MicroRNA-374b accelerates the development of lung cancer through downregulating PTEN expression via activating PI3K/Akt pathway.
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To elucidate whether microRNA-374b could participate in the development of lung cancer (LC) through downregulating PTEN (gene of phosphate and tensin homolog deleted on chromosome ten) expression via activating PI3K/Akt pathway.Expression levels of microRNA-374b and PTEN in LC tissues and adjacent normal tissues were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Moreover, the expression level of microRNA-374b in LC cell lines was detected as well. The microRNA-374b inhibitor was constructed and transfected to downregulate microRNA-374b expression in A549 and H358 cells. The regulatory effects of microRNA-374b on migratory and proliferative capacities of LC cells were explored by wound healing and cell counting kit-8 (CCK-8) assay, respectively. After co-transfection of microRNA-374b inhibitor and si-PTEN in LC cells, expression levels of PTEN/PI3K/Akt were determined by qRT-PCR and Western blot.QRT-PCR results showed that microRNA-374b expression was higher, while PTEN expression was lower in LC tissues than adjacent tissues. Identically, microRNA-374b was also highly expressed in LC cell lines. PTEN expression was negatively correlated with microRNA-374b expression in LC. The downregulation of microRNA-374b in A549 and H358 cells inhibited their migratory and proliferative potentials. Subsequently, we verified that microRNA-374b could bind to PTEN through dual-luciferase reporter gene assay. MicroRNA-374b could inhibit PTEN expression and activate the PI3K/Akt pathway. Furthermore, PTEN knockdown enhanced migratory and proliferative abilities of LC cells, which were attenuated by co-transfection of microRNA-374b inhibitor.MicroRNA-374b promotes the development of LC by downregulating PTEN expression through activating PI3K/Akt pathway.Keywords:
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Objective To discuss the activity of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/phosphatidylinositol 3-kinase (PI3K)/AKT pathway and the clinical significance of PTEN protein expression in clear-cell renal-cell carcinoma(CCRCC) tissues.Methods The protein of PTEN and AKT(phosphorylation at Ser473)of 36 paired CCRCC and adjacent non-neoplastic renal samples were analysed by Western-blot.The effect of PTEN on AKT activation was detected by Western-blot after transfected with si-RNA against PTEN in A-498 cell line.Results The significantly increased AKT(phosphorylation at Ser473)with decreased PTEN protein were observed in CCRCC tissues compared with the adjacent non-neoplastic renal samples while the PTEN protein expression had no significant association with pathological parameters.Blocking PTEN resulting in up-regulation of AKT phosphorylation.Conclusions Our findings indicate that as PTEN dominantly inhibits AKT activation,the coexistence of high levels of the PTEN protein with enhanced AKT activation suggests the existence of novel mechanisms which attenuate PTEN function in CCRCC.These mechanisms may reduce PTEN function or increase AKT activation.
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PTEN-Long is a translational variant of PTEN (Phosphatase and Tensin Homolog). Like PTEN, PTEN-Long is able to antagonize the PI3K-Akt pathway and inhibits tumor growth. In this study, we investigated the role PTEN-Long plays in the development and progression of clear cell renal cell carcinoma (ccRCC) and explored the therapeutic possibility using proteinaceous PTEN-Long to treat ccRCC. We found that the protein levels of PTEN-Long were drastically reduced in ccRCC, which was correlated with increased levels of phosphorylated Akt (pAkt). Gain of function experiments showed overexpression of PTEN-Long in the ccRCC cell line 786-0 suppressed PI3K-Akt signaling, inhibited cell proliferation, migration and invasion, and eventually induced cell death. When purified PTEN-Long was added into cultured 786-0 cells, it entered cells, blocked Akt activation, and induced apoptosis involving Caspase 3 cleavage. Furthermore, PTEN-Long inhibited proliferation of 786-0 cells in xenograft mouse model. Our results implicated that understanding the roles of PTEN-Long in renal cell carcinogenesis has therapeutic significance.
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Deep genetic studies revealed that PTEN mutations or loss of expression are not early events in cancer development, but characterize tumor progression and invasion. Loss of PTEN function causes a full activation of the pro-survival PI3K/AKT/mTOR pathway, but the treatment with specific inhibitors of PI3K/AKT/mTOR did not produce the expected results. One of the alternative targets of PTEN is the FAK kinase, mainly involved in the control of cancer cell spread. The connection between PTEN and FAK has been demonstrated in different tumor types, with reduced PTEN activity often correlated with increased expression and phosphorylation of FAK. FAK inhibition may thus represent a promising strategy, and some clinical trials are testing FAK inhibitors alone or combined with other agents in a number of solid tumors. However, only few pre-clinical and clinical data described the effects of the combination of PI3K/AKT/mTOR and FAK inhibitors. Increasing knowledge on the PTEN/FAK connection could confirm PTEN as a good prognostic marker for a combination strategy based on concomitant inhibition of PI3K/AKT and FAK signaling, in advanced metastatic malignancies with altered or reduced PTEN expression.
