ONCOGENE
·
2018
·Vol. 37
·期 22
·2953-2966
·
IF 6.854
Cheng Yan,Gao Xing-Hua,Li Xian-Jing,Cao Qiu-Hua,Zhao Dan-Dan,Zhou Jin-Rong,Wu Hong-Xi,Wang Yun,You Lin-Jun,Yang Hong-Bao,He Yun-Long,Li Yong-Ren,Bian Jin-Song,Zhu Qing-Yi,Birnbaumer Lutz,Yang Yong
Depression drives cancer progression and induces poor clinical outcome. However, the mechanisms underlying depression and cancer outcomes are unclear. In this work, we investigated 98 prostate cancer patients and found that patients with high score of psychological depression were correlated with tumor invasion and metastasis. We found focal adhesion kinase (FAK) was increased in cancer patients with metastatic features and high score of depression. FAK knockdown completely blocked depression-promoted tumor invasion in orthotopic transplantation tumors. In Hi-myc mice and a murine model of depression, sympathetic activation was detected in the prostate tissue. Further we showed that FAK activation was dependent on a cAMP-PKA signaling pathway. Our results demonstrated that the activation of a sympathetic-FAK signaling pathway in prostate cancer patients with high degrees of depression facilitates tumor invasion. We suggest that blocking β2AR with propranolol or inhibiting FAK activation with PF562 271 may be novel strategies for depressed patients with invasive prostate cancer.
研究领域:
肿瘤学
·
精神病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2018
·Vol. 9
·期 9
·1-11
·
IF 5.638
Wang Yunchuan,Zheng Jianping,Han Yue,Zhang Yijie,Su Linlin,Hu Dahai,Fu Xiaobing
Junctional adhesion molecule-A (JAM-A) belongs to the immunoglobulin superfamily, it predominantly exists at the tight junctions of epithelial and endothelial cells. JAM-A is known to regulate leukocyte trans-endothelial migration, however, how it affects the proliferation and migration of keratinocytes, the two essential steps during wound healing, has less been explored. In this study, we showed that JAM-A was significantly expressed in normal skin epidermis. RNAi-mediated JAM-A knockdown remarkably promoted the proliferation and migration of keratinocytes. We also found that loss of JAM-A increased the protein levels of p -FAK, p -Erk1/2, and p -JNK; however, FAK inhibitor PF-562271 restrained the expression of p -FAK and p -Erk1/2 elevated by JAM-A RNAi, but not p -JNK, and also slowed down keratinocyte proliferation and migration. Finally, in a rat wound model we showed that absence of JAM-A significantly promoted the wound healing process, while the use of PF-562271 or Erk1/2 inhibitor PD98059 repressed those effects. These data collectively demonstrate that suppressing JAM-A expression could promote the proliferation and migration of keratinocytes and accelerate the healing process of rat skin wounds, potentially via FAK/Erk pathway, indicating that JAM-A might serve as a potential therapeutic target for the treatment of chronic refractory wounds.
研究领域:
分子生物学
·
细胞生物学
·
伤口愈合研究
·
信号通路
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Liming Hou,Xiaoming Wang,Min Bai,Qian Li,Wei Zhang,Hui Su,Yan Liu
Myocardial ischemia–reperfusion (MI/R) injury represents a significant complication associated with reperfusion therapy for myocardial infarction. Leucine-rich repeat-containing protein 8A (LRRC8A), a volume-regulated anion channel protein, involved in cellular homeostasis, has been implicated in the progression of cardiovascular events, but its role in MI/R remains uninvestigated. Here, we sought to characterize the role of LRRC8A in MI/R injury and uncover its potential mechanism. A rat MI/R model was developed via left anterior descending coronary artery ligation for 45 min followed by 4 h reperfusion to assess changes in LRRC8A expression in the myocardium. The results revealed that LRRC8A was upregulated in rat hearts after MI/R injury. To silence LRRC8A expression, we injected adenovirus encoding LRRC8A shRNA into the myocardium of MI/R rats 3 days before ischemic surgery. We observed that LRRC8A silencing in post-MI/R rats reduced myocardial infarct area, suppressed cardiomyocyte apoptosis and enhanced cardiac function. Furthermore, rat H9c2 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to simulate MI/R injury in vivo , and the findings indicated that LRRC8A silencing reduced OGD/R-induced cardiomyocyte apoptosis, while its upregulation had an opposite effect, as Bcl-2 expression, Tunel staining demonstrated. Mechanistically, LRRC8A can interact with tripartite motif containing 21 (TRIM21) and subsequently suppress the focal adhesion kinase (FAK)/NF-κB pathway, thereby facilitating cardiomyocyte apoptosis. TRIM21 knockdown eliminated the pro-apoptotic effect of LRRC8A and decreased the inhibitory effect of LRRC8A on the FAK/NF-κB pathway in MI/R rats as well as in OGD/R-exposed cardiomyocytes.
