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BMC Cancer
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Hepatocellular Carcinoma | Research

Role of pelitinib in the regulation of migration and invasion of hepatocellular carcinoma cells via inhibition of Twist1

Authors: Sewoong Lee, Eunjeong Kang, Unju Lee, Sayeon Cho

Published in: BMC Cancer | Issue 1/2023

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Abstract

Background

Overexpression of Twist1, one of the epithelial-mesenchymal transition-transcription factors (EMT-TFs), is associated with hepatocellular carcinoma (HCC) metastasis. Pelitinib is known to be an irreversible epidermal growth factor receptor tyrosine kinase inhibitor that is used in clinical trials for colorectal and lung cancers, but the role of pelitinib in cancer metastasis has not been studied. This study aimed to investigate the anti-migration and anti-invasion activities of pelitinib in HCC cell lines.

Methods

Using three HCC cell lines (Huh7, Hep3B, and SNU449 cells), the effects of pelitinib on cell cytotoxicity, invasion, and migration were determined by cell viability, wound healing, transwell invasion, and spheroid invasion assays. The activities of MMP-2 and -9 were examined through gelatin zymography. Through immunoblotting analyses, the expression levels of EMT-TFs (Snail1, Twist1, and ZEB1) and EMT-related signaling pathways such as mitogen-activated protein kinases (MAPKs) and Akt signaling pathways were measured. The activity and expression levels of target genes were analyzed by reporter assay, RT-PCR, quantitative RT-PCR, and immunoblotting analysis. Statistical analysis was performed using one-way ANOVA with Dunnett's Multiple comparison tests in Prism 3.0 to assess differences between experimental conditions.

Results

In this study, pelitinib treatment significantly inhibited wound closure in various HCC cell lines, including Huh7, Hep3B, and SNU449. Additionally, pelitinib was found to inhibit multicellular cancer spheroid invasion and metalloprotease activities in Huh7 cells. Further investigation revealed that pelitinib treatment inhibited the migration and invasion of Huh7 cells by inducing Twist1 degradation through the inhibition of MAPK and Akt signaling pathways. We also confirmed that the inhibition of cell motility by Twist1 siRNA was similar to that observed in pelitinib-treated group. Furthermore, pelitinib treatment regulated the expression of target genes associated with EMT, as demonstrated by the upregulation of E-cadherin and downregulation of N-cadherin.

