CELL BIOLOGY INTERNATIONAL
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2024
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IF 3.3
Guoqiang Xing,Hekai Chen,Zhiyue Guo,Yu Cui,Yongyuan Li,Jianwei Shen
Cholangiocarcinoma (CCA) is a hepatobiliary carcinoma with uncontrolled cell proliferation, poor prognosis, and high mortality. The ovarian tumor structural domain (OTU) containing protein 6B (OTUD6B) belongs to the OTU deubiquitin family and is vital in tumor development. However, its expression and biological function in CCA remain unknown. The expression of OTUD6B in CCA was analyzed using TIMER2.0, UALCAN, and GEO databases. MTT, clonal formation assay, immunofluorescence staining, immunohistochemistry staining, and flow cytometry examined the regulation of OTUD6B on cell proliferation, cycle, and apoptosis. The effects of OTUD6B on tumor volume and weight were assessed using the xenograft tumor model. The activities of PTK2 and STAT3 were detected by western blot and CO-IP. The biological database identified that OTUD6B was upregulated in CCA. In CCA cells, OTUD6B knockdown reduced CCA cell proliferation and promoted apoptosis. Cell cycle analysis indicated that the cycle stopped at the G0/G1 phase after OTU6B downregulation. Furthermore, OTUD6B knockdown resulted in a decrease in tumor volume and weight in xenograft tumor models. Mechanistically, OTUD6B is involved in the deubiquitination of PTK2. PTK2 further affected the phosphorylation of STAT3 thereby regulating the CCA process. Our study demonstrates that OTUD6B knockdown participates in the ubiquitination of PTK2 and phosphorylation of STAT3 to alleviate the process of CCA. These results suggest that OTUD6B may be a potential new strategy for CCA treatment.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LABORATORY INVESTIGATION
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2023
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IF 5
Zhiguang Chen,Haibin Zhao,Lingshuai Meng,Shengwei Yu,Zhenning Liu,Jinqi Xue
Fracture healing is a complex physiological process in which angiogenesis plays an essential role. Microfibril-associated glycoprotein-2 (MAGP2) has been reported to possess a proangiogenic activity via integrin αvβ3, yet its role in bone repair is unexplored. In this study, a critical-sized femoral defect (2 mm) was created in mice, followed by the delivery of an adenovirus-based MAGP2 overexpression vector or its negative control at the fracture site. At days 7, 14, 21, and 28 postfracture, bone fracture healing was evaluated by radiography, micro–computed tomography, and histopathologic analysis. Adenovirus-based MAGP2 overexpression vector–treated mice exhibited increased bone mineral density and bone volume fraction. MAGP2 overexpression contributed to an advanced stage of endochondral ossification and induced cartilage callus into the bony callus. Further analysis indicated that MAGP2 was associated with enhanced angiogenesis, as evidenced by marked MAGP2 and integrin αvβ3 costaining and increased levels of endothelial cell markers such as endomucin and CD31, as well as elevated phosphorylation of protein tyrosine kinase 2 (PTK2) and AKT serine/threonine kinase 1 (AKT) in the callus. In vitro , recombinant human MAGP2 treatment enhanced the viability, migration, and tube formation ability of human microvascular endothelial cells, which was partially reversed by integrin αvβ3 inhibition or MK-2206, a specific AKT inhibitor. Inhibition of integrin αvβ3 abolished MAGP2-induced PTK2 and AKT activation. Taken together, our data provide the first evidence that MAGP2 promotes angiogenesis and bone formation by activating the integrin αvβ3/PTK2/AKT signaling pathway.
研究领域:
骨科
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生物学
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分子生物学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Autophagy
·
2026
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IF 18.6
Ming-Yue Wu,Wan Tang,Xiao-Wen Zhang,Meng-Ni Zhang,He-Dan Xu,Si-Rui Yu,Yue Cheng,Ling Li,Ying Chen,Sen Liang,Qiong Pan,Jia-Hong Lu,Jin Chai
Macroautophagy/autophagy represents a promising therapeutic target in oncology, exhibiting context-dependent roles in tumor progression. Kinase inhibitors are a large group of anti-cancer drugs, and elucidating the regulatory effects of different kinase inhibitors on autophagy offers a valuable strategy to advance our understanding of autophagy regulation in cancer and develop innovative anti-cancer therapies. In this study, we developed a drug screening platform and performed high-content screening using a kinase inhibitor library. The screening identified PTK2/FAK (protein tyrosine kinase 2) inhibitors as potent autophagy inducers. Mechanistic investigations revealed that PTK2/FAK inhibition triggers rapid autophagy flux through a non-classical mechanism dependent on PTK2/FAK expression, which is associated with the spatial redistribution of ER exit sites (ERES). Further analysis demonstrated that PTK2/FAK inhibitor (FAKi)-induced ERES-associated autophagy is not contingent upon full PREB/SEC12 and SEC16 expression, but is sensitized to TMED9 expression level. Additionally, we identified AKAP13 as a novel FAKi-responsive protein that undergoes dephosphorylation upon FAKi treatment and contributes to TMED9-mediated ERES-associated autophagy. Given that ERES-associated autophagy is initiated through membrane contact between ERES and the ER-Golgi intermediate compartment (ERGIC), we further observed enhanced TMED9-ERGIC interactions following FAKi treatment. Furthermore, functional studies confirmed that FAKi-induced autophagy promotes pancreatic ductal adenocarcinoma (PDAC) cell survival both in vitro and in vivo. Collectively, our work unveils a previously unrecognized mechanism of FAKi-mediated autophagy induction and provides new insights for developing targeted therapies against PDAC.
✓ 已验证
DOI
PubMed
高影响因子
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