM, Herndon JE 2nd, Reardon DA, Graner MW, et al. Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme. Clin cancer Res Off J Am Assoc Cancer Res. 2006;12(7 Pt 1):1970–82.

Article  CAS  Google Scholar 

Tyburczy ME, Kotulska K, Pokarowski P, Mieczkowski J, Kucharska J, Grajkowska W, et al. Novel proteins regulated by mTOR in subependymal giant cell astrocytomas of patients with tuberous sclerosis complex and new therapeutic implications. Am J Pathol. 2010;176(4):1878–90.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rose AAN, Grosset A-A, Dong Z, Russo C, Macdonald PA, Bertos NR, et al. Glycoprotein nonmetastatic B is an independent prognostic indicator of recurrence and a novel therapeutic target in breast cancer. Clin cancer Res Off J Am Assoc Cancer Res. 2010;16(7):2147–56.

Article  CAS  Google Scholar 

Onaga M, Ido A, Hasuike S, Uto H, Moriuchi A, Nagata K, et al. Osteoactivin expressed during cirrhosis development in rats fed a choline-deficient, L-amino acid-defined diet, accelerates motility of hepatoma cells. J Hepatol. 2003;39(5):779–85.

Article  CAS  PubMed  Google Scholar 

Ruan W-M, Li Y-L, Nie G, Zhou W-X, Zou X-M. Differential expression of glycoprotein non-metastatic melanoma protein B (GPNMB) involved in trichostatin A-induced apoptosis in gastric cancer. Int J Clin Exp Med. 2014;7(12):4857–66.

PubMed  PubMed Central  Google Scholar 

Williams MD, Esmaeli B, Soheili A, Simantov R, Gombos DS, Bedikian AY, et al. GPNMB expression in uveal melanoma: a potential for targeted therapy. Melanoma Res. 2010;20(3):184–90.

Article  CAS  PubMed  Google Scholar 

Li Y-N, Zhang L, Li X-L, Cui D-J, Zheng H-D, Yang S-Y, et al. Glycoprotein nonmetastatic B as a prognostic indicator in small cell lung cancer. APMIS. 2014;122(2):140–6.

Article  CAS  PubMed  Google Scholar 

Zhao Y, Qiao Z, Shan S, Sun Q, Zhang J. Expression of glycoprotein non-metastatic melanoma protein B in cutaneous malignant and benign lesions: a tissue microarray study. Chin Med J (Engl). 2012;125(18):3279–82.

CAS  PubMed  Google Scholar 

Meng Y, Zhao Q, Sang Y, Liao J, Ye F, Qu S, et al. GPNMB(+) Gal-3(+) hepatic parenchymal cells promote immunosuppression and hepatocellular carcinogenesis. EMBO J. 2023;42(24):e114060.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Saroj M, Prakash S, Vikram NK, Saraya A, Priyatma, Ganie MA et al. Hyperactive behaviour of growth differentiation factor- 15 (GDF-15) in conjunction with iron trafficking transporters and suppression of Nrf-2 gene in diabetes and metabolic syndrome. Mol Cell Biochem [Internet]. 2024;479(5):1109–20. https://doi.org/10.1007/s11010-023-04782-4

Tsou P-S, Sawalha AH. Glycoprotein nonmetastatic melanoma protein B: a key mediator and an emerging therapeutic target in autoimmune diseases. FASEB J [Internet]. 2020;34(7):8810–23. https://faseb.onlinelibrary.wiley.com/doi/abs/https://doi.org/10.1096/fj.202000651

Haralanova-Ilieva B, Ramadori G, Armbrust T. Expression of osteoactivin in rat and human liver and isolated rat liver cells. J Hepatol [Internet]. 2005;42(4):565–72. https://doi.org/10.1016/j.jhep.2004.12.021

Safadi FF, Xu J, Smock SL, Rico MC, Owen TA, Popoff SN. Cloning and characterization of osteoactivin, a novel cDNA expressed in osteoblasts. J Cell Biochem. 2001;84(1):12–26.

