Downregulation of dual‐specificity phosphatase 4 enhances cell proliferation and invasiveness in colorectal carcinomas

Abstract

It is widely accepted that aberrant activation of the Wnt signaling pathway is responsible for the development of precursor lesions of colorectal cancer (CRC). However, the molecular mechanisms involved in the process of progression from these precursor lesions to invasive lesions of CRC are not fully understood. Recently, we reported that constitutive activation of MAPK accompanied by downregulation of dual‐specificity phosphatase 4 (DUSP4), a MAPK phosphatase, contributes to the progression of precursor lesions in the pancreas. In this study, we found that downregulation of DUSP4 was related to constitutive activation of ERKs in CRC cells. Restoration of DUSP4 resulted in inactivation of ERKs, leading to suppression of both proliferation and invasiveness, as shown by treatment with an MEK inhibitor. Furthermore, immunohistochemistry revealed that DUSP4 expression was upregulated in the superficial region of CRC tissue, whereas it was significantly downregulated in the deep region. In contrast, ERKs in the deep region were markedly hyperactivated compared to those in the superficial region. These results suggest that activation of the MAPK signaling pathway caused by downregulation of DUSP4 is responsible for progression of CRCs and would be a promising therapeutic target.

Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction

“…All of the drugs used reduced Wnt signaling in these tumor cells already at sublethal concentrations ( Figure S4B) and within 8 h after application ( Figures 2G, 2I, and S4C). In these cells, the effects of XAV939 and the other compounds were less pronounced on the b-catenin level compared to HEK293 cells (Li et al, 2015), most likely due to a mutation in the b-catenin itself in HCT116 (Ichimanda et al, 2018;Shikata et al, 2017). Similar results were obtained in another colon cancer line, DLD1, characterized by constitutively active Wnt signaling due to a truncation in adenomatous polyposis coli (APC) (Homfray et al, 1998;Kishida et al, 1998), concerning viability upon treatment ( Figure S4D), reduction of Wnt signaling (Figures S4E and S4G), ATP depletion ( Figure S4F), and endoplasmic reticulum stress ( Figure S4G).…”

Low DUSP4 Expression Is Associated With Aggressive Phenotypes and Poor Prognosis in Gastric Cancer

“…Ichimanda et al reported that colorectal cancer tissue showed a higher expression of DUSP4 than that in normal tissue. However, compared to the superficial region, DUSP4 expression decreased in the deep region of the tumor, and the activity of ERKs increased (26). Saigusa et al demonstrated that decreased DUSP4 expression in colorectal cancer was significantly correlated with tumor progression and distance metastasis (10).…”

Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer

“…Moreover, DUSP4 overexpression in CRC cell lines produced upregulation of MAPK targets, such as EGR1, FOS, and MYC, and downregulation of the mismatch repair gene MSH2, all these effects leading to an increase in cell proliferation (Gröschl et al, 2013). In contrast, it has been more recently reported that the decrease in the expression of DUSP4 in CRC cell lines activated ERKs, causing cell proliferation and invasiveness (Ichimanda et al, 2018). Interestingly, DUSP4 overexpression in CRC cell lines decreases their sensitivity to doxorubicin, a drug used to treat CRC (Kang et al, 2017).…”