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Background: The phosphatidylinositol 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/v-akt murine thymoma viral oncogene homolog (Akt)/mammalian target of rapamycin (mTOR) pathway is central in the transmission of growth regulatory signals originating from cell surface receptors. Objective: This review discusses how mutations occur that result in elevated expression the PI3K/PTEN/Akt/mTOR pathway and lead to malignant transformation, and how effective targeting of this pathway may result in suppression of abnormal growth of cancer cells. Methods: We searched the literature for articles which dealt with altered expression of this pathway in various cancers including: hematopoietic, melanoma, non-small cell lung, pancreatic, endometrial and ovarian, breast, prostate and hepatocellular. Results/conclusions: The PI3K/PTEN/Akt/mTOR pathway is frequently aberrantly regulated in various cancers and targeting this pathway with small molecule inhibitors and may result in novel, more effective anticancer therapies.
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Recent studies have shown that miR-494-3p is oncogene and has a central role in many solid tumors; however, the role of miR-494-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. In this study, it was found that miR-494-3p was up-regulated in HCC tissues. The high level of miR-494-3p in HCC tumors was correlated with aggressive clinicopathological characteristics and predicted poor prognosis in HCC patients. Functional study demonstrated that miR-494-3p significantly promoted HCC cell metastasis in vitro and vivo. Since phosphoinositide 3-kinase/protein kinase-B (PI3K/AKT) signaling is a basic oncogenic driver in HCC, a potential role of miR-494-3p was explored as well as its target genes in PI3K/AKT activation. Of all the predicted target genes of miR-494-3p, the tumor-suppressor phosphatase and tensin homolog (PTEN) were identified. In conclusion, the data we collected could define an original mechanism of PI3K/AKT hyperactivation and sketch the regulatory role of miR-494-3p in suppressing the expression of PTEN. Therefore, targeting miR-494-3p could provide an effective therapeutic method for the treatment of the disease.
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// Tsung-Ming Chang 1, * , Yan-Shen Shan 2, 3, * , Pei-Yi Chu 4, 1, 5, * , Shih Sheng Jiang 1 , Wen-Chun Hung 1 , Yu-Lin Chen 1 , Hsiu-Chi Tu 1 , Hui-You Lin 1 , Hui-Jen Tsai 1, 6, 7 and Li-Tzong Chen 1, 6, 7, 8 1 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan 2 Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan 3 Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan 4 Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan 5 School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan 6 Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan 7 Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 8 Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan * These authors contributed equally to this work Correspondence to: Hui-Jen Tsai, email: hjtsai@nhri.org.tw Keywords: pancreatic neuroendocrine tumor, PTEN, LKB1, mTOR, c-Myc Received: June 15, 2017 Accepted: September 03, 2017 Published: September 16, 2017 ABSTRACT Pancreatic neuroendocrine tumor (pNET) is an uncommon type of pancreatic neoplasm. Low Phosphatase and Tensin Homologue (PTEN) expression and activation of the mechanistic target of rapamycin (mTOR) pathway have been noted in pNETs, and the former is associated with poor survival in pNET patients. Based on the results of the RADIANT-3 study, everolimus, an oral mTOR inhibitor, has been approved to treat advanced pNETs. However, the exact regulatory mechanism for the mTOR pathway in pNETs remains largely unknown. PTEN and liver kinase B1 (LKB1) are well-known for their regulatory role in the mTOR pathway. We evaluated the expression of PTEN and LKB1 in 21 pNET patients, and low PTEN and LKB1 expression levels were noted in 48% and 24% of the patients, respectively. Loss of PTEN and LKB1 synergistically promoted cell proliferation of pNET, attenuated the sensitivity of cells to mTOR inhibitors and enhanced c-Myc expression, which back-regulated PTEN, AKT, mTOR and its downstream effectors. For pNET cells with low expression levels of PTEN and LKB1, silencing the expression of c-Myc by shRNA reduced their proliferative rate, while adding either c-Myc inhibitor or AMP-activated protein kinase activator reversed their resistance to mTOR inhibitors in vitro and in vivo . Furthermore, high c-Myc expression was subsequently identified in 81% of pNETs, suggesting that up-regulation of c-Myc expression in pNETs may occur through PTEN/LKB1-dependent and PTEN/LKB1-independent regulation. The results delineated the regulation of PTEN and LKB1 on the AKT/mTOR/c-Myc axis and suggested that both c-Myc and mTOR are potential therapeutic targets for pNET.
