Fibulin-2 Facilitates Malignant Progression of Hepatocellular Carcinoma

Overview

Journal Turk J Gastroenterol

Publisher Aves

Specialty Gastroenterology

Date 2023 May 10

PMID 37162505

Authors

Xinyan Hu

Tianze Liu

Luting Li

Hairun Gan

Tiancheng Wang

Pengfei Pang

Junjie Mao

Affiliations

Soon will be listed here.

Abstract

Background: Identification of biomarkers to assist in the clinical management of hepatocellular carcinoma represents an urgent requirement. Fibulin-2 is known to contribute to the development and progression of various cancer types. This research investigated the role of fibulin-2 in hepatocellular carcinoma and explored the possible mechanisms.

Methods: The expression of fibulin-2 in hepatocellular carcinoma was measured by bioinformatic analysis and confirmed by western blot and immunohistochemical staining in cell lines or patients' samples. The clinicopathologic features of hepatocellular carcinoma patients was analyzed. Cell viability assays were used to explore the role of fibulin-2 on proliferation in hepatocellular carcinoma. Western blot was conducted to uncover changes of protein expression of Ras-MEK-ERK1/2 pathway when Fibulin-2 was overexpressed or silenced. Flow cytometry analyses were used to determine the roles of fibulin-2 in the function of apoptosis and cell cycle. Subcutaneous xenograft mouse models showed the tumor growth pattern after fibulin-2 silence in vivo.

Results: We reported the upregulation of fibulin-2 in most hepatocellular carcinoma tissues and cells lines. Fibulin-2 promoted the proliferation of hepatocellular carcinoma cells in vitro by regulating Ras-MEK-ERK1/2 signaling pathway, whereas knockdown of fibulin-2 incurred the opposite effect on proliferation. Consistently, knockdown of fibulin-2 resulted in increased apoptosis and induced growth arrest during the G0/G1 phase transition. In vivo xenograft assessment confirmed that knockdown of fibulin-2 inhibited hepatocellular carcinoma tumor growth.

Conclusions: Fibulin-2 exhibited tumor promotor activities in malignant progression of hepatocellular carcinoma. The results of the study highlighted the potential of fibulin-2 to be utilized as a promising biomarker and therapeutic target for hepatocellular carcinoma.

Citing Articles

Lung Inflammatory Phenotype in Mice Deficient in Fibulin-2 and ADAMTS-12.

Mohamedi Y, Fontanil T, Vega J, Cobo T, Cal S, Obaya A Int J Mol Sci. 2024; 25(4).

PMID: 38396702 PMC: 10888546. DOI: 10.3390/ijms25042024.

References

Li L, Zhao G, Shi Z, Qi L, Zhou L, Fu Z . The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncol Lett. 2016; 12(5):3045-3050. PMC: 5103898. DOI: 10.3892/ol.2016.5110. View

Ramaswamy S, Ross K, Lander E, Golub T . A molecular signature of metastasis in primary solid tumors. Nat Genet. 2002; 33(1):49-54. DOI: 10.1038/ng1060. View

Delire B, Starkel P . The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications. Eur J Clin Invest. 2015; 45(6):609-23. DOI: 10.1111/eci.12441. View

Lu L, Jiang J, Zhan M, Zhang H, Wang Q, Sun S . Targeting Tumor-Associated Antigens in Hepatocellular Carcinoma for Immunotherapy: Past Pitfalls and Future Strategies. Hepatology. 2020; 73(2):821-832. DOI: 10.1002/hep.31502. View

Yang W, Ma Y, Liu Y, Smith-Warner S, Simon T, Chong D . Association of Intake of Whole Grains and Dietary Fiber With Risk of Hepatocellular Carcinoma in US Adults. JAMA Oncol. 2019; 5(6):879-886. PMC: 6567825. DOI: 10.1001/jamaoncol.2018.7159. View

Xin Y, Jin D, Eppler S, Damico-Beyer L, Joshi A, Davis J . Population pharmacokinetic analysis from phase I and phase II studies of the humanized monovalent antibody, onartuzumab (MetMAb), in patients with advanced solid tumors. J Clin Pharmacol. 2013; 53(11):1103-11. DOI: 10.1002/jcph.148. View