Conclusion

Based on our novel finding of pelitinib from the perspective of EMT, pelitinib has the ability to inhibit EMT activity of HCC cells via inhibition of Twist1, and this may be the potential mechanism of pelitinib on the suppression of migration and invasion of HCC cells. Therefore, pelitinib could be developed as a potential anti-cancer drug for HCC.
Appendix
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Literature
1.
2.
Targe M, Yasam VR, Nagarkar R. Hepatocellular carcinoma with uncommon sites of metastasis: a rare case report. Egypt J Radiol Nucl Med. 2021;52(1):228.CrossRef
3.
Kwon S, Ban K, Hong YK, et al. PROX1, a Key Mediator of the Anti-Proliferative Effect of Rapamycin on Hepatocellular Carcinoma Cells. Cells. 2022;11(3):446.PubMedPubMedCentralCrossRef
4.
5.
6.
Hyeon J, Ahn S, Park CK. CHD1L Is a Marker for Poor Prognosis of Hepatocellular Carcinoma after Surgical Resection. Korean J Pathol. 2013;47(1):9–15.PubMedPubMedCentralCrossRef
7.
Saung MTPelosof LCasak S, et al. FDA Approval Summary: Nivolumab Plus Ipilimumab for the Treatment of Patients with Hepatocellular Carcinoma Previously Treated with Sorafenib. Oncologist. 2021;26(9):797–806.CrossRef
8.
Kaseb AOHasanov ECao HST, et al. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2022;7(3):208–18.CrossRef
9.
Yang T, Chen Y, Xu J, et al. Bioinformatics screening the novel and promising targets of curcumin in hepatocellular carcinoma chemotherapy and prognosis. BMC Complement Med Ther. 2022;22(1):21.PubMedPubMedCentralCrossRef
10.
Wang J, Xia S, Chen Y, et al. Screening and validation of prognostic indicator genes in the progression of HBV related hepatocellular carcinoma. Biomedical Technology. 2023;1:10–7.CrossRef
11.
Huang Q, Li J, Wei A. Identification of potential therapeutic targets in hepatocellular carcinoma using an integrated bioinformatics approach. Transl Cancer Res. 2018;7(4):849–58.CrossRef
12.
Meier MANuciforo SCoto-Llerena M, et al. Patient-derived tumor organoids for personalized medicine in a patient with rare hepatocellular carcinoma with neuroendocrine differentiation: a case report. Commun Med (Lond). 2022;2:80.
13.
Xie C, Gu A, Khan M, et al. Opportunities and challenges of hepatocellular carcinoma organoids for targeted drugs sensitivity screening. Front Oncol. 2022;12:7379.
14.
15.
Lin Y, Xu J, Lan H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol. 2019;12(1):76.PubMedPubMedCentralCrossRef
16.
Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.PubMedCrossRef
17.
Yuan KXie KLan T, et al. TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin. Cell Death Differ. 2020;27(4):1355–68.CrossRef
18.
Yu XZheng YZhu X, et al. Osteopontin promotes hepatocellular carcinoma progression via the PI3K/AKT/Twist signaling pathway. Oncol Lett. 2018;16(4):5299–308.
19.
Hou CH, Lin FL, Hou SM, et al. Cyr61 promotes epithelial-mesenchymal transition and tumor metastasis of osteosarcoma by Raf-1/MEK/ERK/Elk-1/TWIST-1 signaling pathway. Mol Cancer. 2014;13:236.PubMedPubMedCentralCrossRef
20.
Bonnomet A, Brysse A, Tachsidis A, et al. Epithelial-to-mesenchymal transitions and circulating tumor cells. J Mammary Gland Biol Neoplasia. 2010;15(2):261–73.PubMedCrossRef
21.
Franco HL, Casasnovas J, Rodríguez-Medina JR, et al. Redundant or separate entities?–roles of Twist1 and Twist2 as molecular switches during gene transcription. Nucleic Acids Res. 2011;39(4):1177–86.PubMedCrossRef
22.
23.
Jakobsen KR, Demuth C, Sorensen BS, et al. The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Transl Lung Cancer Res. 2016;5(2):172.PubMedPubMedCentralCrossRef
24.
Mawrin CSasse TKirches E, et al. Different activation of mitogen-activated protein kinase and Akt signaling is associated with aggressive phenotype of human meningiomas. Clin Cancer Res. 2005;11(11):4074–82.CrossRef
25.
Paraiso KH, Van Der Kooi K, Messina JL, et al. Measurement of constitutive MAPK and PI3K/AKT signaling activity in human cancer cell lines. Methods Enzymol. 2010;484:549–67.PubMedPubMedCentralCrossRef
26.
