ARID1A Inactivation Increases Expression of circ0008399 and Promotes Cisplatin Resistance in Bladder Cancer

Objective Cisplatin(CDDP)-based chemotherapy is a first-line,drug regimen for muscle-invasive bladder cancer(BC)and metastatic bladder cancer.Clinically,resistance to CDDP restricts the clinical benefit of some bladder cancer patients.AT-rich interaction domain 1A(ARID1A)gene mutation occurs frequently in bladder cancer;however,the role of CDDP sensitivity in BC has not been studied.Methods We established ARID1A knockout BC cell lines using CRISPR/Cas9 technology.IC50 determination,flow cytometry analysis of apoptosis,and tumor xenograft assays were performed to verify changes in the CDDP sensitivity of BC cells losing ARID1A.qRT-PCR,Western blotting,RNA interference,bioinformatic analysis,and ChIP-qPCR analysis were performed to further explore the potential mechanism of ARID1A inactivation in CDDP sensitivity in BC.Results It was found that ARID1A inactivation was associated with CDDP resistance in BC cells.Mechanically,loss of ARID1A promoted the expression of eukaryotic translation initiation factor 4A3(EIF4A3)through epigenetic regulation.Increased expression of EIF4A3 promoted the expression of hsa_circ_0008399(circ0008399),a novel circular RNA(circRNA)identified in our previous study,which,to some extent,showed that ARID1A deletion caused CDDP resistance through the inhibitory effect of circ0008399 on the apoptosis of BC cells.Importantly,EIF4A3-IN-2 specifically inhibited the activity of EIF4A3 to reduce circ0008399 production and restored the sensitivity of ARID1A inactivated BC cells to CDDP.Conclusion Our research deepens the understanding of the mechanisms of CDDP resistance in BC and elucidates a potential strategy to improve the efficacy of CDDP in BC patients with ARID1A deletion through combination therapy targeting EIF4A3.

Erratum to:ARID1A Inactivation Increases Expression of circ0008399 and Promotes Cisplatin Resistance in Bladder Cancer

The original version of this article was revised due to production error by the vendor.The author“Hua-min DING”is one of the co-authors,and the name should be labeled correctly as appears on PDF.The affiliation of“Yu-jun SHUAI”and“Chao HUANG”is“Department of Urology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China”,and both of them should be labeled as 1,as correctively appears on PDF.

F：lole of Jaggedl-Heyl Signal in Angiotensin II-induced Impairment of Myocardial Angiogenesis

Background： Angiotensin II （Ang ll） is a major contributor to the development of heart failure. However, the molecular and cellular mechanisms that underlie this process remain elusive. Inadequate angiogenesis in the myocardium leads to a transition from cardiac hypertrophy to dysfunction, and our previous study showed that Ang II significantly impaired the angiogenesis response. The current study was designed to examine the role of Jaggedl-Notch signaling in the effect of Ang II during impaired angiogenesis and cardiac hypertrophy. Methods： Ang II was subcutaneously infused into 8-week-old male C57BL/6 mice at a dose of 200 ng·kg^-1·min^-1 for 2 weeks using Alzet micro-osmotic pumps. N-[N-（3, 5-difluorophenacetyl）-L-alanyl]-S-phenylglycine tert-butyl ester （DAPT）, a y-secretase inhibitor, was injected subcutaneously during Ang II infusion at a dose of 10.0 mg.kg^-1·d^-1. Forty mice were divided into four groups （n = 10 per group）： control group; Ang 11 group, treated with Ang I1; DAPT group, treated with DAPT; and Ang II ＋ DAPT group, treated with both Ang I1 and DAPT. At the end of experiments, myocardial （left ventricle [LV]） tissue from each experimental group was evaluated using immunohistochemistry, Western blotting, and real-time polymerase chain reaction, Data were analyzed using one-way analysis of variance test followed by the least significant difference method or independent samples t-test. Results： Ang II treatment significantly induced cardiac hypertrophy and impaired the angiogenesis response compared to controls, as shown by hematoxylin and eosin （HE） staining and immunohistochemistry fbr CD31, a vascular marker （P 〈 0.05 for both）. Meanwhile, Jaggedl protein was significantly increased, but gene expression for both Jagl and Heyl was decreased in the LV following Ang II treatment, compared to that in controls （relative ratio for Jag1 gene： 0.45 ± 0.13 vs. 0.84± 0.15; relative ratio for Heyl gene： 0.51 ± 0.08 vs. 0.91 ± 0.09; P 〈 0.05）. All these cellular and molecular effects induced by Ang II in the hearts of mice were reduced by DAPT treatment. Interestingly, Ang II stimulated Heyl, a known Notch target, but did not affect the expression of Hey2, another Notch target gene. Conclusions： A Jaggedl-Heyl signal might mediate the impairment of angiogenesis induced by Ang II during cardiac hypertrophy.