OLA1 promotes colorectal cancer tumorigenesis by activation of HIF1α/CA9 axis

Background: Obg-like ATPase 1 (OLA1) is a highly conserved GTPase, which was over expressed in a variety of malignant tumors, but its role in colorectal cancer (CRC) was poorly studied. Patients and methods: Three public CRC gene databases were applied for OLA1 mRNA expression detection. The clinical data of 111 CRC patients were retrospectively collected from the Second Affiliated Hospital of Zhejiang University (SAHZU) for OLA1 protein expression and Kaplan-Meier Survival analysis. OLA1 stably knocked out CRC cell lines were conducted by CRISPR-Cas9 for experiments in vitro and in vivo. Results: OLA1 was highly expressed in 84% CRC compared to matched surrounding tissues. Patients with OLA1 high expression had a significantly lower 5-year survival rate (47%) than those with OLA1 low expression (75%). OLA1 high expression was an independent factor of poor prognosis in CRC patients. OLA1-KO CRC cell lines showed lower ability of growth and tumorigenesis in vitro and in vivo. By mRNA sequence analysis, we found 113 differential express genes in OLA1-KO cell lines, of which 63 were hypoxic related. HIF1 alpha was a key molecule in hypoxic regulation. Further molecular mechanisms showed HIF1 alpha/CA9 mRNA and/or protein levels were heavily downregulated in OLA1-KO cell lines, which could explain the impaired tumorigenesis. According to previous studies, HIF1 alpha was a downstream gene of GSK3 beta, we verified GSK3 beta was over-activated in OLA1-KO cell lines. Conclusion: OLA1 was a new gene that was associated with carcinogenesis and poor outcomes in CRC by activation of HIF1 alpha/CA9 axis, which may be interpreted by GSK3 beta.

Automated summary

The study found that OLA1 was highly expressed in CRC and was associated with lower survival rate and poor prognosis. Knocking out OLA1 gene inhibited the growth and tumorigenesis ability of CRC cells. Further analysis revealed that the expression levels of hypoxic-related genes HIF1 alpha/CA9 were significantly downregulated after OLA1 knockdown, which may explain the impaired tumorigenesis. Additionally, OLA1 knockout resulted in over-activation of GSK3 beta. Therefore, OLA1 may contribute to the occurrence and prognosis of CRC through the activation of HIF1 alpha/CA9 axis and GSK3 beta.