Zhang L, Zhou F, ten Dijke P. Signaling interplay between transforming growth factor-β receptor and PI3K/AKT pathways in cancer. Trends Biochem Sci. 2013;38(12):612–20.PubMedCrossRef
27.
28.
Sepporta MVPraz VBalmas Bourloud K, et al. TWIST1 expression is associated with high-risk neuroblastoma and promotes primary and metastatic tumor growth. Commun Biol. 2022;5(1):42.CrossRef
29.
Yang MH, Chen CL, Chau GY, et al. Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology. 2009;50(5):1464–74.PubMedCrossRef
30.
Khot M, Sreekumar D, Jahagirdar S, et al. Twist1 induces chromosomal instability (CIN) in colorectal cancer cells. Hum Mol Genet. 2020;29(10):1673–88.PubMedPubMedCentralCrossRef
31.
Shen J, Chen Q, Li N, et al. TWIST1 expression and clinical significance in type I endometrial cancer and premalignant lesions: A retrospective clinical study. Medicine. 2020;99(48):e23397.PubMedPubMedCentralCrossRef
32.
Sun T, Zhao N, Zhao XL, et al. Expression and functional significance of Twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry. Hepatology. 2010;51(2):545–56.PubMedCrossRef
33.
Xie BLiu YZhao Z, et al. MYB Proto-oncogene-like 1-TWIST1 Axis Promotes Growth and Metastasis of Hepatocellular Carcinoma Cells. Mol Ther Oncolytics. 2020;18:58–69.CrossRef
34.
Zhao P-W, Zhang J-W, Liu Y, et al. SRC-1 and Twist1 are prognostic indicators of liver cancer and are associated with cell viability, invasion, migration and epithelial-mesenchymal transformation of hepatocellular carcinoma cells. Transl Cancer Res. 2020;9(2):603.PubMedPubMedCentralCrossRef
35.
To KK, Poon DC, Wei Y, et al. Pelitinib (EKB-569) targets the up-regulation of ABCB1 and ABCG2 induced by hyperthermia to eradicate lung cancer. Br J Pharmacol. 2015;172(16):4089–106.PubMedPubMedCentralCrossRef
36.
Lee AR, Lee S, Shin JY, et al. Biomarker LEPRE1 induces pelitinib-specific drug responsiveness by regulating ABCG2 expression and tumor transition states in human leukemia and lung cancer. Sci Rep. 2022;12(1):2928.PubMedPubMedCentralCrossRef
37.
Kim H, Lim HY. Novel EGFR-TK inhibitor EKB-569 inhibits hepatocellular carcinoma cell proliferation by AKT and MAPK pathways. J Korean Med Sci. 2011;26(12):1563–8.PubMedPubMedCentralCrossRef
38.
Jorissen RN, Walker F, Pouliot N, et al. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003;284(1):31–53.PubMedCrossRef
39.
Ellis LM. Epidermal growth factor receptor in tumor angiogenesis. Hematol Oncol Clin North Am. 2004;18(5):1007–21.PubMedCrossRef
40.
Singh PK, Singh H, Silakari O. Kinases inhibitors in lung cancer: From benchside to bedside. BBA Rev Cancer. 2016;1866(1):128–40.
41.
López-García J, Lehocký M, Humpolíček P, et al. HaCaT Keratinocytes Response on Antimicrobial Atelocollagen Substrates: Extent of Cytotoxicity, Cell Viability and Proliferation. J Funct Biomater. 2014;5(2):43–57.PubMedPubMedCentralCrossRef
42.
Weng C-J, Wu C-F, Huang H-W, et al. Evaluation of anti-invasion effect of resveratrol and related methoxy analogues on human hepatocarcinoma cells. J Agric Food Chem. 2010;58(5):2886–94.PubMedCrossRef
43.
44.
Kang E, Seo J, Yoon H, et al. The post-translational regulation of epithelial–mesenchymal transition-inducing transcription factors in cancer metastasis. Int J Mol Sci. 2021;22(7):3591.PubMedPubMedCentralCrossRef
45.
Qin Q, Xu Y, He T, et al. Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms. Cell Res. 2012;22(1):90–106.PubMedCrossRef
46.
Loh C-Y, Chai JY, Tang TF, et al. The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition: signaling, therapeutic implications, and challenges. Cells. 2019;8(10):1118.PubMedPubMedCentralCrossRef
47.
Fares J, Fares MY, Khachfe HH, et al. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther. 2020;5(1):1–17.
48.
Chen H, Hu L, Luo Z, et al. A20 suppresses hepatocellular carcinoma proliferation and metastasis through inhibition of Twist1 expression. Mol Cancer. 2015;14(1):1–14.CrossRef
49.
Wu Y, Ma Z, Zhang Y, et al. Cyclophilin A regulates the apoptosis of A549 cells by stabilizing Twist1 protein. J Cell Sci. 2022;135(2):jcs259018.PubMedCrossRef
