The Novel Epithelial-mesenchymal Transition-related Proteins and Their Therapeutic Targets in Cholangiocarcinoma: a Narrative Review

Overview

Journal J Gastrointest Oncol

Date 2023 Jul 12

PMID 37435208

Authors

Phongsaran Kimawaha

Anchalee Techasen

Affiliations

Soon will be listed here.

Abstract

Background And Objective: Cholangiocarcinoma (CCA), a liver cancer of bile duct epithelial cells, is a severe health issue in northeastern Thailand. The epithelial-mesenchymal transition (EMT) is a crucial process in the development of CCA. To comprehend oncogenic EMT in CCA, several newly found EMT factors are being explored in these underlying pathways. This narrative review explained the latest and findings on the molecular mechanisms of 21 new EMT-related proteins that affect CCA progression.

Methods: We evaluated the PubMed database for relevant articles that fulfilled our criteria for investigating the molecular pathways of the novel EMT markers involved in oncogenic EMT and how they contribute to CCA development, including cell proliferation, apoptosis, invasion, migration, and chemoresistance.

Key Content And Findings: We discuss the potential of these new EMT markers as diagnostic, prognostic, and therapeutic indicators for CCA and describe their underlying mechanisms in the development of the disease. The discovery of several oncogenic EMT proteins and their key signaling pathways and downstream targets will also broaden novel paths of investigation into the diagnosis and targeted treatment of CCA.

Conclusions: The EMT-related proteins that were found are good sources of knowledge and interesting information for future research. The possible ways to treat CCA that could be tested in clinical trials were also discussed.

References

Mao X, Duan X, Jiang B . Fascin Induces Epithelial-Mesenchymal Transition of Cholangiocarcinoma Cells by Regulating Wnt/β-Catenin Signaling. Med Sci Monit. 2016; 22:3479-3485. PMC: 5045920. DOI: 10.12659/msm.897258. View

Evensen N, Kuscu C, Nguyen H, Zarrabi K, Dufour A, Kadam P . Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration. J Natl Cancer Inst. 2013; 105(18):1402-16. PMC: 3776264. DOI: 10.1093/jnci/djt224. View

Manning B, Toker A . AKT/PKB Signaling: Navigating the Network. Cell. 2017; 169(3):381-405. PMC: 5546324. DOI: 10.1016/j.cell.2017.04.001. View

Liang S, Guo H, Ma K, Li X, Wu D, Wang Y . A PLCB1-PI3K-AKT Signaling Axis Activates EMT to Promote Cholangiocarcinoma Progression. Cancer Res. 2021; 81(23):5889-5903. PMC: 9397629. DOI: 10.1158/0008-5472.CAN-21-1538. View

Yothaisong S, Dokduang H, Techasen A, Namwat N, Yongvanit P, Bhudhisawasdi V . Increased activation of PI3K/AKT signaling pathway is associated with cholangiocarcinoma metastasis and PI3K/mTOR inhibition presents a possible therapeutic strategy. Tumour Biol. 2013; 34(6):3637-48. DOI: 10.1007/s13277-013-0945-2. View

Lee S, Jeon H, Ju M, Jeong E, Kim C, Park H . Dlx-2 and glutaminase upregulate epithelial-mesenchymal transition and glycolytic switch. Oncotarget. 2016; 7(7):7925-39. PMC: 4884964. DOI: 10.18632/oncotarget.6879. View

Lan Y, Zhang D, Xu C, Hance K, Marelli B, Qi J . Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med. 2018; 10(424). DOI: 10.1126/scitranslmed.aan5488. View

Ling H, Roux E, Hempel D, Tao J, Smith M, Lonning S . Transforming growth factor β neutralization ameliorates pre-existing hepatic fibrosis and reduces cholangiocarcinoma in thioacetamide-treated rats. PLoS One. 2013; 8(1):e54499. PMC: 3547926. DOI: 10.1371/journal.pone.0054499. View

Tringler B, Zhuo S, Pilkington G, Torkko K, Singh M, Lucia M . B7-h4 is highly expressed in ductal and lobular breast cancer. Clin Cancer Res. 2005; 11(5):1842-8. DOI: 10.1158/1078-0432.CCR-04-1658. View

10.

Sun R, Liu Z, Qiu B, Chen T, Li Z, Zhang X . Annexin10 promotes extrahepatic cholangiocarcinoma metastasis by facilitating EMT via PLA2G4A/PGE2/STAT3 pathway. EBioMedicine. 2019; 47:142-155. PMC: 6796529. DOI: 10.1016/j.ebiom.2019.08.062. View

11.

Chinnadurai R, Grakoui A . B7-H4 mediates inhibition of T cell responses by activated murine hepatic stellate cells. Hepatology. 2010; 52(6):2177-85. PMC: 2995273. DOI: 10.1002/hep.23953. View

12.

Pavlova N, Thompson C . The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016; 23(1):27-47. PMC: 4715268. DOI: 10.1016/j.cmet.2015.12.006. View

13.

Deng X, Jiang P, Chen J, Li J, Li D, He Y . GATA6 promotes epithelial-mesenchymal transition and metastasis through MUC1/β-catenin pathway in cholangiocarcinoma. Cell Death Dis. 2020; 11(10):860. PMC: 7567063. DOI: 10.1038/s41419-020-03070-z. View

14.

Lv B, Ma L, Tang W, Huang P, Yang B, Wang L . FXR Acts as a Metastasis Suppressor in Intrahepatic Cholangiocarcinoma by Inhibiting IL-6-Induced Epithelial-Mesenchymal Transition. Cell Physiol Biochem. 2018; 48(1):158-172. DOI: 10.1159/000491715. View

15.

Bergquist A, von Seth E . Epidemiology of cholangiocarcinoma. Best Pract Res Clin Gastroenterol. 2015; 29(2):221-32. DOI: 10.1016/j.bpg.2015.02.003. View

16.

Quintavalle C, Burmeister K, Piscuoglio S, Quagliata L, Karamitopoulou E, Sepe R . High mobility group A1 enhances tumorigenicity of human cholangiocarcinoma and confers resistance to therapy. Mol Carcinog. 2017; 56(9):2146-2157. DOI: 10.1002/mc.22671. View

17.

Shin S, Dixon C . Targeting α7 nicotinic acetylcholine receptors: a future potential for neuroprotection from traumatic brain injury. Neural Regen Res. 2015; 10(10):1552-4. PMC: 4660732. DOI: 10.4103/1673-5374.165309. View

18.

Chen S, Kang X, Liu G, Zhang B, Hu X, Feng Y . α7-Nicotinic Acetylcholine Receptor Promotes Cholangiocarcinoma Progression and Epithelial-Mesenchymal Transition Process. Dig Dis Sci. 2019; 64(10):2843-2853. DOI: 10.1007/s10620-019-05609-3. View

19.

Yu D, Shi X, Meng G, Chen J, Yan C, Jiang Y . Kidney-type glutaminase (GLS1) is a biomarker for pathologic diagnosis and prognosis of hepatocellular carcinoma. Oncotarget. 2015; 6(10):7619-31. PMC: 4480704. DOI: 10.18632/oncotarget.3196. View

20.

Sripa B, Kaewkes S, Sithithaworn P, Mairiang E, Laha T, Smout M . Liver fluke induces cholangiocarcinoma. PLoS Med. 2007; 4(7):e201. PMC: 1913093. DOI: 10.1371/journal.pmed.0040201. View