title: Decreased tumor progression and invasion by a novel anti-cell motility target for human colorectal carcinoma cells.
abstract: We have previously described a novel modulator of the actin cytoskeleton that also regulates Ras and mitogen-activated protein kinase activities in TGFβ-sensitive epithelial cells. Here we examined the functional role of this signaling regulatory protein (km23-1) in mediating the migration, invasion, and tumor growth of human colorectal carcinoma (CRC) cells. We show that small interfering RNA (siRNA) depletion of km23-1 in human CRC cells inhibited constitutive extracellular signal-regulated kinase (ERK) activation, as well as pro-invasive ERK effector functions that include phosphorylation of Elk-1, constitutive regulation of c-Fos-DNA binding, TGFβ1 promoter transactivation, and TGFβ1 secretion. In addition, knockdown of km23-1 reduced the paracrine effects of CRC cell-secreted factors in conditioned medium and in fibroblast co-cultures. Moreover, km23-1 depletion in human CRC cells reduced cell migration and invasion, as well as expression of the ERK-regulated, metastasis-associated scaffold protein Ezrin. Finally, km23-1 inhibition significantly suppressed tumor formation in vivo. Thus, our results implicate km23-1 as a novel anti-metastasis target for human colon carcinoma cells, capable of decreasing tumor growth and invasion via a mechanism involving suppression of various pro-migratory features of CRC. These include a reduction in ERK signaling, diminished TGFβ1 production, decreased expression of the plasma membrane-cytoskeletal linker Ezrin, as well as attenuation of the paracrine effects of colon carcinoma-secreted factors on fibroblast migration and mitogenesis. As such, km23-1 inhibitors may represent a viable therapeutic strategy for interfering with colon cancer progression and invasion.
authors.affiliation: Department of Biochemistry and Molecular Biology, Penn State Hershey College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Qunyan
authors.initials: Q
authors.lastname: Jin
authors.forename: Guangming
authors.initials: G
authors.lastname: Liu
authors.forename: Phillip P
authors.initials: PP
authors.lastname: Domeier
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Mulder
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000737:chemistry; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D056445:Cytoplasmic Dyneins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015194:Diffusion Chambers, Culture; D004338:Drug Combinations; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006801:Humans; D007797:Laminin / Q000737:chemistry; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011509:Proteoglycans / Q000737:chemistry; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism; D000099149:Ezrin
chemical_list: D003094:Collagen; D056445:Cytoplasmic Dyneins; D003598:Cytoskeletal Proteins; D004338:Drug Combinations; D048049:Extracellular Signal-Regulated MAP Kinases; D007797:Laminin; D011509:Proteoglycans; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D050807:ets-Domain Protein Elk-1; D000099149:Ezrin; C504797:DYNLRB1 protein, human; C059485:matrigel