Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

LMO3 promotes hepatocellular carcinoma invasion, metastasis and anoikis inhibition by directly interacting with LATS1 and suppressing Hippo signaling

Authors: Yang Cheng, Tianlu Hou, Jian Ping, Tianyang Chen, Baobing Yin

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Login to get access

Abstract

Background

In this research, we aimed to investigate the biological functions of LIM domain only 3 (LMO3) in hepatocellular carcinoma (HCC) and uncover the underlying molecular mechanism in it.

Methods

HCC tissue microarray (n = 180) was used to analyze the correlation between LMO3 expression and clinicopathological findings. In vitro transwell matrigel invasion assay and annexin V anoikis assay in HCC cells were conducted to investigate LMO3 related biological functions. In vivo intrahepatic and lung metastasis models were used to determine the role of LMO3 in HCC metastasis. Quantitative real-time PCR, western blotting and immunohistochemical staining were performed to investigate the expression and mechanism of LMO3 in HCC.

Results

We found that the expression of LMO3 was significantly upregulated in HCC tissues, and it was closely related to clinicopathological findings and patient prognoses. Knockdown of LMO3 suppressed the invasion and anoikis inhibition of HCC cells in vitro. Meanwhile, the metastasis of SMMC-7721 cells was also suppressed by LMO3 knockdown in vivo. Furthermore, we found that LMO3 knockdown increased the phosphorylation of YAP and LATS1, and decrease Rho GTPases activities. LMO3 directly interacted with LATS1, and thus suppressed Hippo signaling. Recombinant LMO3 (rLMO3) protein administration decreased the phosphorylation of YAP and LATS1, and increased Rho GTPases activities. The inhibitors of the Hippo pathway abrogated rLMO3 protein-induced HCC cell invasion and anoikis inhibition.

