Atypical role of sprouty in p21 dependent inhibition of cell proliferation in colorectal cancer

Abstract

Sprouty (SPRY) appears to act as a tumor suppressor in cancer, whereas we reported that SPRY2 functions as a putative oncogene in colorectal cancer (CRC) [Oncogene, 2010, 29: 5241–5253]. In general, various studies established inhibition of cell proliferation by Sprouty in cancer. The mechanisms by which SPRY regulates cell proliferation in CRC are investigated. We demonstrate, for the first time, suppression of SPRY2 augmented EGF-dependent oncogenic signaling, however, surprisingly decreased cell proliferation in colon cancer cells. Our data suggest that cell cycle inhibitor p21WAF1/CIP1 transcriptional activity being regulated by SPRY2. Indeed, suppression of SPRY2 significantly increased p21WAF1/CIP1 mRNA and protein expression as well as p21WAF1/CIP1 promoter activity. Conversely, overexpressing SPRY2 triggered a decrease in p21WAF1/CIP1 promoter activity. Concurrent down-regulation of both SPRY1 and SPRY2 also increased p21WAF1/CIP1 expression in colon cancer cells. Increased nuclear localization of p21WAF1/CIP1 in SPRY2 downregulated colon cancer cells may explain the inhibition of cell proliferation in colon cancer cells. Underscoring the biological relevance of these findings in SPRY1 and SPRY2 mutant mouse, recombination of floxed SPRY1 and SPRY2 alleles in mouse embryonic fibroblasts (MEFs) resulted in increased expression and nuclear localization of p21WAF1/CIP1 and decreased cell proliferation. In CRC, the relationship of SPRY with p21 may provide unique strategies for cancer prevention and treatment.

CRISPR-Cas9-mediated knockout of SPRY2 in human hepatocytes leads to increased glucose uptake and lipid droplet accumulation

“…Pathway analysis revealed many DE upregulated genes arising from SPRY2 KO to be involved with DNA replication and cell cycle regulation; this is consistent with the established role for SPRY2 in inhibiting cell proliferation and acting as a tumour suppressor in certain types of cancer [14, 46]. Among the highly significant terms several were related to the metabolic processes that regulate cholesterol biosynthesis and fatty acid metabolism, which correlates with our experimental findings suggesting that SPRY2 regulates metabolic processes, such as glucose uptake and lipid accumulation.…”

Sprouty2 enhances the tumorigenic potential of glioblastoma cells

“…This is consistent with previous findings that suppression of ERK levels or activity in both human and mouse primary cells prevented proliferation arrest due to oncogenic stress induced by activated Ras. 34 Zhang et al 35 also reported that SPRY2 KD decreases cell proliferation of colon cancer cells in the presence of increased EGF-dependent ERK and Akt signaling and induction of the cyclin-dependent kinase inhibitor p21 CIP1 . We suggest here that decreased cell proliferation may be caused by oncogene-induced DNA replication stress because silencing SPRY2 causes premature S-phase entry and increased DNA damage.…”

The pseudogene derived from long non-coding RNA DUXAP10 promotes colorectal cancer cell growth through epigenetically silencing of p21 and PTEN

“…The functional role of p21 and PTEN has been previously illustrated in colorectal cancer 32 , 33 . Numerous findings have shown that p21 and PTEN can function as tumor suppressors and closely related with cell proliferation and apoptosis 34 .…”