title: Myristoylated Alanine-Rich protein Kinase C Substrate (MARCKS) expression modulates the metastatic phenotype in human and murine colon carcinoma in vitro and in vivo.
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.
authors: Department of Internal Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy. k.rombouts@dmi.unifi.it
authors: Krista
authors: K
authors: Rombouts
authors: Vinicio
authors: V
authors: Carloni
authors: Tommaso
authors: T
authors: Mello
authors: Sara
authors: S
authors: Omenetti
authors: Sara
authors: S
authors: Galastri
authors: Stefania
authors: S
authors: Madiai
authors: Andrea
authors: A
authors: Galli
authors: Massimo
authors: M
authors: Pinzani
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000556:secondary; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008938:Mitosis; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D000199:Actins; D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases