Dual‐specificity phosphatase 6 deletion protects the colonic epithelium against inflammation and promotes both proliferation and tumorigenesis

Abstract

The Ras/mitogen‐activated protein kinase (MAPK) pathway controls fundamental cellular processes such as proliferation, differentiation, and apoptosis. The dual‐specificity phosphatase 6 (DUSP6) regulates cytoplasmic MAPK signaling by dephosphorylating and inactivating extracellular signal‐regulated kinase (ERK1/2) MAPK. To determine the role of DUSP6 in the maintenance of intestinal homeostasis, we characterized the intestinal epithelial phenotype of Dusp6 knockout (KO) mice under normal, oncogenic, and proinflammatory conditions. Our results show that loss of Dusp6 increased crypt depth and epithelial cell proliferation without altering colonic architecture. Crypt regeneration capacity was also enhanced, as revealed by ex vivo Dusp6 KO organoid cultures. Additionally, loss of Dusp6 induced goblet cell expansion without affecting enteroendocrine and absorptive cell differentiation. Our data also demonstrate that Dusp6 KO mice were protected from acute dextran sulfate sodium‐induced colitis, as opposed to wild‐type mice. In addition, Dusp6 gene deletion markedly enhanced tumor load in Apc Min/+ mice. Decreased DUSP6 expression by RNA interference in HT29 colorectal cancer cells enhanced ERK1/2 activation levels and promoted both anchorage‐independent growth in soft agar as well as invasion through Matrigel. Finally, DUSP6 mRNA expression in human colorectal tumors was decreased in advanced stage tumors compared with paired normal tissues. These results demonstrate that DUSP6 phosphatase, by controlling ERK1/2 activation, regulates colonic inflammatory responses, and protects the intestinal epithelium against oncogenic stress.

Dusp6 Depletion Enhances Gut Barrier Integrity and Microbiota Eubiosis Against Dextran Sulfate Sodium-Induced Colitis in Mice

“…The effects of gut microbiota may be another key factor contributing to the discrepant results compared to our study, as we found that the gut microbiota derived from Dusp6-deficient mice could confer host resistance to DSS-induced colonic injury. A recent report from Beaudry et al also indicated that Dusp6-knockout mice are more resistant to DSS-induced colonic injury compared to WT mice [37], which is consistent with our findings. However, the Beaudry et al…”

LRIG3 represses cell motility by inhibiting slug via inactivating ERK signaling in human colorectal cancer

“…Dual‐specificity phosphatase 6 (DUSP6) is a member of the MAPK phosphatase family that can specifically bind to ERK1/2 and subsequently dephosphorylate ERK, resulting in the inactivation of oncogenic ERK pathway . DUSP6 was reported to be significantly downregulated in a variety of human cancers including endometrial adenocarcinoma, non‐small cell lung lancer, thyroid cancer, cutaneous squamous cell carcinoma, and CRC . However, our data showed that LRIG3 exerted the metastasis‐inhibiting role in CRC not by upregulation of DUSP6 expression, but by affecting the interaction between DUSP6 and ERK.…”

Knockdown of TRIM9 attenuates irinotecan‑induced intestinal mucositis in IEC‑6 cells by regulating DUSP6 expression via the P38 pathway

“…TRIM9 directly interacts with DUSP6 in IEC-6 cells. due to the more current reports concerning the roles of duSP members in irinotecan-induced intestinal mucositis (22,(40)(41)(42), duSP1, duSP4, duSP5, duSP6 and duSP10 were investigated in the current study. it was found that the protein expression levels of duSP1, duSP4, duSP5, duSP6 and duSP10 were decreased in iec-6 cells transfected with oeTriM9.…”

“…Dual-specificity phosphatases (DUSPs) are mitogen-activated protein kinase phosphatases (MKPs) characterized by their variable N-terminal mitogen-activated protein kinase (MAPK)-binding region, which contains the kinase interaction motif, and can govern the specificity of the substrate and stability of interactions ( 22 ). Notably, a previous study showed that DUSP1 is elevated in the differentiated villi cells of the adult intestine, but not in the proliferating crypt cells ( 23 ).…”