ROR1 Expression and Its Functional Significance in Hepatocellular Carcinoma Cells

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2019 Mar 6

PMID 30832318

Citations 10

Authors

Metin Cetin

Gorkem Odabas

Leon R Douglas

Patrick J Duriez

Pelin Balcik-Ercin

Irem Yalim-Camci

Abdulkadir Emre Sayan

Tamer Yagci

Affiliations

Soon will be listed here.

Abstract

Background: Hepatocellular carcinoma (HCC) is a common and deadly cancer; however, very little improvement has been made towards its diagnosis and prognosis. The expression and functional contribution of the receptor tyrosine kinase ROR1 have not been investigated in HCC before. Hence, we investigated the expression of ROR1 in HCC cells and assessed its involvement in hepatocarcinogenesis.

Methods: Recombinant bacterial ROR1 protein was used as an immunogen to generate ROR1 monoclonal antibodies. transcript levels were detected by RT-qPCR and the protein expression of ROR1 in HCC was assessed by Western blotting by using homemade anti-ROR1 monoclonal antibodies. Apoptosis, cell cycle, trans-well migration, and drug efflux assays were performed in shRNA-ROR1 HCC cell clones to uncover the functional contribution of ROR1 to hepatocarcinogenesis.

Results: New ROR1 antibodies specifically detected endogenous ROR1 protein in human and mouse HCC cell lines. ROR1-knockdown resulted in decreased proliferation and migration but enhanced resistance to apoptosis and anoikis. The observed chemotherapy-resistant phenotype of ROR1-knockdown cells was due to enhanced drug efflux and increased expression of multi-drug resistance genes.

Conclusions: ROR1 is expressed in HCC and contributes to disease development by interfering with multiple pathways. Acquired ROR1 expression may have diagnostic and prognostic value in HCC.

Citing Articles

Hormone correction of dysfunctional metabolic gene expression in stem cell-derived liver tissue.

Kasarinaite A, Ramos M, Beltran-Sierra M, Sutherland E, Rei P, Zhao M Stem Cell Res Ther. 2025; 16(1):130.

PMID: 40069876 PMC: 11899078. DOI: 10.1186/s13287-025-04238-0.

Downregulation of RORl via STAT3 and P300 Promotes P38 Pathway- Dependent Lens Epithelial Cells Apoptosis in Age-Related Cataract.

Zhang Y, Hu Y, Su D, Fu Y, Chen X, Zhang X Biochem Genet. 2025; .

PMID: 40019609 DOI: 10.1007/s10528-025-11067-6.

Novel humanized monoclonal antibodies against ROR1 for cancer therapy.

Wei R, Liao X, Li J, Mu X, Ming Y, Peng Y Mol Cancer. 2024; 23(1):165.

PMID: 39138527 PMC: 11321157. DOI: 10.1186/s12943-024-02075-y.

Receptor tyrosine kinase-like orphan receptor 1: A novel antitumor target in gastrointestinal cancers.

Wu Z, Wang Y, Jia X, Wang Y, Wang H World J Clin Oncol. 2024; 15(5):603-613.

PMID: 38835843 PMC: 11145958. DOI: 10.5306/wjco.v15.i5.603.

Plasma Pattern of Extracellular Vesicles Isolated from Hepatitis C Virus Patients and Their Effects on Human Vascular Endothelial Cells.

Grossini E, Smirne C, Venkatesan S, Tonello S, DOnghia D, Minisini R Int J Mol Sci. 2023; 24(12).

PMID: 37373343 PMC: 10299492. DOI: 10.3390/ijms241210197.

