Abstract
Here we study the effects of inducible oncogenic K-Ras (G12V) expression on the polarized morphogenesis of colonic epithelial cells. We provide evidence that the autocrine production of heregulins, ligands for the ErbB3 receptor tyrosine kinase, is responsible for the hyperproliferation and aberrant 3D morphogenesis upon oncogenic K-Ras expression. This is in line with results obtained in primary intestinal organoid cultures, in which exogenous heregulin is shown to interfere with normal tissue architecture. Importantly, ErbB3 inhibition and heregulin gene silencing rescued K-RasG12V-induced features of cell transformation. Together with the increased ErbB3 positivity detected in human high-grade primary colorectal cancers, our findings provide support for an autocrine signaling loop engaged by oncogenic K-Ras involving ErbB3 that contributes to the dedifferentiation of the intestinal epithelium during tumor initiation and progression.
Highlights
Colorectal cancer (CRC) originates from the neoplastic transformation of epithelial cells, progressing from an adenoma to a carcinoma stage [1]
Together with the increased ErbB3 positivity detected in human high-grade primary colorectal cancers, our findings provide support for an autocrine signaling loop engaged by oncogenic K-Ras involving ErbB3 that contributes to the dedifferentiation of the intestinal epithelium during tumor initiation and progression
ErbB1 phosphorylation was readily detectable in both control and K-RasG12V-expressing cells, whereas no phosphorylation was visible for ErbB2 and ErbB3
Summary
Colorectal cancer (CRC) originates from the neoplastic transformation of epithelial cells, progressing from an adenoma to a carcinoma stage [1]. In approximately 40% of CRC cases, somatic missense mutations in codons 12, 13, or 61 of K-Ras impair its GTPase activity, resulting in constitutive activation of the protein [1,2,3] This is thought to uncouple Ras activation from extracellular signaling cues such as growth factor binding to receptor tyrosine kinases (RTKs), thereby conferring growth factor independence to mutant cells. Upon binding of specific peptide ligands the receptors homo- and heterodimerize, triggering tyrosine phosphorylation of the cytoplasmic tails and activation of downstream signaling This includes activation of the Ras proteins, and subsequently the MAPK and PI3K pathways, www.impactjournals.com/oncotarget which mediate biological responses such as proliferation, invasion and survival [6]. The presence of several consensus sites for the p85 subunit of PI3K mediates the potent induction of PI3K-Akt signaling by phosphorylated ErbB3 [8, 10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