研究领域:
心血管疾病
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ATHEROSCLEROSIS
·
2025
·
IF 5.7
Zhenyu Zhu,Hao Liu,Liyun Feng,Lihe Lu,Jiahui Zhu,Qingchun Liang,Zirong Lan,Yuanzhi Ye,Siyi Wang,An Chen,Jianyun Yan
Introduction Extracellular matrix (ECM) proteases have been closely linked to the pathogenesis of vascular calcification. A disintegrin and metalloprotease with thrombospondin motifs-5 (ADAMTS5) is an ECM-degrading enzyme involved in ECM remodeling. Versican, a critical ECM component in the arteries, can be proteolytically cleaved by ADAMTS5 and activates integrin β1. However, whether ADAMTS5 is involved in the regulation of the pathogenesis of vascular calcification remains unclear. This study investigates the regulatory role of ADAMTS5 in vascular calcification and its mechanistic link to versican-integrin β1/FAK signaling. Methods and results Western blot, immunofluorescence, and immunohistochemistry analysis revealed that ADAMTS5 expression was significantly downregulated in rat and human vascular smooth muscle cells (VSMCs), as well as in rat and human arteries during vascular calcification. In addition, both pharmacological inhibition of ADAMTS5 and knockdown of ADAMTS5 by siRNA significantly aggravated mineral deposition in rat and human VSMCs under osteogenic conditions. Moreover, adenovirus-mediated ADAMTS5 overexpression markedly attenuated calcification of VSMCs and aortic calcification in rats with chronic kidney disease. Furthermore, inhibition of ADAMTS5 promoted aortic calcification in VitD 3 -overloaded mice. Mechanistically, overexpression of ADAMTS5 significantly reduced versican protein levels, and inhibited integrin β1 and FAK phosphorylation in rat VSMCs, but increased versikine protein levels. Moreover, either knockdown of versican or pharmacological inhibition of FAK phosphorylation repressed VSMC calcification mediated by loss of ADAMTS5. Conclusions We have demonstrated for the first time that ADAMTS5 deficiency promotes versican accumulation and activates integrin β1/FAK signaling. These findings suggest ADAMTS5 as a potential therapeutic target for vascular calcification.
研究领域:
心血管疾病
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-14
·
IF 16.6
Jia Yuanbo,Hu Jiahui,An Keli,Zhao Qiang,Dang Yang,Liu Hao,Wei Zhao,Geng Songmei,Xu Feng
Atopic dermatitis (AD) is a chronic skin disease caused by skin immune dyshomeostasis and accompanied by severe pruritus. Although oxidative stress and mechanical scratching can aggravate AD inflammation, treatment targeting scratching is often overlooked, and the efficiency of mechano-chemically synergistic therapy remains unclear. Here, we find that enhanced phosphorylation of focal adhesion kinase (FAK) is associated with scratch-exacerbated AD. We then develop a multifunctional hydrogel dressing that integrates oxidative stress modulation with FAK inhibition to synergistically treat AD. We show that the adhesive, self-healing and antimicrobial hydrogel is suitable for the unique scratching and bacterial environment of AD skin. We demonstrate that it can scavenge intracellular reactive oxygen species and reduce mechanically induced intercellular junction deficiency and inflammation. Furthermore, in mouse AD models with controlled scratching, we find that the hydrogel alleviates AD symptoms, rebuilds the skin barrier, and inhibits inflammation. These results suggest that the hydrogel integrating reactive oxygen species scavenging and FAK inhibition could serve as a promising skin dressing for synergistic AD treatment.
研究领域:
皮肤病学
·
材料科学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanotechnology Reviews
·
2019
·Vol. 8
·期 1
·645-660
·
IF 2.759
Yu Miao,Jiawei Lu,Junhui Yin,Changchun Zhou,Yaping Guo,Shumin Zhou
Melanoma is the most lethal dermal tumor, and a high recurrence rate and skin defects are two main serious problems. An antimelanoma material,which effectively inhibits tumor recurrence and possesses excellent biocompatibility, is urgently needed to treat melanoma. In this study, we developed a novel antitumor Yb 3+ [Yb(NO 3 ) 3 ]containing chitosan hydrogel (Yb-CS hydrogel) by dissolving Yb(NO 3 ) 3 and chitosan in acetic acid solution and forming composite hydrogels by a freeze-drying process after adding NaOH to the mixed solution. In vitro studies demonstrated that the Yb 3+ produces effect of inducing cell death in Yb-CS hydrogel. Moreover, we found that the Yb-CS hydrogel inhibited a focal adhesion kinase (FAK)-dependent signaling pathway and induced B-16 cell anoikis. However, the Yb-CS hydrogel was less effective on L929 normal mouse dermal cells. In vivo studies showed that the Yb-CS hydrogel inhibited the recurrence of melanoma in a mouse bare xenograft tumor model. We concluded that the Yb-CS hydrogel could potentially be used in the antimelanoma field, especially in the inhibition of melanoma recurrence.
研究领域:
肿瘤学
·
材料科学
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
Advanced Composites and Hybrid Materials
·
2025
·Vol. 8
·期 1
·1-18
·
IF 21.8
Chang Yu,Huang Kexin,Tang Han,Yao Yuwei,Min Jie,Quan Hong,Xu Kai,Wang Hongbo,Zhang Jiaming,Zhao Yingchao
Radiation therapy (RT) remains the primary treatment modality for advanced cervical cancer, however, recurrence due to radioresistance presents a significant challenge. Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) are key contributors to this resistance, driven by their inherent radioresistance and radiation-induced phenotypic adaptations. Addressing this issue requires strategies specifically designed to target CAFs and enhance their radiosensitivity. In this study, we developed a biomimetic metal–organic framework (MOF) nanoplatform for the dual-targeted co-delivery of the FAK inhibitor IN10018 and Bismuth (Bi), aimed at improving radiosensitivity in cervical cancer. The IN10018 and Bi-loaded zeolitic imidazolate framework 8 (ZIF-8) nanoparticles (IZB) were further coated with hybrid membranes derived from CAFs and cancer cells, enabling precise targeting of both cell types. Upon exposure to an acidic environment, the nanoparticles disassemble, releasing IN10018, which reduces CAFs infiltration and enhances radiosensitivity. Simultaneously, the incorporation of Bi enhances radiation absorption efficiency, further sensitizing tumor cells to radiotherapy. This dual-target strategy represents a promising approach to overcoming radioresistance in cervical cancer and exemplifies how integrating nanotechnology with targeted therapies can enhance RT efficacy and improve patient outcomes. Graphic Schematic Illustration of IZB@CCM Construction and Application for Cervical Cancer to Improve Radiosensitivity. (1) IZB was fabricated through the one-pot method. (2) Preparation of hybrid CAF-cancer cell membrane. (3) IZB@CCM were obtained by co-extrusion of IZB and hybrid membrane (CCM). (4) IZB@CCM demonstrated the ability to target CAFs and cancer cells. (5) IZB@CCM inhibited the expression of FAK and released radiosensitizer Bi to enhance the radiosensitivity of cervical cancer.
研究领域:
肿瘤学
·
纳米医学
·
放射生物学
✓ 已验证
产品关联
DOI
高影响因子
LUNG
·
2022
·Vol. 200
·期 5
·619-631
·
IF 3.777
Zhai Cui,Zhang Nana,Wang Jian,Cao Meng,Luan Jing,Liu Huan,zhang Qianqian,Zhu Yanting,Xue Yuxin,Li Shaojun
Purpose It has been shown that activation of autophagy promotes the development of pulmonary arterial hypertension (PAH). Meanwhile, forkhead box M1 (FOXM1) has been found to induce autophagy in several types of cancer. However, it is still unclear whether FOXM1 mediates autophagy activation in PAH, and detailed mechanisms responsible for these processes are indefinite. Method PAH was induced by a single intraperitoneal injection of monocrotaline (MCT) to rats. The right ventricle systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), percentage of medial wall thickness (%MT), α-smooth muscle actin (α-SMA) staining, and Ki67 staining were performed to evaluate the development of PAH. The protein levels of FOXM1, phospho-focal adhesion kinase (p-FAK), FAK, and LC3B were determined by immunoblotting or immunohistochemistry. Results FOXM1 protein level and FAK activity were significantly increased in MCT-induced PAH rats, this was accompanied with the activation of autophagy. Pharmacological inhibition of FOXM1 or FAK suppressed MCT-induced autophagy activation, decreased RVSP, RVHI and %MT in MCT-induced PAH rats, and inhibited the proliferation of pulmonary arterial smooth muscle cells and pulmonary vessel muscularization in MCT-induced PAH rats. Conclusion FOXM1 promotes the development of PAH by inducing FAK phosphorylation and subsequent activation of autophagy in MCT-treated rats.
研究领域:
心血管疾病
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
OncoTargets and Therapy
·
2019
·
IF 3.046
Jianghong Wu,Ziwen Long,Hong Cai,Shengjia Yu,Xiaowen Liu
Aim: To study the carcinogenetic mechanism of HOXB7 in gastric cancer (GC) remains. Methods: Two human GC cell lines — SGC7901 and SNU1 — were used for this study. SGC7901 cells were transfected with siRNA-HOXB7 (siHOXB7) to knock down HOXB7 expression, whereas, SNU1 cells were transduced with pCDNA3.1-HOXB7 to overexpress HOXB7. After transfection, cancer progression was assessed by determining cell proliferation, wound-healing process, cell cycle, apoptosis, invasion, and migration. The effect of HOXB7 on epithelial–mesenchymal transition (EMT) was measured by observing changes in F-actin cytoskeleton and evaluating the expression of EMT markers. p-Scr and p-FAK were evaluated to assess the mechanism. Results: Knockdown of HOXB7 suppressed cell proliferation, alleviated the wound-healing process, inhibited cell migration and invasion, and arrested the cell cycle while promoting cell apoptosis, suggesting the tumor-suppressive effect of siHOXB7 in human GC cells. On the contrary, HOXB7 overexpression showed a tumor-promoting effect on human GC cells. Moreover, we confirmed an inhibitory effect of siHOXB7 on the EMT process by preventing epithelial cells from acquiring a mesenchymal phenotype and downregulating mesenchymal markers (vimentin, β-catenin, N-cadherin, Twist) while upregulating epithelial markers (E-cadherin). Our data revealed that HOXB7 was associated with Src/FAK and favored the activation of the Src–FAK pathway in human GC cells. Conclusion: HOXB7 accelerated the malignancy of GC, by facilitating EMT and regulating the Scr–FAK pathway.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
·
2022
·Vol. 66
·期 7
·2101088
·
IF 6.575
Hui-jian Chen,Xi-yue Yan,Ao Sun,Li Zhang,Jing Zhang,You-e Yan
Scope High-fat-diet (HFD) is an important factor in obesity. Extracellular matrix (ECM) regulates white adipose tissue (WAT), but its mechanism is unknown. Methods and Results This study uses three models—HFD-fed mice, human with obesity, and 3T3-L1 adipocytes with oleic acid (OA)/macromolecular crowders (MMC) treatment. Glucose and lipids metabolic disorders, increased collagen I/IV and laminin α2/4 (LAMA2/4), and upregulated integrins (ITGA1/ITGA7) – focal adhesion kinase (FAK) – c-Jun N-terminal kinase (JNK)/extracellular regulated protein kinase 1/2 (ERK1/2) signals in obese WAT from mice and human are observed. The upregulation of ECM – integrin – FAK signals is stronger in subcutaneous WAT than that in visceral WAT of mice, but these results are reversed in human. In vitro, oleic acid (OA) promotes lipid accumulation and upregulates collagen IV, LAMA4, and p-JNK. MMC is used to induce ECM deposition in adipocytes. MMC promotes adipocyte differentiation and integrins – FAK – JNK/ERK1/2 signals. When FAK phosphorylation is inhibited, downstream p-JNK is decreased. Inhibition of FAK phosphorylation reduces adipocyte differentiation, but MMC partially reverses this effect. Conclusion HFD-induced ECM deposition, whose signals are transmitted into adipocytes through upregulating ITGA1/ITGA7, activates the phosphorylation of intracellular FAK – JNK/ERK1/2 signals, and promotes adipogenesis in WAT. This mechanism provides novel therapeutic targets to treat obesity.
研究领域:
营养学
·
细胞生物学
·
分子生物学
·
代谢紊乱
·
肥胖研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DNA AND CELL BIOLOGY
·
2020
·Vol. 39
·期 3
·355-367
·
IF 3.314
Jiuwei Zhang,Yaodong Chen,Jing Lin,Ruimei Jia,Tingting An,Tianxiu Dong,Yu Zhang,Xiuhua Yang
Hepatocellular carcinoma (HCC), the sixth most common malignancy worldwide, is characterized by a dismal prognosis due to high recurrence and metastasis rates. Thus, the need for the development of novel chemotherapeutic drugs is urgent. Cyclovirobuxine D (CVB-D), a steroidal alkaloid extracted from Buxus microphylla that has been extensively used to relieve the symptoms of cardiovascular diseases, has shown promising antineoplastic effects in recent studies. However, the therapeutic effects and underlying mechanisms of CVB-D on HCC remain largely unelucidated. This study experimentally indicated that CVB-D can repress HCC cell proliferation by arresting the cell cycle in G2 phase and can facilitate apoptosis. In addition, the migratory and invasive capabilities of HCC cells were noticeably attenuated by a nonlethal dose of CVB-D, and this attenuation was correlated with the inhibition of epithelial–mesenchymal transition (EMT). Moreover, in vivo, CVB-D displayed excellent anticancer effects in HCC tumor-bearing nude mice. Regarding the molecular mechanisms of CVB-D activity, decreased Slug expression was determined to be associated with the aforementioned anti-HCC functions of this extract, which might be regulated by epidermal growth factor receptor (EGFR) through the focal adhesion kinase (FAK)-associated PI3K/AKT and MEK/ERK1/2 signaling pathways. Collectively, our results revealed the suppressive effects of CVB-D on progressive behaviors of HCC, including proliferation, migration, invasion, and EMT, in addition to its outstanding proapoptotic effects, which were correlated with the inhibition of the EGFR-FAK-AKT/ERK1/2-Slug signaling pathway. These discoveries provide an experimental and theoretical foundation for the use of CVB-D as a promising candidate for HCC therapy.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR BIOLOGY REPORTS
·
2024
·Vol. 51
·期 1
·1-12
·
IF 2.6
Zheng Ruzhen,He Yibo,Yang Lingrong,Chen Yidan,Wang Rui,Xie Shangnao
Background Our previous study has demonstrated that Nischarin (NISCH) exerts its antitumor effects in breast cancer (BC) by suppressing cell migration and invasion. This study aims to explore the underlying mechanism through which NISCH functions in BC. Methods and results The relevance between EGF Like Repeats and Discoidin Domains 3 (EDIL3) mRNA expression and the overall survival of tumor patients was depicted by the Kaplan-Meier curve. The findings revealed that overexpressed NISCH attenuated cell motility and colony-forming capacities of Hs578T cells, yet silenced NISCH in MDA-MB-231 cells led to contrasting results. Western blot (WB) analysis indicated that overexpression of NISCH significantly down-regulated the Vimentin and Slug expression, and inactivated the FAK/ERK signaling pathway. RNA sequencing (RNA-seq) was performed in NISCH-overexpressed Hs578T cells and the control cells to analyze differentially expressed genes (DeGs), and the results showed a significant down-regulation of EDIL3 mRNA level upon overexpression of NISCH. Subsequent functional analyses demonstrated that overexpression of EDIL3 attenuated the inhibitory effect of NISCH on cell migration, invasion, colony formation, and tube formation. Conclusion In summary, our finding preliminarily revealed that NISCH inhibits the epithelial-mesenchymal transition (EMT) process and angiogenesis in BC cells by down-regulating EDIL3 to inactivate the FAK/ERK signaling pathway, thereby suppressing the progression of BC. Our results hold promise for contributing to the deep understanding of BC pathogenesis and identifying new therapeutic strategies for clinical application.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）