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Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells

Authors: Xiaoqing He, Liying Wang, Heimo Riedel, Kai Wang, Yong Yang, Cerasela Zoica Dinu, Yon Rojanasakul

Published in: Molecular Cancer | Issue 1/2017

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Abstract

Background

Lung cancer and pleural mesothelioma are two of the most deadly forms of cancer. The prognosis of lung cancer and mesothelioma is extremely poor due to limited treatment modalities and lack of understanding of the disease mechanisms. We have identified mesothelin as a potentially unique therapeutic target that as a specific advantage appears nonessential in most cell types. Mesothelin (MSLN), a plasma membrane differentiation antigen, is expressed at a high level in many human solid tumors, including 70% of lung cancer and nearly all mesotheliomas. However, the role of MSLN in the disease process and underlying mechanisms is largely unknown.

Methods

ShRNA knockdown and overexpression of MSLN were performed in human cancer cell lines and corresponding normal cells, respectively. Tumorigenic and metastatic effects of MSLN were examined by tumor sphere formation, migration, and invasion assays in vitro, as well as xenograft tumor assay in vivo. EMT and CSCs were detected by qPCR array, immunoblotting and flow cytometry.

Results

MSLN plays a key role in controlling epithelial-to-mesenchymal transition (EMT) and stem properties of human lung cancer and mesothelioma cells that control their tumorigenicity and metastatic potential. Firstly, MSLN was found to be highly upregulated in non-small cell lung cancer (NSCLC) patient tissues and in lung carcinoma and mesothelioma cell lines. Secondly, genetic knockdown of MSLN significantly reduced anchorage-independent cell growth, tumor sphere formation, cell adhesion, migration and invasion in vitro, as well as tumor formation and metastasis in vivo. Thirdly, ectopic overexpression of MSLN induced the malignant phenotype of non-cancerous cells, supporting its role as an oncogene. Finally, mechanistic studies revealed that knockdown of MSLN reversed EMT and attenuated stem cell properties, in addition to inhibiting tumor growth and metastasis.

Conclusions

These results indicate an essential role of MSLN in controlling EMT and stem cell properties of human lung cancer and mesothelioma cells. Since EMT is an important process in tumor progression and metastasis, and MSLN is nonessential in most normal tissue, our findings on MSLN may provide new insights into the disease mechanisms and may aid in the development of novel targeted therapy for lung cancer and mesothelioma.
Literature
1.
2.
3.
Sugarbaker DJ. Multimodality management of malignant pleural mesothelioma: Introduction. YSTCS. 2009;21:95–6.
4.
Frieden TR, Jaffe HW, Stephens JW, Thacker SB. Morbidity and Mortality Weekly Report Centers for Disease Control and Prevention. MMWR Editorial and Production Staff. MMWR. 2012;61:869–88.
5.
Chang K, Pastan I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Cell Biol. 1996;93:136–40.
6.
Scholler N, Fu N, Yang Y, Ye Z, Goodman GE, Hellstrm KE, et al. Soluble member(s) of the mesothelin͞megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma. Med Sci. 1999;96:11531–6.
7.
Morello A, Sadelain M, Adusumilli PS. Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov. 2016;6:133–46.CrossRefPubMed
8.
Somers EB, O’Shannessy DJ. Folate receptor alpha, mesothelin and megakaryocyte potentiating factor as potential serum markers of chronic kidney disease. Biomark Insights. 2014;9:29–37.PubMedCentralPubMed
9.
Kachala SS, Bograd AJ, Villena-Vargas J, Suzuki K, Servais EL, Kadota K, et al. Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma. Clin Cancer Res. 2014;20:1020–8.CrossRefPubMed
10.
Melaiu O, Stebbing J, Lombardo Y, Bracci E, Uehara N, Bonotti A, et al. MSLN gene silencing has an anti-malignant effect on cell lines overexpressing mesothelin deriving from malignant pleural mesothelioma. PLoS One. 2014;9:e85935.CrossRefPubMedCentralPubMed
11.
Wang K, Bodempudi V, Liu Z, Borrego-Diaz E, Yamoutpoor F, Meyer A, et al. Inhibition of mesothelin as a novel strategy for targeting cancer cells. PLoS One. 2012;7:e33214.CrossRefPubMedCentralPubMed
12.
Uehara N, Matsuoka Y, Tsubura A. Mesothelin promotes anchorage-independent growth and prevents anoikis via extracellular signal-regulated kinase signaling pathway in human breast cancer cells. Mol Cancer Res. 2008;6:186–93.CrossRefPubMed
13.
Bharadwaj U, Marin-Muller C, Li M, Chen C, Yao Q. Mesothelin confers pancreatic cancer cell resistance to TNF-α-induced apoptosis through Akt/PI3K/NF-κB activation and IL-6/Mcl-1 overexpression. Mol Cancer. 2011;10:106.CrossRefPubMedCentralPubMed
14.
Chang M-C, Chen C-A, Hsieh C-Y, Lee C-N, Su Y-N, Hu Y-H, et al. Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway. Biochem J. 2009;424:449–58.CrossRefPubMed
15.
Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.CrossRefPubMed
16.
Lan L, Luo Y, Cui D, Shi B-Y, Deng W, Huo L-L, et al. Epithelial-mesenchymal transition triggers cancer stem cell generation in human thyroid cancer cells. Int J Oncol. 2013;43:113–20.PubMed
17.
Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.CrossRefPubMedCentralPubMed
18.
Hayashida T, Jinno H, Kitagawa Y, Kitajima M, Hayashida T, Jinno H, et al. Cooperation of cancer stem cell properties and epithelial-mesenchymal transition in the establishment of breast cancer metastasis. J Oncol. 2011;2011:1–7.CrossRef
19.
Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14:818–29.CrossRefPubMed
20.
21.
Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, et al. E-Cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol. 1991;113:173–85.CrossRefPubMed
22.
Sowa G, Sowa G. Novel insights into the role of caveolin-2 in cell- and tissue-specific signaling and function. Biochem Res. 2011;2011:1–9.CrossRef
23.
Caramel J, Papadogeorgakis E, Hill L, Browne GJ, Richard G, Wierinckx A, et al. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell. 2013;24:466–80.CrossRefPubMed
24.
Moreno-Bueno G, Portillo F, Cano A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene. 2008;27:6958–69.CrossRefPubMed
25.
26.
Raha D, Wilson TR, Peng J, Peterson D, Yue P, Evangelista M, et al. The cancer stem cell marker aldehyde dehydrogenase is required to maintain a drug-tolerant tumor cell subpopulation. Cancer Res. 2014;74:3579–90.CrossRefPubMed
27.
28.
Bharadwaj U, Marin-Muller C, Li M, Chen C, Yao Q. Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation. Carcinogenesis. 2011;32:1013–24.CrossRefPubMedCentralPubMed
29.
Servais EL, Colovos C, Rodriguez L, Bograd AJ, Nitadori J, Sima C, et al. Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients. Clin Cancer Res. 2012;1:2478–89.CrossRef
30.
Kallergi G, Papadaki MA, Politaki E, Mavroudis D, Georgoulias V, Agelaki S. Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Res. 2011;13(R59):1–11.
31.
Giordano A, Gao H, Anfossi S, Cohen E, Mego M, Lee B-N, et al. Molecular medicine in practice epithelial–mesenchymal transition and stem cell markers in patients with HER2-positive metastatic breast cancer. Cancer Ther. 2012;11:2526–34.CrossRef
32.
Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339:580–4.CrossRefPubMedCentralPubMed
33.
Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin- low and metaplastic breast cancer subtypes. Proc Natl Acad Sci USA. 2010;107:15449–54.CrossRefPubMedCentralPubMed
34.
Morata-Tarifa C, Jiménez G, García MA, Entrena JM, Griñán-Lisón C, Aguilera M, et al. Low adherent cancer cell subpopulations are enriched in tumorigenic and metastatic epithelial-to-mesenchymal transition-induced cancer stem-like cells. Sci Rep. 2016;6:1–13. e18772.CrossRef
35.
Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, Mccallister F, et al. EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148:349–61.CrossRefPubMedCentralPubMed
36.
Van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin: Introduction to E-cadherin. Cell Mol Life Sci. 2008;65:3756–88.CrossRefPubMed
37.
38.
Du D, Xu F, Yu L, Zhang C, Lu X, Yuan H, et al. The tight junction protein, occludin, regulates the directional migration of epithelial cells. Dev Cell. 2010;18:52–63.CrossRefPubMed
39.
Martin TA, Mansel RE, Jiang WG. Loss of occludin leads to the progression of human breast cancer. Int J Mol Med. 2010;26:723–34.CrossRefPubMed
40.
Je. The role of transcription factor TWIST in cancer cells. J Genet Syndr Gene Ther. 2013;4:1–7.
41.
Barrallo-Gimeno A, Angela NM. The snail genes as inducers of cell movement and survival: implication in development and cancer. Development. 2005;132:3151–61.CrossRefPubMed
42.
43.
Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.CrossRefPubMed
44.
Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008;68:3645–54.CrossRefPubMed
Metadata
Title
Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells
Authors
Xiaoqing He
Liying Wang
Heimo Riedel
Kai Wang
Yong Yang
Cerasela Zoica Dinu
Yon Rojanasakul
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0633-8

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