Head and neck squamous cell carcinoma is the sixth most common tumor worldwide,and half of head and neck squamous cell carcinoma patients are with oral squamous cell carcinoma(OSCC).300,000 new cases of OSCC were repo...Head and neck squamous cell carcinoma is the sixth most common tumor worldwide,and half of head and neck squamous cell carcinoma patients are with oral squamous cell carcinoma(OSCC).300,000 new cases of OSCC were reported annually.Even with multi-modality treatment,the prognosis of OSCC remains unsatisfactory.Thus,it is urgent to discover novel therapeutic targets for OSCC.Some microarray studies have revealed that Keratin 4(KRT4)is downregulated in OSCC,whereas its role in OSCC development remains unknown.The present study revealed that KRT4 suppressed OSCC progression by inducing cell apoptosis and inhibiting cell invasion.In addition,KRT4 over-expression inhibited autophagy by blocking the interaction of autophagy-related 4B cysteine peptidase(ATG4B)and microtubule-associated protein 1A/1B light chain 3(LC3)to regulate apoptosis and invasion of OSCC.In conclusion,KRT4 played an important role in OSCC development through regulating ATG4B-mediated autophagy and may be a novel therapeutic drug target of OSCC.展开更多
Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs(miRNAs) play multiple roles in biological processes...Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs(miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34 c-5 p on cardiac hypertrophy and the mechanism involved. The expression of miR-34 c-5 p was proved to be elevated in heart tissues from isoprenaline(ISO)-infused mice. ISO also promoted miR-34 c-5 p level in primary cultures of neonatal rat cardiomyocytes(NRCMs). Transfection with miR-34 c-5 p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor(Anf) and β-myosin heavy chain(β-Mhc) in NRCMs. In contrast, treatment with miR-34 c-5 p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34 c-5 p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34 c-5 p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34 c-5 p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4 B(ATG4 B) was identified as a direct target of miR-34 c-5 p, and miR-34 c-5 p was certified to interact with 3’untranslated region of Atg4 b mRNA by dual-luciferase reporter assay. miR-34 c-5 p reduced the expression of ATG4 B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34 c-5 p abolished the detrimental effects of ISO by restoring ATG4 B and increasing autophagy. In conclusion, our findings illuminate that miR-34 c-5 p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4 B and autophagy. It suggests that regulation of miR-34 c-5 p may offer a new way for handling hypertrophy-related cardiac dysfunction.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.81500864)Guangzhou Science and Technology Project(Grant No.201804010040)Sun Yat-Sen University Young Teacher Cultivation Project(Grant No.18ykpy29).
文摘Head and neck squamous cell carcinoma is the sixth most common tumor worldwide,and half of head and neck squamous cell carcinoma patients are with oral squamous cell carcinoma(OSCC).300,000 new cases of OSCC were reported annually.Even with multi-modality treatment,the prognosis of OSCC remains unsatisfactory.Thus,it is urgent to discover novel therapeutic targets for OSCC.Some microarray studies have revealed that Keratin 4(KRT4)is downregulated in OSCC,whereas its role in OSCC development remains unknown.The present study revealed that KRT4 suppressed OSCC progression by inducing cell apoptosis and inhibiting cell invasion.In addition,KRT4 over-expression inhibited autophagy by blocking the interaction of autophagy-related 4B cysteine peptidase(ATG4B)and microtubule-associated protein 1A/1B light chain 3(LC3)to regulate apoptosis and invasion of OSCC.In conclusion,KRT4 played an important role in OSCC development through regulating ATG4B-mediated autophagy and may be a novel therapeutic drug target of OSCC.
基金supported by grants from the National Natural Science Foundation of China (81872860,81673433,and82070268)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093,China)+4 种基金National Major Special Projects for the Creation and Manufacture of New Drugs (2019ZX09301104,China)National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province,2017B090903004,China)Special Program for Applied Science and Technology of Guangdong Province (2015B020232009,China)Guangdong Basic and Applied Basic Research Foundation(2020A1515011512,China)Young Teacher Training Program of Sun Yat-sen University (18ykpy26,China)。
文摘Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs(miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34 c-5 p on cardiac hypertrophy and the mechanism involved. The expression of miR-34 c-5 p was proved to be elevated in heart tissues from isoprenaline(ISO)-infused mice. ISO also promoted miR-34 c-5 p level in primary cultures of neonatal rat cardiomyocytes(NRCMs). Transfection with miR-34 c-5 p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor(Anf) and β-myosin heavy chain(β-Mhc) in NRCMs. In contrast, treatment with miR-34 c-5 p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34 c-5 p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34 c-5 p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34 c-5 p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4 B(ATG4 B) was identified as a direct target of miR-34 c-5 p, and miR-34 c-5 p was certified to interact with 3’untranslated region of Atg4 b mRNA by dual-luciferase reporter assay. miR-34 c-5 p reduced the expression of ATG4 B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34 c-5 p abolished the detrimental effects of ISO by restoring ATG4 B and increasing autophagy. In conclusion, our findings illuminate that miR-34 c-5 p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4 B and autophagy. It suggests that regulation of miR-34 c-5 p may offer a new way for handling hypertrophy-related cardiac dysfunction.
