Details

Autor(en) / Beteiligte

• He, Miao
• Yang, Huan
• Shi, Hangchuan
• Hu, Yixi
• Chang, Chawnshang
• Liu, Shunfang
• Yeh, Shuyuan

Titel

Sunitinib increases the cancer stem cells and vasculogenic mimicry formation via modulating the lncRNA-ECVSR/ERβ/Hif2-α signaling

Ist Teil von

• Cancer letters, 2022-01, Vol.524, p.15-28

Ort / Verlag

Ireland: Elsevier B.V

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Sunitinib is the first-line drug for treating renal cell carcinoma (RCC), and it functions mainly through inhibition of tumor angiogenesis. However, the patients may become insensitive or develop resistance toward sunitinib treatment, but the underlying mechanisms have not yet been fully elucidated. Herein, it was found that sunitinib could have adverse effects of promoting RCC progression by increasing vascular mimicry (VM) formation of RCC cells. Mechanism dissection revealed that sunitinib can increase the expression of a long non-coding RNA (lncRNA), lncRNA-ECVSR, thereby enhancing the stability of estrogen receptor β (ERβ) mRNA. Subsequently, the increased ERβ expression can then function via transcriptional up-regulation of Hif2-α. Notably, sunitinib-increased lncRNA-ECVSR/ERβ/Hif2-α signaling resulted in an increased cancer stem cell (CSC) phenotype, thereby promoting VM formation. Furthermore, the sunitinib/lncRNA-ECVSR-increased ERβ expression can transcriptionally regulate lncRNA-ECVSR expression via a positive-feedback loop. Supportively, preclinical studies using RCC mouse xenografts demonstrated that combining sunitinib with the small molecule anti-estrogen PHTPP can increase sunitinib efficacy with reduced VM formation. Collectively, the findings of this study may aid in the development of potential biomarker(s) and novel therapies to better monitor and suppress RCC progression. •The function of LncRNA-ECVSR in RCC is new and an under-explored area.•The regulatory loop of ERβ-LncRNA-ECVSR in the sunitinib treatment and vasculogenic mimicry formation may help to develop new biomarkers to monitor, or alternative therapies for the RCC treatment.•Vasculogenic mimicry formation is induced during sunitinib treatment of RCC and may be a treatment target for increasing sunitinib efficacy.