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Honglei Wang Yongjie Zhao Lei Cao Judong Zhang Yu Wang Min Xu 《Journal of cellular biochemistry》2019,120(3):3447-3454
Epithelial-mesenchymal transition (EMT) is a crucial event for cancer progression and metastasis. Metastasis suppressor protein 1 (MTSS1) is a metastasis suppressor in several cancers. In this study, we elucidated the potential physiological function of MTSS1 in the invasion and migration of gastric cancer (GC), and its distinct role in EMT and subsequently determined the potential molecular mechanism. We observed that MTSS1 expression was downregulated in GC tissues and several GC cell lines (SGC-7901, MGC-803, MKN-28, MKN-45, and BGC-823). Importantly, forced expression of MTSS1 drastically diminished the cell viability in both SGC-7901 and MKN-45 cells. Moreover, overexpression of MTSS1 attenuated the invasion ability of these two cell lines. In addition to the invasive capability, introduction of MTSS1 led to a loss of migratory potential. Furthermore, augmentation of MTSS1 exhibited the typical EMT phenotype switch, accompanied by enhanced the expression of vimentin and N-cadherin and reduced E-cadherin expression. Interestingly, MTSS1 also repressed transforming growth factor beta 1 (TGF-β1)-induced EMT. Our mechanistic investigations revealed that MTSS1 was positively regulated by the phosphatase and tensin homolog (PTEN), and it functioned as a tumor suppressor, possibly by inactivating the phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene (AKT) pathway in GC cells. Collectively, our data provide insight into an important role for MTSS1 in suppressing tumor cell invasion, migration and EMT, which indicates that MTSS1 may act as a prospective prognostic biological marker and a promising therapeutic target for GC. 相似文献
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Cervical cancer is common cancer among women with high morbidity. MicroRNAs (miRs) are involved in the progression and development of cervical cancer. This study aimed to explore the effect of miR-99b-5p (miR-99b) on invasion and migration in cervical cancer through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway. The microarray-based analysis was used to screen out differentially expressed miRNAs. Expression of miR-99b, PI3K, AKT, mTOR, and ribosomal protein S6 kinase (p70S6K) was determined in both cervical cancer tissues and paracancerous tissues. Next, alteration of miR-99b expression in cervical cancer was conducted to evaluate levels of PI3K, AKT, mTOR, p70S6K matrix metallopeptidase 2, epithelial cell adhesion molecule, and intercellular adhesion molecule 1, as well as the effect of miR-99b on cell proliferation, invasion, migration, cell cycle distribution, and apoptosis. The results demonstrated that miR-99b expression was decreased and levels of PI3K, AKT, mTOR, and p70S6K were elevated in cervical cancer tissues. More important, overexpressed miR-99b repressed the PI3K/AKT/mTOR signaling pathway, inhibited cell proliferation, invasion, and migration, blocked cell cycle entry, and promoted apoptosis in cervical cancer. These results indicate that miR-99b attenuates the migration and invasion of human cervical cancer cells through downregulation of the PI3K/AKT/mTOR signaling pathway, which provides a therapeutic approach for cervical cancer treatment. 相似文献
