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

Shakti Ranjan Satapathy,Fredrik Ek,Wondossen Sime,Geriolda Topi,Anita Sjölander,Karin Hellman,Lubna M Mehdawi,Janina Osman,Roger Olsson

doi:10.1038/s41389-020-00256-0

Shakti Ranjan Satapathy, Fredrik Ek + Show 7 more

Open Access

https://doi.org/10.1038/s41389-020-00256-0

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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 (CysLT2R) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) levels exhibit good prognoses. However, both CysLT2R and 15-PGDH, which act as tumour suppressors, are often suppressed in colorectal cancer. We previously reported that leukotriene C4 (LTC4)-induced differentiation in colon cancer via CysLT2R 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 CysLT2R, 15-PGDH, and Mucin-2 and overall survival compared with the low-GLI1 group. LTC4-induced 15-PGDH downregulated both the mRNA and protein expression of GLI1 in a protein kinase A (PKA)-dependent manner. Interestingly, the LTC4-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 LTC4-induced effects, indicating the importance of both 15-PGDH and GLI1. LTC4-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 CysLT2R activation might benefit colorectal cancer patients.

Highlights

Colorectal cancer (CRC), one of the most prevalent cancers in the world, has a high metastatic efficacy and a low 5-year survival rate[1]
PGDH, and Mucin-2 expression in CRC patients To elucidate the regulatory activity of GLI1 on the antitumorigenic proteins CysLT2R and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and the differentiation marker Mucin-2 in colon cancer, we used a tissue microarray (TMA) of primary CRCs from 326 patients[22]
These results suggest that GLI1 expression is negatively correlated with CysLT2R, 15PGDH, and Mucin-2 expression but positively with the mucinous status of the patients

Summary

Introduction

Colorectal cancer (CRC), one of the most prevalent cancers in the world, has a high metastatic efficacy and a low 5-year survival rate[1]. In CRC, abnormal Hh signalling functions in a liganddependent manner and is activated in human CC cell lines[7] and xenograft models[4]. The role of Hh signalling and its importance in cell survival in CRC are not well defined. Some previous studies have failed to derive a positive correlation between Hh signalling and CRC initiation and maintenance[8,9], major bodies of evidence point to a positive correlation[3,4,7]. Previous reports have suggested high activity of the Hh–SMO–GLI axis in CRC cell survival and metastasis, which is coordinated by either canonical signalling

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