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// Lili Jiang 1, 2 , Chanjuan Wang 3 , Fangyong Lei 2 , Longjuan Zhang 4 , Xin Zhang 2 , Aibin Liu 5 , Geyan Wu 5 , Jinrong Zhu 5 , Libing Song 2 1 Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, China 2 State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Centre, Sun Yat-sen University, Guangzhou 510060, China 3 Department of the Central Laboratory, The First Affiliated Hospital/School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou 510080, China 4 Laboratory of Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China 5 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China Correspondence to: Libing Song, e-mail: lb.song1@gmail.com Lili Jiang, e-mail: jianglili126@163.com Keywords: PI3K/Akt, miR-93, gliomas Received: December 02, 2014 Accepted: January 26, 2015 Published: March 13, 2015 ABSTRACT The PI3K/Akt signaling pathway is frequently activated in various human cancer types and plays essential roles in development and progression of cancers. Multiple regulators, such as phosphatase and tensin homolog (PTEN) and PH domain leucine rich repeat protein phosphatases (PHLPP), have also found to be involved in suppression of the PI3K/Akt signaling pathway. However, how suppressive effects mediated by these regulators are concomitantly disrupted in cancers, which display constitutively activated PI3K/Akt signaling, remains puzzling. In the present study, we reported that the expression of miR-93 was markedly upregulated in glioma cell lines and clinical glioma tissues. Statistical analysis revealed that miR-93 levels significantly correlated with clinicopathologic grade and overall survival in gliomas. Furthermore, we found that overexpressing miR-93 promoted, but inhibition of miR-93 reduced, glioma cell proliferation and cell-cycle progression. We demonstrated that miR-93 activated PI3K/Akt signaling through directly suppressing PTEN, PHLPP2 and FOXO3 expression via targeting their 3’UTRs. Therefore, our results suggest that miR-93 might play an important role in glioma progression and uncover a novel mechanism for constitutive PI3K/Akt activation in gliomas.
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Objective To discuss the activity of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/phosphatidylinositol 3-kinase (PI3K)/AKT pathway and the clinical significance of PTEN protein expression in clear-cell renal-cell carcinoma( CCRCC) tissues. Methods The protein of PTEN and AKT( phosphorylation at Ser473) of 36 paired CCRCC and adjacent non-neoplastic renal samples were analysed by Western blotting. Results The significantly increased AKT (phosphorylation at Ser473 ) with decreased PTEN protein were observed in CCRCC tissues compared with the adjacent non-neoplastic renal samples while the PTEN protein expression has no significant association with pathological parameters. Conclusion Our findings indicated that as PTEN dominantly inhibits AKT activation, the coexistence of high levels of the PTEN protein with enhanced AKT activation suggests the existence of novel mechanisms which attenuate PTEN function in CCRCC. These mechanisms may reduce PTEN function or increase AKT activation.
Key words:
Clear-cell renal-cell carcinoma; PTEN; PI3K/ AKT pathway
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Esophageal squamous cell carcinoma (ESCC) is one of the most frequently diagnosed cancers in China, but the etiology and mode of carcinogenesis of this disease remain poorly understood. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), as a negative regulator of Akt/mTOR pathway, frequently mutates or is inactive in many cancers. Although mTOR has been thought a promising cancer therapeutic target, the sensitivity of tumor cells to rapamycin was still to be revaluated. In this study, we measured the effects of rapamycin on cell proliferation and phosphorylation of Akt in ESCC cells with varying degrees of differentiation. And then, the relationship between PTEN status and the sensitivity of cells to rapamycin was investigated in EC9706 cells with or without wild-type PTEN in vitro and in vivo. The results demonstrated ESCC cells with poor differentiation were insensitive to rapamycin of high concentration and rapamycin obviously promoted the phosphorylation of Akt in these cells, but it had no obvious effects on p-Akt in cells with well differentiation. Also, we showed that wild-type PTEN improved the sensitivity of poor differentiation cells to rapamycin through inhibiting phosphorylation of Akt in vitro and in vivo. This study explored the possible molecular mechanism of some ESCC cells insensitive to rapamycin and provided a measure for treating ESCC patients with PTEN inactivation using mTOR inhibitors.
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MicroRNAs (miRs) are essential regulators in the development and progression of cancer. The role of miR-494-3p in endometrial cancer (EC) has not yet been investigated. In the present study, the expression levels of miR‑494‑3p were significantly upregulated in EC tissues compared with adjacent normal tissues. Furthermore, upregulation of miR‑494‑3p in patients with EC indicated poorer prognosis; miR‑494‑3p overexpression significantly promoted the proliferation, migration and invasion of HHUA and JEC cells in vitro. Consistently, inhibition of miR‑494‑3p in HHUA cells significantly suppressed tumor growth in vivo in a xenograft model. Additionally, phosphatase and tensin homolog (PTEN) was revealed to be a direct target of miR‑494‑3p in EC cells. Furthermore, overexpression of miR‑494‑3p inhibited PTEN expression and consequently activated the downstream phosphoinositide 3‑kinase/protein kinase B (PI3K/AKT) signialing pathway. Restoration of PTEN or inhibition of PI3K/AKT pathway also abolished miR‑494‑3p‑mediated proliferation, migration and invasion of HHUA and JEC cells. In summary, the results of the present study revealed the importance of the miR‑494‑3p/PTEN/PI3K/AKT axis in the progression of EC, which may provide novel insight into potential therapeutic targets for the treatment of EC.
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