Conclusions

These results suggest that LMO3 promotes HCC cell invasion and anoikis inhibition by interacting with LATS1 and suppressing Hippo signaling. LMO3 may serve as a potential therapeutic target for HCC in future.
Appendix
Available only for authorised users
Literature
1.
El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.CrossRef
2.
Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, et al. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol. 2007;25:3069–75.CrossRef
3.
Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology. 2008;48:2047–63.CrossRef
4.
Bacac M, Stamenkovic I. Metastatic cancer cell. Annu Rev Pathol. 2008;3:221–47.CrossRef
5.
Zender L, Villanueva A, Tovar V, Sia D, Chiang DY, Llovet JM. Cancer gene discovery in hepatocellular carcinoma. J Hepatol. 2010;52:921–9.CrossRef
6.
Mínguez B, Hoshida Y, Villanueva A, Toffanin S, Cabellos L, Thung S, et al. Gene-expression signature of vascular invasion in hepatocellular carcinoma. J Hepatol. 2011;55:1325–31.CrossRef
7.
Yimlamai D, Fowl BH, Camargo FD. Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. J Hepatol. 2015;63:1491–501.CrossRef
8.
Wu H, Wei L, Fan F, Ji S, Zhang S, Geng J, et al. Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis. Nat Commun. 2015;6:6239.CrossRef
9.
Janse van Rensburg HJ, Yang X. The roles of the Hippo pathway in cancer metastasis. Cell Signal. 2016;28:1761–72.CrossRef
10.
11.
Rabbitts TH. LMO T-cell translocation oncogenes typify genes activated by chromosomal translocations that alter transcription and developmental processes. Genes Dev. 1998;12:2651–7.CrossRef
12.
Sum EY, Segara D, Duscio B, Bath ML, Field AS, Sutherland RL, et al. Overexpression of LMO4 induces mammary hyperplasia, promotes cell invasion, and is a predictor of poor outcome in breast cancer. Proc Natl Acad Sci U S A. 2005;102:7659–64.CrossRef
13.
Visvader JE, Venter D, Hahm K, Santamaria M, Sum EY, O’Reilly L, et al. The LIM domain gene LMO4 inhibits differentiation of mammary epithelial cells in vitro and is overexpressed in breast cancer. Proc Natl Acad Sci U S A. 2001;98:14452–7.CrossRef
14.
Aoyama M, Ozaki T, Inuzuka H, Tomotsune D, Hirato J, Okamoto Y, et al. LMO3 interacts with neuronal transcription factor, HEN2, and acts as an oncogene in neuroblastoma. Cancer Res. 2005;65:4587–97.CrossRef
15.
Isogai E, Ohira M, Ozaki T, Oba S, Nakamura Y, Nakagawara A. Oncogenic LMO3 collaborates with HEN2 to enhance neuroblastoma cell growth through transactivation of Mash1. PLoS One. 2011;6:e19297.CrossRef
16.
Song YF, Hong JF, Liu DL, Lin QA, Lan XP, Lai GX. miR-630 targets LMO3 to regulate cell growth and metastasis in lung cancer. Am J Transl Res. 2015;7:1271–9.PubMedPubMedCentral
17.
Watanabe H, Francis JM, Woo MS, Etemad B, Lin W, Fries DF, et al. Integrated cistromic and expression analysis of amplified NKX2-1 in lung adenocarcinoma identifies LMO3 as a functional transcriptional target. Genes Dev. 2013;27:197–210.CrossRef
18.
Zhang Z, et al. Migration of epithelial cells on laminins: RhoA antagonizes directionally persistent migration. Eur J Cell Biol. 2011;90:1–12.CrossRef
19.
Liu Y, Ding Y, Huang J, Wang S, Ni W, Guan J, et al. MiR-141 suppresses the migration and invasion of HCC cells by targeting Tiam1. PLoS One. 2014;9:e88393.CrossRef
20.
Wang YH, Dong YY, Wang WM, Xie XY, Wang ZM, Chen RX, et al. Vascular endothelial cells facilitated HCC invasion and metastasis through the Akt and NF-κB pathways induced by paracrine cytokines. J Exp Clin Cancer Res. 2013;32:51.CrossRef
21.
Chen B, Tang J, Guo YS, Li Y, Chen ZN, Jiang JL. Calpains are required for invasive and metastatic potentials of human HCC cells. Cell Biol Int. 2013;37:643–52.CrossRef
22.
Xie B, Xing R, Chen P, Gou Y, Li S, Xiao J, et al. Down-regulation of c-Met expression inhibits human HCC cells growth and invasion by RNA interference. J Surg Res. 2010;162:231–8.CrossRef
23.
Cui JF, Liu YK, Zhang LJ, Shen HL, Song HY, Dai Z, et al. Identification of metastasis candidate proteins among HCC cell lines by comparative proteome and biological function analysis of S100A4 in metastasis in vitro. Proteomics. 2006;6:5953–61.CrossRef
24.
Han Q, Lin X, Zhang X, Jiang G, Zhang Y, Miao Y, et al. WWC3 regulates the Wnt and Hippo pathways via Dishevelled proteins and large tumour suppressor 1, to suppress lung cancer invasion and metastasis. J Pathol. 2017;242:435–47.CrossRef
25.
Tong R, Yang B, Xiao H, Peng C, Hu W, Weng X, et al. KCTD11 inhibits growth and metastasis of hepatocellular carcinoma through activating Hippo signaling. Oncotarget. 2017;8:37717–29.PubMedPubMedCentral
26.
Varzavand A, Hacker W, Ma D, Gibson-Corley K, Hawayek M, Tayh OJ, et al. α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway. Cancer Res. 2016;76:6577–87.CrossRef
27.
Wei C, Wang Y, Li X. The role of Hippo signal pathway in breast cancer metastasis. Onco Targets Ther. 2018;11:2185–93.CrossRef
28.
Salcedo Allende MT, Zeron-Medina J, Hernandez J, Macarulla T, Balsells J, Merino X, et al. Overexpression of Yes Associated Protein 1, an Independent Prognostic Marker in Patients With Pancreatic Ductal Adenocarcinoma, Correlated With Liver Metastasis and Poor Prognosis. Pancreas. 2017;46:913–20.CrossRef
29.
Qiao Y, Chen J, Lim YB, Finch-Edmondson ML, Seshachalam VP, Qin L, et al. YAP Regulates Actin Dynamics through ARHGAP29 and Promotes Metastasis. Cell Rep. 2017;19:1495–502.CrossRef
30.
Li C, Wang S, Xing Z, Lin A, Liang K, Song J, et al. A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis. Nat Cell Biol. 2017;19:106–19.CrossRef
31.
32.
Qiu YS, Jiang NN, Zhou Y, Yu KY, Gong HY, Liao GJ. LMO3 promotes gastric cancer cell invasion and proliferation through Akt-mTOR and Akt-GSK3β signaling. Int J Mol Med. 2018;41:2755–63.PubMedPubMedCentral
Metadata
Title
LMO3 promotes hepatocellular carcinoma invasion, metastasis and anoikis inhibition by directly interacting with LATS1 and suppressing Hippo signaling
Authors
Yang Cheng
Tianlu Hou
Jian Ping
Tianyang Chen
Baobing Yin
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0903-3

Other articles of this Issue 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Go to the issue

Research

Over-expressed lncRNA HOTAIRM1 promotes tumor growth and invasion through up-regulating HOXA1 and sequestering G9a/EZH2/Dnmts away from the HOXA1 gene in glioblastoma multiforme

Research

Tunicamycin specifically aggravates ER stress and overcomes chemoresistance in multidrug-resistant gastric cancer cells by inhibiting N-glycosylation

Research

ERRα suppression enhances the cytotoxicity of the MEK inhibitor trametinib against colon cancer cells

Research

Semaphorin 5A drives melanoma progression: role of Bcl-2, miR-204 and c-Myb

Review

Clinical applications of liquid biopsy as prognostic and predictive biomarkers in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA

Research

An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits