Transgelin increases metastatic potential of colorectal cancer cells in vivo and alters expression of genes involved in cell motility

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Abstract

Background

Transgelin is an actin-binding protein that promotes motility in normal cells. Although the role of transgelin in cancer is controversial, a number of studies have shown that elevated levels correlate with aggressive tumor behavior, advanced stage, and poor prognosis. Here we sought to determine the role of transgelin more directly by determining whether experimental manipulation of transgelin levels in colorectal cancer (CRC) cells led to changes in metastatic potential in vivo.

Methods

Isogenic CRC cell lines that differ in transgelin expression were characterized using in vitro assays of growth and invasiveness and a mouse tail vein assay of experimental metastasis. Downstream effects of transgelin overexpression were investigated by gene expression profiling and quantitative PCR.

Results

Stable overexpression of transgelin in RKO cells, which have low endogenous levels, led to increased invasiveness, growth at low density, and growth in soft agar. Overexpression also led to an increase in the number and size of lung metastases in the mouse tail vein injection model. Similarly, attenuation of transgelin expression in HCT116 cells, which have high endogenous levels, decreased metastases in the same model. Investigation of mRNA expression patterns showed that transgelin overexpression altered the levels of approximately 250 other transcripts, with over-representation of genes that affect function of actin or other cytoskeletal proteins. Changes included increases in HOOK1, SDCCAG8, ENAH/Mena, and TNS1 and decreases in EMB, BCL11B, and PTPRD.

Conclusions

Increases or decreases in transgelin levels have reciprocal effects on tumor cell behavior, with higher expression promoting metastasis. Chronic overexpression influences steady-state levels of mRNAs for metastasis-related genes.

Electronic supplementary material

The online version of this article (doi:10.1186/s12885-016-2105-8) contains supplementary material, which is available to authorized users.

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Most cited references 47

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The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers.

Selvaraju Veeriah, Cameron Brennan, Shasha Meng … (2009)

Tyrosine phosphorylation plays a critical role in regulating cellular function and is a central feature in signaling cascades involved in oncogenesis. The regulation of tyrosine phosphorylation is coordinately controlled by kinases and phosphatases (PTPs). Whereas activation of tyrosine kinases has been shown to play vital roles in tumor development, the role of PTPs is much less well defined. Here, we show that the receptor protein tyrosine phosphatase delta (PTPRD) is frequently inactivated in glioblastoma multiforme (GBM), a deadly primary neoplasm of the brain. PTPRD is a target of deletion in GBM, often via focal intragenic loss. In GBM tumors that do not possess deletions in PTPRD, the gene is frequently subject to cancer-specific epigenetic silencing via promoter CpG island hypermethylation (37%). Sequencing of the PTPRD gene in GBM and other primary human tumors revealed that the gene is mutated in 6% of GBMs, 13% of head and neck squamous cell carcinomas, and in 9% of lung cancers. These mutations were deleterious. In total, PTPRD inactivation occurs in >50% of GBM tumors, and loss of expression predicts for poor prognosis in glioma patients. Wild-type PTPRD inhibits the growth of GBM and other tumor cells, an effect not observed with PTPRD alleles harboring cancer-specific mutations. Human astrocytes lacking PTPRD exhibited increased growth. PTPRD was found to dephosphorylate the oncoprotein STAT3. These results implicate PTPRD as a tumor suppressor on chromosome 9p that is involved in the development of GBMs and multiple human cancers.

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Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors.