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摘要 目的：探讨辅酶Q10B（COQ10B）影响食管鳞癌细胞恶性生物学行为的分子机制。方法：采用qRT-PCR检测3种人ESCC细胞系（KYSE150、KYSE450和TE-1）和食管上皮细胞系Het-1A细胞中COQ10B表达情况。对敲减COQ10B的KYSE150细胞进行RNA测序筛选差异表达基因,通过KEGG通路分析寻找密切相关信号通路。利用慢病毒构建COQ10B过表达KYSE150和TE-1细胞稳转株,Western blot方法检测过表达效率。采用CCK8法检测PI3K/AKT信号通路抑制剂LY294002对食管鳞癌细胞的半抑制浓度（IC50）值。通过EDU、平板克隆实验、流式细胞术、创面愈合实验、Transwell侵袭小室检测过表达COQ10B以及加入LY294002抑制剂后对食管鳞癌细胞增殖、凋亡、迁移及侵袭能力的影响。同时采用Western blot技术检测过表达COQ10B以及加入LY294002抑制剂后对KYSE150食管鳞鳞癌细胞中PI3K/AKT信号通路相关蛋白（PI3K、AKT、p-PI3K和p-AKT）表达的影响。结果：COQ10B在ESCC细胞系中相对高表达。RNA-seq筛选出显著性差异表达基因共319个,包括285个上调基因、34个下调基因,通过KEGG通路分析筛选出PI3K/AKT信号通路作为后续分子机制的研究对象。PI3K/AKT信号通路抑制剂LY294002随浓度和作用时间的增加,对食管鳞癌细胞的毒性作用增强,后续实验中使用LY294002作用48 h的IC50值左右的药物浓度。与阴性对照组相比,在KYSE150和TE-1食管鳞癌细胞中过表达COQ10B后可显著增强细胞的增殖、迁移及侵袭并抑制其凋亡。然而,在加入LY294002抑制剂处理48h后,COQ10B过表达所增强的ESCC细胞增殖、迁移、侵袭能力均被显著抑制,而凋亡能力的抑制被逆转。同时与阴性对照组相比,KYSE150食管鳞癌细胞中过表达COQ10B后PI3K/AKT信号通路中p-PI3K、p-AKT蛋白表达水平显著升高。而在加入LY294002抑制剂处理48 h后可显著抑制COQ10B过表达所增强的PI3K/AKT信号通路相关蛋白p-PI3K、p-AKT表达水平。结论：COQ10B可通过激活PI3K/AKT信号通路促进食管鳞癌细胞的增殖、迁移、侵袭,并抑制其凋亡。 相似文献
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细胞骨架调节蛋白3(diaphanous related formin3,DIAPH3)参与肌动蛋白重塑和调节细胞的运动和黏附,在多种肿瘤发生发展中发挥重要作用,但其在食管鳞状细胞癌(简称:食管鳞癌)中作用尚未见报道。本研究探究DIAPH3在食管鳞癌中的作用及其分子机制。首先,基因表达谱交互分析(gene expression profiling interactive analysis,GEPIA)数据库和免疫组织化学染色法,用于分析食管鳞癌组织中DIAPH3在转录水平和蛋白质水平的表达。结果显示,食管鳞癌组织中DIAPH3mRNA和蛋白质的表达高于癌旁组织,其与肿瘤分化和淋巴结转移密切相关(P<0.05)。利用Western印迹检测食管鳞癌组织中DIAPH3蛋白的表达量。结果表明:与癌旁组织相比,食管鳞癌组织中蛋白质的表达量升高(P<0.05)。再利用CCK-8、划痕愈合实验和Transwell侵袭实验,分别检测细胞的增殖、迁移和侵袭能力。实验结果显示:与对照组相比,干扰DIAPH3组细胞的增殖、迁移和侵袭能力下降(P<0.05),而过表达DIAPH3组细胞的增殖、迁移和侵袭能力增强(P<0.05)。最后,利用Western 印迹检测过表达/干扰DIAPH3细胞中的细胞周期蛋白D1(cyclin D1)、E-钙黏着蛋白(E-cadherin)和波形蛋白(vimentin)的表达。Western 印迹结果显示:与对照组相比,干扰DIAPH3组细胞中,E-钙黏着蛋白表达增加,且波形蛋白和细胞周期蛋白D1表达减少(P<0.05),而过表达DIAPH3组细胞中,E-钙黏着蛋白表达减少,且波形蛋白和细胞周期蛋白D1表达增加(P<0.05)。这些研究表明,DIAPH3促进食管鳞癌细胞的增殖、迁移和侵袭。其结果为食管鳞癌的诊治提供了新思路。 相似文献
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LncRNAs exhibit crucial roles in various pathological diseases, including hepatocellular carcinoma (HCC). Therefore, it is significant to recognize the dysregulated lncRNAs in HCC progression. Recently, LINC01133 has been identified in several tumors. However, the biological role of LINC01133 in HCC remains poorly understood. Currently, we focused on the function of LINC01133 in HCC development. We observed that LINC01133 was significantly increased in HCC cells including HepG2, Hep3B, MHCC-97L, SK-Hep-1, and MHCC-97H cells compared with the normal human liver cell line HL-7702. In addition, PI3K/AKT signaling was highly activated in HCC cells. Knockdown of LINC01133 was able to inhibit HCC cell proliferation, cell colony formation, cell apoptosis, and blocked cell cycle arrest in the G1 phase. For another, downregulation of LINC01133 repressed HCC cell migration and invasion. Subsequently, the PI3K/AKT signaling pathway was strongly suppressed by silence of LINC01133 in Hep3B and HepG2 cells. Then, in vivo tumor xenografts models were established using Hep3B cells to explore the function of LINC01133 in HCC progression. Consistently, our study indicated that knockdown of LINC01133 dramatically repressed HCC tumor progression through targeting the PI3K/AKT pathway in vivo. Taken these together, we revealed that LINC01133 contributed to HCC progression by activating the PI3K/AKT pathway. 相似文献
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Farzad Rahmani Aghigh Ziaeemehr Soodabeh Shahidsales Masoumeh Gharib Majid Khazaei Gordon A. Ferns Mikhail Ryzhikov Amir Avan Seyed M. Hassanian 《Journal of cellular physiology》2020,235(5):4146-4152
Hepatocellular carcinoma (HCC) is one of the common malignant human tumors with high morbidity worldwide. Aberrant activation of the oncogenic phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling is related to clinicopathological features of HCC. Emerging data revealed that microRNAs (miRNAs) have prominent implications for regulating cellular proliferation, differentiation, apoptosis, and metabolism through targeting the PI3K/AKT/mTOR signaling axis. The recognition of the crucial role of miRNAs in hepatocarcinogenesis represents a promising area to identify novel anticancer therapeutics for HCC. The present study summarizes the major findings about the regulatory role of miRNAs in the PI3K/AKT/mTOR pathway in the pathogenesis of HCC. 相似文献
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白藜芦醇(resveratrol)可抑制人肾癌786-O细胞增殖,并诱导其凋亡,但是白藜芦醇对786-O细胞自噬(autophagy)的影响及机制尚不清楚.为探究其机制,体外培养786-O细胞,采用CCK-8检测786-O细胞活力;TUNEL染色检测786-O细胞凋亡;透射电子显微镜观察786-O细胞自噬体;吖啶橙染色... 相似文献
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Oridonin, an active diterpenoid isolated from Rabdosia rubescens, has been reported for its antitumor activity on several cancers. However, its effect on human esophageal cancer remains unclear. In this study, we demonstrated that oridonin could inhibit the growth of human esophageal cancer cells both in vitro and in vivo. Oridonin not only suppressed the proliferation, but also induced cell cycle arrest and mitochondrial-mediated apoptosis in KYSE-30, KYSE-150, and EC9706 cells with dose-dependent manner. Further mechanism studies revealed that oridonin led cell cycle arrest in esophageal cancer cells via downregulating cell cycle-related proteins, such as cyclin B1 and CDK2, while upregulating p53 and p21. Oridonin also increased proapoptotic protein Bax and reduced antiapoptotic protein Bcl-2, as well as the increased expression of cleaved caspase-3, -8, and -9. In addition, oridonin treatment could significantly inhibit the PI3K/Akt/mTOR and Ras/Raf signaling pathway. In vivo results further demonstrated that oridonin treatment markedly inhibited tumor growth in the esophageal cancer xenograft mice model. Taken together, these results suggest that oridonin may be a potential anticancer agent for the treatment of esophageal cancer. 相似文献
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摘要 目的：探究miR-20a与CCND1蛋白在皮肤鳞状细胞癌（CSCC）中的作用关系,以及其可能涉及的信号通路分子机制。方法：分别收集皮肤鳞状细胞癌患者的皮肤癌组织及其邻近正常皮肤组织,采用qRT-PCR分析组织中miR-20a和CCND1基因表达水平。为探究miR-20a对CSCC细胞的影响,将SCL-1细胞分为对照组（不转染）、miR-NC组（转染miR-NC）和miR-20a mimics组（转染miR-20a mimics）;为探究CCND1与PI3K/AKT信号通路的关系,将SCL-1细胞分为对照组（不转染）、si-NC组（转染si-NC）和si-CCND1组（转染si-CCND1）;为探究miR-20a与CCND1间的作用关系及对CSCC细胞的影响,将SCL-1细胞分为miR-NC组（转染miR-NC）、miR-20a mimics组（转染miR-20a mimics）、mimics+pcDNA组（共转染miR-20a mimics和pcDNA）和mimics+CCND1组（共转染miR-20a mimics和pcDNA-CCND1）。采用Western blot分析p-AKT、AKT、p-PI3K、PI3K和GSK-3β蛋白表达水平;采用MTT检测细胞增殖情况;采用流式细胞术检测细胞凋亡情况;采用Transwell分析细胞迁移和侵袭情况;采用双荧光素酶报告基因检测分析miR-20a与CCND1的靶向关系。结果：CSCC癌组织和SCL-1中miR-20a均低表达,CCND1高表达。与对照组和miR-NC组比较,miR-20a mimics组SCL-1细胞增殖水平以及侵袭和迁移数量均降低（P<0.05）,SCL-1细胞凋亡水平升高（P<0.05）,PI3K和AKT蛋白磷酸化水平降低（P<0.05）。TargetScanHuman数据库分析和双荧光素酶报告基因检测结果显示miR-20a与CCND1存在靶向作用关系。与对照组和si-NC组比较,si-CCND1组SCL-1细胞中CCND1和GSK-3β蛋白表达水平以及PI3K和AKT蛋白磷酸化水平均降低（P<0.01）。与miR-20a mimics组或mimics+pcDNA组比较,mimics+CCND1组SCL-1细胞增殖水平以及侵袭和迁移数量均升高（P<0.05）,SCL-1细胞凋亡水平降低（P<0.05）,PI3K和AKT蛋白磷酸化水平均升高（P<0.05）。结论：过表达miR-20a可能通过靶向抑制CCND1的表达而抑制PI3K/AKT信号通路的激活,从而抑制CSCC细胞的增殖、侵袭和迁移,并促进癌细胞凋亡。 相似文献
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卵巢癌是一种常见的威胁女性健康的恶性肿瘤。然而卵巢癌的发生机制尚不清楚。该研究旨在探讨褪黑激素受体MT1在人卵巢癌SKOV3细胞中的作用及其主要机制。采用MT1-pcDNA3.1质粒(MT1组)与空载体pcDNA3.1(对照组)转染SKOV3细胞,未转染SKOV3细胞作为阴性对照组。转染48 h后,新鲜培养基培养24 h或48 h,观察细胞周期、增殖、凋亡情况,上清液检测褪黑激素表达。此外,在血清缺乏培养基培养细胞并转48 h后,更换新鲜培养基并加入4μmol/L PF-04691502抑制剂孵化24 h。测定AKT蛋白水平、总mTOR蛋白水平和相应磷酸化蛋白水平。结果显示,与NC组相比,MT1组在细胞周期S期阻滞(P<0.05),伴随增殖减少和早期凋亡(P<0.05)。3组细胞上清液检测到褪黑激素分泌均随时间增加(P<0.05)。Western blot分析显示,MT1过表达抑制了PI3K/AKT/mTOR信号通路的激活。该研究得出,SKOV3细胞有自行分泌褪黑激素的能力。MT1过表达可与内源性褪黑激素结合,抑制PI3K/AKT/mTOR信号通路的激活,最终发挥抗癌作用。 相似文献
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目的：探讨P13K特异性抑制剂LY294002逆转顺铂耐药口腔鳞癌细胞TCA8113／CDDP的可行性。方法：采用间歇性加药,逐步递增CDDP药量,体外连续诱导培养TCA8113／CDDP细胞;用不同浓度的LY294002和顺铂处理TCA8113和TCA8113／CDDP细胞;MTT法观察对细胞增殖的影响,Western印迹分析LY294002作用前后p-Akt、Akt、P13K蛋白的表达。结果：建立了舌鳞癌耐药细胞TCA8113／CDDP,耐药指数为7．7;MTT实验显示LY294002对TCA8113和TCA8113／CDDP细胞的抑制作用与浓度及作用时间呈正相关;LY294002联合顺铂对2种细胞的抑制作用比单用顺铂效果好;P13K、Akt、P—AKT蛋白表达明显降低,其中TCA8113／CDDP细胞中P13K、AKT、p-AKT蛋白的表达比TCA8113细胞明显增多（P〈0．05）。结论：LY294002能增加耐药口腔鳞癌顺铂化疗的敏感性。 相似文献
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Oral squamous cell carcinoma (OSCC) is a common cancer with poor prognosis and high mortality. The role of CCN5 has attracted a great focus on the regulation of cancer progression. However, the biological function and mechanism of CCN5 in OSCC are still not well elucidated. The current study was designed to determine the effects of CCN5 on OSCC cell proliferation and apoptosis using two OSCC cell lines. Further, LY294002, a PI3K/AKT antagonist, was employed to explore the mechanism underlying the effects of CCN5 in the regulation of OSCC. The results showed that overexpression of CCN5 in TSCCa cells significantly reduced viable cell number, arrested cell cycle, and suppressed cell‐cycle