Objective We investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness.
Design HCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed.
Results We showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1α deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1α. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2α and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1α.
Conclusions Taken together, our findings suggest the significance of this positive feedback loop between HIF-1α and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.
- HEPATOCELLULAR CARCINOMA
- MOLECULAR BIOLOGY
- MOLECULAR PATHOLOGY
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Contributors C-PC and IOLN provided study concept and design. C-PC, CC-LW, AK-LK, DW-HH, EY-TL, Y-MT, TK-WL and IOLN collected and analysed the data. CPC, CCW, DWH, LKC, TKL and IOLN interpreted the data. C-PC, CC-LW, AK-LK, EY-TL, Y-MT, JM-FL and TK-WL performed the experiments. T-TC, KS-HC, ACYC, RC-LL and IOLN collected the patients' samples. C-PC and IOLN wrote the manuscript. All authors approved the final version of manuscript.
Funding This work was supported by the Hong Kong Research Grants Council (RGC) Theme-based Research Scheme (T12-704116-R), RGC General Research Fund (17111315), Hong Kong Scholars programme (81572373), SK Yee Medical Research Fund 2011 and Lee Shiu Family Foundation.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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