Abstract
Abstract Background: Colorectal cancer is a leading cause of cancer related deaths in US. Various intrinsic and extrinsic factors contribute to the development of colorectal tumors. Prolactin (PRL), a peptide endocrine hormone associated with regulating diverse physiological activities from lactation to stimulating oligodendrocyte cell proliferation is now receiving increasing attention in relation to tumorigenesis. Acting through prolactin receptor (PRLR), prolactin modulates various downstream events via the Jak-STAT and MAPK pathway. Clinical evidences suggest an increased serum prolactin levels in patients with breast, prostate and colorectal cancers. The present study is aimed to understanding the role of PRL in colorectal tumorogenesis. Method: Colorectal cancer cell lines HCT116, HT29 and SW620 were used in the study. Cell growth and proliferation was measured by hexoseaminidase assay. Real Time PCR and Western blot analysis were performed to study the cancer promoting genes, stem cell markers and matrix metalloproteases (MMPs). Spheroid (colosphere) formation was used to assess stem cells in a population. Scratch plate assay was used to assay migration. Prolactin treatment was done in serum free media supplemented with prolactin alone or in combination with reduced levels of EGF, FGF, Heparin and B12 supplements for spheroid formation assay. Results: Quantative RT-PCR and western blot analyses demonstrated that colon cancer cell lines express PRLR. Alternative splicing has been shown to produce different human PRLR isoforms, wherein the short forms can act as dominant negative receptors. However, our studies demonstrated that the colon cancer cell lines expressed predominantly the long form. We next determined the effect of recombinant human prolactin on HCT116 and HT29 cells. PRL treatment did not cause a significant change in proliferation but increased expression of cancer promoting genes including cyclooxygenase-2 (COX-2), interleukin-8 (IL-8), vascular endothelial growth factor- A (VEGF-A) and RNA binding protein protooncogene RBM3. PRL treatment also increased the size and number of colospheres suggesting that PRL affects stem cells. Furthermore, PRL treatment enhanced the expression of CD133 and also of the colon cancer stem cell marker, DCLK1 (doublecortin calmodulin like kinase 1). In addition, PRL treatment resulted in increased migration of SW620 cells when compared to untreated control. This increase in migration was further confirmed by increased expression of MMP-2 and MMP-7 and increased FAK activation. Conclusions: Taken together, these data demonstrate that PRL increases the viability of colon cancer stem cells, expression of cancer promoting genes and migratory capacity. Future Directions: Further investigations would be directed towards understanding the mechanism of PRL signaling in colorectal cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3340. doi:1538-7445.AM2012-3340
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