regulators (cyclin D1, cyclin E, and CDK2). CCN5 overexpression increased the apoptotic ratio and Hoechst‐positive cell number, and altered the apoptotic‐related proteins (caspase‐3/9, Bax, and Bcl‐2). However, CCN5 silencing induced opposite effects on cell proliferation and apoptosis in Tca‐8113 cells. In addition, we observed that CCN5 knockdown increased the expression levels of PI3K (p85α and p110α) and phosphorylated AKT at serine 473 (p‐AKT Ser473) in Tca‐8113 cells. Inhibiting PI3K/AKT signaling with LY294002 rescued the apoptotic process in CCN5‐silenced OSCC cells. Finally, xenograft analysis showed that CCN5 represses tumorigenesis of OSCC cells. These findings together suggest that CCN5 functions as a tumor suppressor for OSCC cell development through inactivation of PI3K/AKT signaling pathway, providing a potential candidate for OSCC therapy. 相似文献
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Zhong-Heng Yang Juan Li Wei-Zhi Chen Fan-Shuang Kong 《Cell biochemistry and function》2020,38(7):943-954
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Shanshan Ma Tengfei Liu Ling Xu Yaping Wang Jiankang Zhou Tuanjie Huang Peng Li Hongtao Liu Yanting Zhang Xinkui Zhou Yuanbo Cui Xingxing Zang Yuming Wang Fangxia Guan 《Journal of cellular physiology》2019,234(12):22400-22410
Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with low survival rate, so new therapies are urgently needed. Histone deacetylases (HDACs) play a critical role in tumorigenesis, and HDACs inhibition is a potential therapeutic target in ESSC. In our study, we evaluated the effect and molecular mechanism of MS-275 (an inhibitor of HDACs) on ESCC cells. We found that HDAC1 and HDAC2 were overexpressed in ESCC tissues and related with clinical pathological features of patients with ESCC. MS-275 markedly reduced HDAC1 and HDAC2 expression, whereas increased the level of AcH3 and AcH2B. MS-275 suppressed proliferation and clonogenicity of ESCC cells in a concentration-dependent manner. In addition, MS-275 induced apoptosis, arrested cell cycle, and inhibited migration, epithelial–mesenchymal transition, and sphere-forming ability of ESCC cells in vitro. Moreover, p-Akt1 and p-mTOR were downregulated by MS-275. Finally, MS-275 significantly inhibited tumor growth in vivo. Taken together, HDAC1 and HDAC2 are associated with the progression of ESCC, and MS-275 hinders the progression and stemness of ESCC cells by suppressing the PI3K/Akt/mTOR pathway. Our findings show that MS-275 inhibits ESCC cells growth in vitro and in vivo, which is a potential drug for the ESCC therapy. 相似文献
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Yun-Xia Wei Shi-Min Dong Yuan-Yuan Wang Pu Zhang Ming-Yu Sun Yun-Xiao Wei Xian-Ce Meng Yue Wang 《Cell biology international》2021,45(2):394-403
