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  • br Considering the basic role of BPTF in the

    2020-08-18


    Considering the basic role of BPTF in the stemness maintenance of embryonic stem MCC950 and embryonic development [11], we supposed and verified its involvement in the stemness maintenance of CSCs, as evidenced by the remarkably down-regulated tumorsphere-forming ability applied in studying cell self-renewal [35,36]. The levels of CSC-related protein markers, including EpCAM, CD133, CD44 and c-Kit, were down-regulated when BPTF was silenced in vitro and in vivo. Of note, BPTF silencing obviously enhanced the anti-cancer effects of chemotherapeutic drugs in HCC cells, resulting in more tumor cell apoptosis. Given the contribution of CSC in the acquirement of ther-apeutic resistance [37–39], the fact that chemosensitivity was regulated by BPTF confirmed again its effect on CSCs in HCC development.
    From current reports, hTERT has been treated as a critical factor that promotes cell immortalization [40,41]. Our experimental evidence demonstrated knockdown of BPTF expression produced pronounced HCC cell growth inhibition and led to markedly decreased expression of hTERT. The overexpression of hTERT gene partially reversed the  Redox Biology 20 (2019) 427–441
    reduced capabilities of colony formation and tumorsphere formation and suppressed expression of CSC-related markers caused by BPTF shRNA treatment, suggesting the key role of hTERT in BPTF-regulated HCC progression. More importantly, we have identified the binding of BPTF at hTERT promoter and its direct regulation on hTERT at tran-scriptional level. Considering BPTF was defined as nuclear transcription factor to achieve its biological function by regulating downstream genes, most likely, hTERT functions as its direct downstream effector to mediate its protumorigenic function. Conceivably, there must be downstream targets other than hTERT, such as Myc and its downstream signaling molecules, regulated by BPTF directly or indirectly to mediate its function. What are these targets? Whether they play the same role as hTERT in BPTF's carcinogenic function? All these points deserve to be better explored in our future study.
    Analysis of the tissue microarray revealed the remarkable con-sistence in the aspect of BPTF and hTERT expression and their clinical significance. Based on the clinical statistics in a cohort of 81 HCC cases, the expression of BPTF and hTERT was found to be significantly asso-ciated with the TNM stage and overall survival of patients. Moreover, patients showing high BPTF expression similarly displayed more per-centage of high hTERT expression, implying again the potential reg-ulation of hTERT by BPTF in HCC progression. Combined with our experimental data in vivo, which demonstrated the suppressed tumor growth and metastasis in mouse model and the significantly down-regulated hTERT expression in tumor tissues upon BPTF silencing, the clinical analysis not only confirmed the key role of BPTF in promoting HCC development but also suggested the synergy and indispensability of hTERT in such an oncogenic role. Of course, it is better to confirm the diagnostic and prognostic significance of BPTF and its relationship with hTERT in a larger patient cohort. However, based on our current de-termination, targeting BPTF and hTERT simultaneously might provide an important strategy in HCC treatment.
    In summary, our data provide functional evidence and mechanistic insights that BPTF drives HCC progression, including promoting tumor cell proliferation, sustaining CSC traits, and increasing tumor metas-tasis, by transcriptionally activating the expression of hTERT. Our data also demonstrate the contribution of BPTF in regulating the sensitivity of HCC cells to chemotherapeutic drugs, as evidenced by the elevated sensitization to DDP and 5-FU and increased apoptosis induction upon BPTF knockdown. All the results suggest that the activation of BPTF might serve as a biomarker to drive tumor progression and predict poor prognosis and as a promising therapeutic target for patients suffering HCC.
    Acknowledgements
    Conflict of interest
    The authors declare no conflict of interest.
    Appendix A. Supplementary material
    References
    [23] A. El-Mazny, M. Sayed, S. Sharaf, Human telomerase reverse transcriptase mes-senger RNA (tert mRNA) as a tumour marker for early detection of hepatocellular carcinoma, Arab J. Gastroenterol.: Off. Publ. Pan-Arab Assoc. Gastroenterol. 15 (2014) 68–71.
    Contents lists available at ScienceDirect
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