50.
Wang J, Nikhil K, Viccaro K, et al. The Aurora-A–Twist1 axis promotes highly aggressive phenotypes in pancreatic carcinoma. J Cell Sci. 2017;130(6):1078–93.PubMedPubMedCentral
51.
Qiao W, Jia Z, Liu H, et al. Prognostic and clinicopathological value of Twist expression in breast cancer: A meta-analysis. PLoS ONE. 2017;12(10):e0186191.PubMedPubMedCentralCrossRef
52.
Vichalkovski A, Gresko E, Hess D, et al. PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage. Oncogene. 2010;29(24):3554–65.PubMedCrossRef
53.
Hong J, Zhou J, Fu J, et al. Phosphorylation of Serine 68 of Twist1 by MAPKs Stabilizes Twist1 Protein and Promotes Breast Cancer Cell InvasivenessTwist1 Phosphorylation and Breast Cancer Invasiveness. Can Res. 2011;71(11):3980–90.CrossRef
54.
55.
He J, Huang Z, Han L, et al. Mechanisms and management of 3rd-generation EGFR-TKI resistance in advanced non-small cell lung cancer (Review). Int J Oncol. 2021;59(5):90.PubMedPubMedCentralCrossRef
56.
Urnauer S, Schmohl KA, Tutter M, et al. Dual-targeted NIS polyplexes—a theranostic strategy toward tumors with heterogeneous receptor expression. Gene Ther. 2019;26(3):93–108.PubMedCrossRef
57.
Lee H-J, Li C-F, Ruan D, et al. The DNA damage transducer RNF8 facilitates cancer chemoresistance and progression through twist activation. Mol Cell. 2016;63(6):1021–33.PubMedPubMedCentralCrossRef
58.
59.
Wei C, Zhao X, Wang L, et al. TRIP suppresses cell proliferation and invasion in choroidal melanoma via promoting the proteasomal degradation of Twist1. FEBS Lett. 2020;594(19):3170–81.PubMedCrossRef
60.
61.
Ryu KJPark SMPark SH, et al. p38 Stabilizes Snail by Suppressing DYRK2-Mediated Phosphorylation That Is Required for GSK3β-βTrCP-Induced Snail Degradation. Can Res. 2019;79(16):4135–48.CrossRef
62.
Lee TK, Poon RT, Yuen AP, et al. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res. 2006;12(18):5369–76.PubMedCrossRef
63.
64.
González-González R, Ortiz-Sarabia G, Molina-Frechero N, et al. Epithelial-Mesenchymal Transition Associated with Head and Neck Squamous Cell Carcinomas: A Review. Cancers. 2021;13(12):3027.PubMedPubMedCentralCrossRef
65.
Agraval H, Yadav UC. MMP-2 and MMP-9 mediate cigarette smoke extract-induced epithelial-mesenchymal transition in airway epithelial cells via EGFR/Akt/GSK3β/β-catenin pathway: Amelioration by fisetin. Chem Biol Interact. 2019;314:108846.PubMedCrossRef
66.
Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011;278(1):16–27.PubMedCrossRef
67.
Scheau C, Badarau IA, Costache R, et al. The role of matrix metalloproteinases in the epithelial-mesenchymal transition of hepatocellular carcinoma. Anal Cell Pathol. 2019;2019:9423907.CrossRef
68.
Khales SA, Abbaszadegan MR, Majd A, et al. TWIST1 upregulates matrix metalloproteinase (MMP) genes family in esophageal squamous carcinoma cells. Gene Expr Patterns. 2020;37:119127.CrossRef
69.
Roomi MW, Kalinovsky T, Bhanap B, et al. In Vitro Effect of Cytokines, Inducers, and Inhibitors on the Secretion of MMP-2 and MMP-9 in Hepatocarcinoma Cell Line SK-Hep-1. Integr Cancer Ther. 2019;18:1534735419889155.PubMedCentralCrossRef
70.
Mou L, Tian X, Zhou B, et al. Improving outcomes of tyrosine kinase inhibitors in hepatocellular carcinoma: new data and ongoing trials. Front Oncol. 2021;11:752725.PubMedPubMedCentralCrossRef
71.
Yang Z, Tam KYJIjobs. Combination strategies using EGFR-TKi in NSCLC therapy: learning from the gap between pre-clinical results and clinical outcomes. Int J Biol Sci. 2018;14(2):204.PubMedPubMedCentralCrossRef
72.
Luo X-Y, Wu K-M, He X-XJJoE, et al. Advances in drug development for hepatocellular carcinoma: clinical trials and potential therapeutic targets. J Exp Clin Cancer Res. 2021;40(1):172.PubMedPubMedCentralCrossRef
Metadata
Title
Role of pelitinib in the regulation of migration and invasion of hepatocellular carcinoma cells via inhibition of Twist1
Authors
Sewoong Lee
Eunjeong Kang
Unju Lee
Sayeon Cho
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-11217-2

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