Vitamin D deficiency is associated with acute myocardial infarction (AMI); thus we aimed to explore improvement effects of 1,25-dihydroxyvitamin D3 (VD3) on the AMI and its potential mechanism. AMI models were constructed using male C57/BL6J mice and randomly treated with normal saline or VD3, using sham rats as control. Heart functions, myocardial damage, apoptosis, and inflammation were evaluated. Cardiomyocytes isolated from 3-day-old suckling mice were used for in vitro verification. After VD3 treatment, AMI-induced cardiac dysfunction was reversed with better cardiac function parameters. VD3 treatment reduced inflammatory cell infiltration and myocardial infarction area accompanied by the reduction of inflammatory factors and myocardial infarction markers compared with the AMI group. VD3 treatment obviously alleviated AMI-induced myocardial apoptosis, along with Bcl-2 upregulation and downregulation of caspase-3, caspase-9, and Bax. Both in vivo and in vitro experiments revealed that VD3 enhanced the expression of LC3II and Beclin-1 and decreased soluble p62. Furthermore, VD3 enhanced the AMI-caused inhibition of PI3K, p-AKT, and p-mTOR expression, which was conversely reversed by the addition of 3-methyladenine in vitro. The study highlights the improvement effects of VD3 on cardiac functions. We proposed a potential mechanism that VD3 protects against myocardial damage, inflammation, and apoptosis by promoting autophagy through PI3K/AKT/mTOR pathway. 相似文献
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F Yang R Deng X-J Qian S-H Chang X-Q Wu J Qin G-K Feng K Ding X-F Zhu 《Cell death & disease》2014,5(3):e1114
The serine/threonine kinase AKT is generally accepted as a promising anticancer therapeutic target. However, the relief of feedback inhibition and enhancement of other survival pathways often attenuate the anticancer effects of AKT inhibitors. These compensatory mechanisms are very complicated and remain poorly understood. In the present study, we found a novel 2-pyrimidyl-5-amidothiazole compound, DC120, as an ATP competitive AKT kinase inhibitor that suppressed proliferation and induced apoptosis in liver cancer cells both in vitro and in vivo. DC120 blocked the phosphorylation of downstream molecules in the AKT signal pathway in dose- and time-dependent manners both in vitro and in vivo. However, unexpectedly, DC120 activated mammalian target of rapamycin complex 1 (mTORC1) pathway that was suggested by increased phosphorylation of 70KD ribosomal protein S6 kinase (P70S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). The activated mTORC1 signal was because of increase of intracellular Ca2+ via Ca2+/calmodulin (CaM)/ signaling to human vacuolar protein sorting 34 (hVps34) upon AKT inhibition. Meanwhile, DC120 attenuated the inhibitory effect of AKT on CRAF by decreasing phosphorylation of CRAF at Ser259 and thus activated the mitogen-activated protein kinase (MAPK) pathway. The activation of the mTORC1 and MAPK pathways by DC120 was not mutually dependent, and the combination of DC120 with mTORC1 inhibitor and/or MEK inhibitor induced significant apoptosis and growth inhibition both in vitro and in vivo. Taken together, the combination of AKT, mTORC1 and/or MEK inhibitors would be a promising therapeutic strategy for liver cancer treatment. 相似文献