Zhu N, Swietlik E, Welch C, Pauciulo M, Hagen J, Zhou X . Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH. Genome Med. 2021; 13(1):80. PMC: 8112021. DOI: 10.1186/s13073-021-00891-1. View

Longmate W, Monichan R, Chu M, Tsuda T, Mahoney M, DiPersio C . Reduced fibulin-2 contributes to loss of basement membrane integrity and skin blistering in mice lacking integrin α3β1 in the epidermis. J Invest Dermatol. 2014; 134(6):1609-1617. PMC: 4020984. DOI: 10.1038/jid.2014.10. View

Li W, Chan T, Huang S, Wu W, Ke H, Liang P . Prognostic Utility of FBLN2 Expression in Patients With Urothelial Carcinoma. Front Oncol. 2020; 10:570340. PMC: 7659889. DOI: 10.3389/fonc.2020.570340. View

10.

Alcendor D, Knobel S, Desai P, Zhu W, Hayward G . KSHV regulation of fibulin-2 in Kaposi's sarcoma: implications for tumorigenesis. Am J Pathol. 2011; 179(3):1443-54. PMC: 3157165. DOI: 10.1016/j.ajpath.2011.05.024. View

11.

Zekri A, Hafez M, Bahnassy A, Hassan Z, Mansour T, Kamal M . Genetic profile of Egyptian hepatocellular-carcinoma associated with hepatitis C virus Genotype 4 by 15 K cDNA microarray: preliminary study. BMC Res Notes. 2008; 1:106. PMC: 2584108. DOI: 10.1186/1756-0500-1-106. View

12.

Senapati S, Gnanapragassam V, Moniaux N, Momi N, Batra S . Role of MUC4-NIDO domain in the MUC4-mediated metastasis of pancreatic cancer cells. Oncogene. 2011; 31(28):3346-56. PMC: 3298579. DOI: 10.1038/onc.2011.505. View

13.

Law E, Cheung A, Kashuba V, Pavlova T, Zabarovsky E, Lung H . Anti-angiogenic and tumor-suppressive roles of candidate tumor-suppressor gene, Fibulin-2, in nasopharyngeal carcinoma. Oncogene. 2011; 31(6):728-38. DOI: 10.1038/onc.2011.272. View

14.

Yang J, Yan J, Liu B . Targeting VEGF/VEGFR to Modulate Antitumor Immunity. Front Immunol. 2018; 9:978. PMC: 5943566. DOI: 10.3389/fimmu.2018.00978. View

15.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

16.

Yuan R, Li Y, Yang B, Jin Z, Xu J, Shao Z . LOXL1 exerts oncogenesis and stimulates angiogenesis through the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis in ICC. Mol Ther Nucleic Acids. 2021; 23:797-810. PMC: 7868718. DOI: 10.1016/j.omtn.2021.01.001. View

17.

Piscaglia F, Dudas J, Knittel T, Di Rocco P, Kobold D, Saile B . Expression of ECM proteins fibulin-1 and -2 in acute and chronic liver disease and in cultured rat liver cells. Cell Tissue Res. 2009; 337(3):449-62. PMC: 2728066. DOI: 10.1007/s00441-009-0823-9. View

18.

Barriga E, Franze K, Charras G, Mayor R . Tissue stiffening coordinates morphogenesis by triggering collective cell migration in vivo. Nature. 2018; 554(7693):523-527. PMC: 6013044. DOI: 10.1038/nature25742. View

19.

Ma Y, Nenkov M, Schroder D, Abubrig M, Gassler N, Chen Y . Fibulin 2 Is Hypermethylated and Suppresses Tumor Cell Proliferation through Inhibition of Cell Adhesion and Extracellular Matrix Genes in Non-Small Cell Lung Cancer. Int J Mol Sci. 2021; 22(21). PMC: 8584407. DOI: 10.3390/ijms222111834. View

20.

Zhang H, Wu J, Dong H, Khan S, Chu M, Tsuda T . Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-β signalling. Clin Sci (Lond). 2013; 126(4):275-88. PMC: 4075193. DOI: 10.1042/CS20120636. View