Tumour suppressor 15-hydroxyprostaglandin dehydrogenase induces differentiation in colon cancer via GLI1 inhibition

Abstract

Inflammation is an established risk factor for colorectal cancer. We and others have shown that colorectal cancer patients with elevated cysteinyl leukotriene receptor 2 (CysLT 2 R) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) levels exhibit good prognoses. However, both CysLT 2 R and 15-PGDH, which act as tumour suppressors, are often suppressed in colorectal cancer. We previously reported that leukotriene C 4 (LTC 4)-induced differentiation in colon cancer via CysLT 2 R signalling. Here, we investigated the involvement of Hedgehog (Hh)-GLI1 signalling, which is often hyperactivated in colorectal cancer. We found that the majority of colorectal cancer patients had high-GLI1 expression, which was negatively correlated with CysLT 2 R, 15-PGDH, and Mucin-2 and overall survival compared with the low-GLI1 group. LTC 4-induced 15-PGDH downregulated both the mRNA and protein expression of GLI1 in a protein kinase A (PKA)-dependent manner. Interestingly, the LTC 4-induced increase in differentiation markers and reduction in Wnt targets remained unaltered in GLI1-knockdown cells. The restoration of GLI1 in 15-PGDH-knockdown cells did not ameliorate the LTC 4-induced effects, indicating the importance of both 15-PGDH and GLI1. LTC 4-mediated reduction in the DCLK1 and LGR5 stemness markers in colonospheres was abolished in cells lacking 15-PGDH or GLI1. Both DCLK1 and LGR5 were highly increased in tumour tissue compared with the matched controls. Reduced Mucin-2 levels were observed both in zebrafish xenografts with GLI1-knockdown cells and in the cysltr2 −/− colitis-associated colon cancer (CAC) mouse model. Furthermore, GLI1 expression was positively correlated with stemness and negatively correlated with differentiation in CRC patients when comparing tumour and mucosal tissues. In conclusion, restoring 15-PGDH expression via CysLT 2 R activation might benefit colorectal cancer patients.

Comprehensive Analysis of Colorectal Cancer Immunity and Identification of Immune-Related Prognostic Targets

“…The gap junction α (GJA) family has been demonstrated to be involved in the cellular proliferation and metastasis of gastric cancer and breast cancer [ 31 , 32 ]. In the current study, we found that CYSLTR2 [ 33 , 34 ], CYP4Z1 [ 35 ], LINC00324 [ 36 ], and PTCSC3 [ 37 ] have shown a close relationship with the initiation and development of tumors and also with the prognosis of the COAD patients.…”

Identification of a Novel Five-Gene Signature as a Prognostic and Diagnostic Biomarker in Colorectal Cancers

“…In our earlier studies, we provided first evidence that LTC 4 , via CysLT 2 R signaling, can induce 15-PGDH expression through the activation of the JNK/AP-1 pathway, and this activation in turn prompts the differentiation of CC cells [ 24 ]. In a follow-up study, we revealed that the induction of 15-PGDH by LTC 4 /CysLT 2 R signaling axis in CC cells downregulated GLI1 and induced differentiation in CC cells [ 25 ].…”

DNA Methylation and Gene Expression of the Cysteinyl Leukotriene Receptors as a Prognostic and Metastatic Factor for Colorectal Cancer Patients

“…Extracted protein was used for western blot analysis of the following proteins: E-Cadherin (#3195, Cell Signaling Technology, Danvers, MA, USA); vimentin (#5741, Cell Signaling Technology, Danvers, MA, USA); CysLT 1 R (NBP2-92396; Novus Biologicals, Centennial, CO, USA). α-Tubulin (sc-8035; Santa Cruz Biotechnology, Heidelberg, Germany) antibodies were used for western blot experiment [ 54 , 62 ].…”