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Myristoylated Alanine-Rich protein Kinase C Substrate (MARCKS) expression modulates the metastatic phenotype in human and murine colon carcinoma in vitro and in vivo
- Source :
- Cancer letters. 333(2)
- Publication Year :
- 2012
-
Abstract
- Several actin-binding proteins have been shown to be altered in metastatic cell lines and tumours and, in particular, Myristoylated Alanine-Rich protein Kinase C substrate (MARCKS) has been implicated in the pathogenesis of various highly metastatic epithelial malignancies. Considering that a large percentage of deaths due to colorectal cancer (CRC) are consequent to hepatic metastasization, aim of this study was to elucidate the involvement and mechanism of MARCKS in CRC by employing in vitro and in vivo approaches. Loss-of and-gain-on function approaches of MARCKS were employed in two human CRC cell lines: Clone A cells expressing MARCKS and LoVo cells known to have a frameshift mutation of MARCKS i.e. typically for MSI-H CRC. The data unveiled that altering MARCKS expression suppresses cell motility and invasion in human colon carcinoma cells when conditioned medium of liver-specific stromal cells (hepatic stellate cells) was used as chemoattractant. Depletion or re-expression of MARCKS inhibited proliferation with a reduction in expression of the mitotic regulator Aurora B kinase (AURKB), whereas AURKB-depletion did not modify MARCKS expression. In murine colon carcinoma CT26 cells, shRNA MARCKS-depletion reduced motility and invasion, and induced an aberrant, prolonged mitotic process. Significantly less metastases were produced in a syngeneic model of colon metastasis by MARCKS-depleted CT26 in comparison to CT26-tumour challenged mice. In conclusion, MARCKS plays an articulated role in the progression of colorectal cancer and might represent a suitable target to interfere and overcome the invasive behaviour of colon carcinoma cells at primary and distant sites.
- Subjects :
- Cancer Research
Stromal cell
metastasi
colon carcinoma
motility
Aurora B kinase
Mitosis
Biology
Protein Serine-Threonine Kinases
Metastasis
Small hairpin RNA
Mice
Liver Neoplasms, Experimental
Aurora Kinases
Cell Movement
Cell Line, Tumor
medicine
Hepatic Stellate Cells
Animals
Aurora Kinase B
Humans
MARCKS
RNA, Small Interfering
Myristoylated Alanine-Rich C Kinase Substrate
Protein kinase C
Mice, Inbred BALB C
Intracellular Signaling Peptides and Proteins
Membrane Proteins
medicine.disease
Actins
Gene Expression Regulation, Neoplastic
Oncology
Cell culture
Colonic Neoplasms
Hepatic stellate cell
Cancer research
Stromal Cells
Colorectal Neoplasms
Subjects
Details
- ISSN :
- 18727980
- Volume :
- 333
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cancer letters
- Accession number :
- edsair.doi.dedup.....5fbdd0e05ad837db0c909fc0d6dc8391