References

Gomaa A, Khan S, Toledano M, Waked I, Taylor-Robinson S . Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol. 2008; 14(27):4300-8. PMC: 2731180. DOI: 10.3748/wjg.14.4300. View

Zhang S, Chen L, Wang-Rodriguez J, Zhang L, Cui B, Frankel W . The onco-embryonic antigen ROR1 is expressed by a variety of human cancers. Am J Pathol. 2012; 181(6):1903-10. PMC: 3509760. DOI: 10.1016/j.ajpath.2012.08.024. View

Pattabiraman D, Weinberg R . Targeting the Epithelial-to-Mesenchymal Transition: The Case for Differentiation-Based Therapy. Cold Spring Harb Symp Quant Biol. 2017; 81:11-19. PMC: 5722631. DOI: 10.1101/sqb.2016.81.030957. View

Cui B, Zhang S, Chen L, Yu J, Widhopf 2nd G, Fecteau J . Targeting ROR1 inhibits epithelial-mesenchymal transition and metastasis. Cancer Res. 2013; 73(12):3649-60. PMC: 3832210. DOI: 10.1158/0008-5472.CAN-12-3832. View

Shim H . One target, different effects: a comparison of distinct therapeutic antibodies against the same targets. Exp Mol Med. 2011; 43(10):539-49. PMC: 3222815. DOI: 10.3858/emm.2011.43.10.063. View

Lamouille S, Xu J, Derynck R . Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014; 15(3):178-96. PMC: 4240281. DOI: 10.1038/nrm3758. View

Krech T, Scheuerer E, Geffers R, Kreipe H, Lehmann U, Christgen M . ABCB1/MDR1 contributes to the anticancer drug-resistant phenotype of IPH-926 human lobular breast cancer cells. Cancer Lett. 2011; 315(2):153-60. DOI: 10.1016/j.canlet.2011.09.038. View

Bruix J, Qin S, Merle P, Granito A, Huang Y, Bodoky G . Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2016; 389(10064):56-66. DOI: 10.1016/S0140-6736(16)32453-9. View

Llovet J . Updated treatment approach to hepatocellular carcinoma. J Gastroenterol. 2005; 40(3):225-35. DOI: 10.1007/s00535-005-1566-3. View

10.

Zhang S, Cui B, Lai H, Liu G, Ghia E, Widhopf 2nd G . Ovarian cancer stem cells express ROR1, which can be targeted for anti-cancer-stem-cell therapy. Proc Natl Acad Sci U S A. 2014; 111(48):17266-71. PMC: 4260559. DOI: 10.1073/pnas.1419599111. View

11.

El-Serag H, Rudolph K . Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007; 132(7):2557-76. DOI: 10.1053/j.gastro.2007.04.061. View

12.

Bang Y, Van Cutsem E, Feyereislova A, Chung H, Shen L, Sawaki A . Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376(9742):687-97. DOI: 10.1016/S0140-6736(10)61121-X. View

13.

Matsuda T, Nomi M, Ikeya M, Kani S, Oishi I, Terashima T . Expression of the receptor tyrosine kinase genes, Ror1 and Ror2, during mouse development. Mech Dev. 2001; 105(1-2):153-6. DOI: 10.1016/s0925-4773(01)00383-5. View

14.

Kim Y, Koo K, Sung J, Yun U, Kim H . Anoikis resistance: an essential prerequisite for tumor metastasis. Int J Cell Biol. 2012; 2012:306879. PMC: 3296207. DOI: 10.1155/2012/306879. View

15.

Mani S, Guo W, Liao M, Eaton E, Ayyanan A, Zhou A . The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133(4):704-15. PMC: 2728032. DOI: 10.1016/j.cell.2008.03.027. View

16.

Hudecek M, Schmitt T, Baskar S, Lupo-Stanghellini M, Nishida T, Yamamoto T . The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood. 2010; 116(22):4532-41. PMC: 2996114. DOI: 10.1182/blood-2010-05-283309. View

17.

Sayan A, Paradisi A, Vojtesek B, Knight R, Melino G, Candi E . New antibodies recognizing p73: comparison with commercial antibodies. Biochem Biophys Res Commun. 2005; 330(1):186-93. DOI: 10.1016/j.bbrc.2005.02.145. View

18.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W . Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350(23):2335-42. DOI: 10.1056/NEJMoa032691. View

19.

Gentile A, Lazzari L, Benvenuti S, Trusolino L, Comoglio P . Ror1 is a pseudokinase that is crucial for Met-driven tumorigenesis. Cancer Res. 2011; 71(8):3132-41. DOI: 10.1158/0008-5472.CAN-10-2662. View

20.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View