Sumanta Goswami, Gerald Wyckoff, Erik Sahai … (2004)

We subjected cells collected using an in vivo invasion assay to cDNA microarray analysis to identify the gene expression profile of invasive carcinoma cells in primary mammary tumors. Expression of genes involved in cell division, survival, and cell motility were most dramatically changed in invasive cells indicating a population that is neither dividing nor apoptotic but intensely motile. In particular, the genes coding for the minimum motility machine that regulates beta-actin polymerization at the leading edge and, therefore, the motility and chemotaxis of carcinoma cells, were dramatically up-regulated. However, ZBP1, which restricts the localization of beta-actin, the substrate for the minimum motility machine, was down-regulated. This pattern of expression implicated ZBP1 as a suppressor of invasion. Reexpression of ZBP1 in metastatic cells with otherwise low levels of ZBP1 reestablished normal patterns of beta-actin mRNA targeting and suppressed chemotaxis and invasion in primary tumors. ZBP1 reexpression also inhibited metastasis from tumors. These experiments support the involvement in metastasis of the pathways identified in invasive cells, which are regulated by ZBP1.

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Transgelin: an actin-binding protein and tumour suppressor.

Ann-Catherine J. Stanton, Puttur D Prasad, Stephen J. Assinder (2009)

Transgelin is a shape change sensitive 22 kDa actin-binding protein of the calponin family. It contains a C-terminal calponin-like module (CLIK(23)) and an upstream positively charged amino acid region required for actin binding. Transgelin is ubiquitous to vascular and visceral smooth muscle and is an early marker of smooth muscle differentiation, where its expression is driven by CArG box, smooth muscle gene promoter. It is also present in fibroblasts, and some epithelium where expression is likely driven by TGF-beta1. Transgelin null mice reveal that, whilst it is not required for smooth muscle development, transgelin may be involved in calcium-independent smooth muscle contraction. Recent evidence suggests that transgelin acts as a tumour suppressor. Its expression is lost in prostate, breast and colon cancers. This is consistent with suppression of the metallo matrix protease-9 (MMP-9) by transgelin, where MMP-9 is upregulated in these common cancers.

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Author and article information

Contributors

Hui-min Zhou: erikoapril@163.com

Yuan-yuan Fang: fangyy2@sina.cn

Paul M. Weinberger: pweinberger@gru.edu

Ling-ling Ding: llding7538@hotmail.com

John K. Cowell: jcowell@gru.edu

Farlyn Z. Hudson: fhudson@gru.edu

Mingqiang Ren: mren@gru.edu

Jeffrey R. Lee: jlee@gru.edu

Qi-kui Chen: qkchen@21cn.com

Hong Su: sophiasucn@hotmail.com

William S. Dynan: wdynan@emory.edu

Ying Lin: linwy@mail.sysu.edu.cn

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 4 February 2016

Publication date PMC-release: 4 February 2016

Publication date Collection: 2016

Volume: 16

Electronic Location Identifier: 55

Affiliations

[ ]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120 China

[ ]Department of Gastroenterology and Hepatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120 China

[ ]Department of Gastroenterology and Hepatology, The First Affiliated Hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, 510000 China

[ ]Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA 30912 USA

[ ]GRU Cancer Center, Georgia Regents University, Augusta, GA USA

[ ]Department of Anatomy, Wu Han University, Wuhan, China

[ ]Institute of Molecular Medicine and Genetics, Georgia Regents University, Augusta, GA USA

[ ]Department of Pathology, Georgia Regents University, and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA USA

[ ]Departments of Radiation Oncology and Biochemistry, Emory University, Atlanta, GA USA

Article

Publisher ID: 2105

DOI: 10.1186/s12885-016-2105-8

PMC ID: 4741053

PubMed ID: 26847345

SO-VID: 84af2889-b459-4f06-b4e6-0030de99e566

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 28 January 2015

Date accepted : 31 January 2016

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: transgelin,colorectal cancer,experimental metastasis,gene regulation,invasiveness,biomarker

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: transgelin, colorectal cancer, experimental metastasis, gene regulation, invasiveness, biomarker

Transgelin increases metastatic potential of colorectal cancer cells in vivo and alters expression of genes involved in cell motility

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Abstract

Background

Methods

Results

Conclusions

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Karger: Oncology

Most cited references 47

The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers.

Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors.

Transgelin: an actin-binding protein and tumour suppressor.

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