Article  CAS  PubMed  Google Scholar 

Kumagai K, Tabu K, Sasaki F, Takami Y, Morinaga Y, Mawatari S, et al. Glycoprotein nonmetastatic melanoma B (Gpnmb)-positive macrophages contribute to the balance between fibrosis and fibrolysis during the repair of acute liver injury in mice. PLoS ONE. 2015;10(11):e0143413.

Article  PubMed  PubMed Central  Google Scholar 

Katayama A, Nakatsuka A, Eguchi J, Murakami K, Teshigawara S, Kanzaki M et al. Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis. Sci Rep [Internet]. 2015;5(1):16920. https://doi.org/10.1038/srep16920

Chandler C, Liu T, Buckanovich R, Coffman LG. The double edge sword of fibrosis in cancer. Transl Res. 2019;209:55–67.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Long C, Yun LQ, Yuan MD, Al-Sultan IIA. The janus-faced biology of GPNMB: from tissue homeostasis to cancer pathogenesis. Front Mol Biosci. 2025;Volume 12–2025.

Hoashi T, Sato S, Yamaguchi Y, Passeron T, Tamaki K, Hearing VJ. Glycoprotein nonmetastatic melanoma protein b, a melanocytic cell marker, is a melanosome-specific and proteolytically released protein. FASEB J. 2010;24(5):1616–29.

Article  CAS  PubMed  PubMed Central  Google Scholar 

The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9.

Article  Google Scholar 

Ott PA, Hamid O, Pavlick AC, Kluger H, Kim KB, Boasberg PD, et al. Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with advanced melanoma. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(32):3659–66.

Article  CAS  Google Scholar 

Furochi H, Tamura S, Mameoka M, Yamada C, Ogawa T, Hirasaka K, et al. Osteoactivin fragments produced by ectodomain shedding induce MMP-3 expression via ERK pathway in mouse NIH-3T3 fibroblasts. FEBS Lett. 2007;581(30):5743–50.

Article  CAS  PubMed  Google Scholar 

Ono Y, Chiba S, Yano H, Nakayama N, Saio M, Tsuruma K, et al. Glycoprotein nonmetastatic melanoma protein B (GPNMB) promotes the progression of brain glioblastoma via Na(+)/K(+)-ATPase. Biochem Biophys Res Commun. 2016;481(1–2):7–12.

Article  CAS  PubMed  Google Scholar 

Tanaka H, Shimazawa M, Kimura M, Takata M, Tsuruma K, Yamada M, et al. The potential of GPNMB as novel neuroprotective factor in amyotrophic lateral sclerosis. Sci Rep. 2012;2:1–11.

Article  Google Scholar 

D’Souza SE, Ginsberg MH, Plow EF. Arginyl-glycyl-aspartic acid (RGD): a cell adhesion motif. Trends Biochem Sci. 1991;16(7):246–50.

Article  PubMed  Google Scholar 

Shikano S, Bonkobara M, Zukas PK, Ariizumi K. Molecular cloning of a dendritic cell-associated transmembrane protein, DC-HIL, that promotes RGD-dependent adhesion of endothelial cells through recognition of heparan sulfate proteoglycans. J Biol Chem. 2001;276(11):8125–34.

Article  CAS  PubMed  Google Scholar 

Tomihari M, Hwang S-H, Chung J-S, Cruz PDJ, Ariizumi K. Gpnmb is a melanosome-associated glycoprotein that contributes to melanocyte/keratinocyte adhesion in a RGD-dependent fashion. Exp Dermatol. 2009;18(7):586–95.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Maric G, Annis MG, Dong Z, Rose AAN, Ng S, Perkins D, et al. GPNMB cooperates with neuropilin-1 to promote mammary tumor growth and engages integrin α5β1 for efficient breast cancer metastasis. Oncogene. 2015;34(43):5494–504.

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