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Ho KH, Chen PH, Shih CM, Lee YT, Cheng CH, Liu AJ, Lee CC, Chen KC. miR-4286 is Involved in Connections Between IGF-1 and TGF-β Signaling for the Mesenchymal Transition and Invasion by Glioblastomas. Cell Mol Neurobiol 2022; 42:791-806. [PMID: 33025417 PMCID: PMC11441231 DOI: 10.1007/s10571-020-00977-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 09/29/2020] [Indexed: 12/17/2022]
Abstract
The insulin-like growth factor (IGF)-1 and transforming growth factor (TGF)-β signal pathways are both recognized as important in regulating cancer prognosis, such as the epithelial-to-mesenchymal transition (EMT) and cell invasion. However, cross-talk between these two signal pathways in glioblastoma multiforme (GBM) is still unclear. In the present study, by analyzing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE) 4412, GBM patients with higher IGF-1 levels exhibited poorer survival. Genes positively correlated with IGF-1 were enriched in EMT and TGF-β signal pathways. IGF-1 treatment enhanced mesenchymal marker expressions and GBM cell invasion. A significant positive correlation was observed for IGF-1 with TGF-β1 (TGFB1) or TGF-β receptor 2 (TGFBR2), both of which participate in TGF-β signaling and are risk genes in the GBM process. IGF-1 stimulation promoted both TGFB1 and TGFBR2 expressions. LY2157299, a TGF-β signaling inhibitor, attenuated IGF-1-enhanced GBM cell invasion and mesenchymal transition. By analyzing IGF-1-regulated microRNA (miR) profiles, miR-4286 was found to be significantly downregulated in IGF-1-treated cells and could be targeted to both TGFB1 and TGFBR2. Overexpression of miR-4286 significantly attenuated expressions of the IGF-1-mediated mesenchymal markers, TGFB1 and TGFBR2. Using kinase inhibitors, only U0126 treatment showed an inhibitory effect on IGF-1-reduced miR-4286 and IGF-1-induced TGFB1/TGFBR2 expressions, suggesting that MEK/ERK signaling is involved in the IGF-1/miR-4286/TGF-β signaling axis. Finally, our results suggested that miR-4286 might act as a tumor suppressive microRNA in inhibiting IGF-1-enhanced GBM cell invasion. In conclusion, IGF-1 is connected to TGF-β signaling in regulating the mesenchymal transition and cell invasion of GBM through inhibition of miR-4286. Our findings provide new directions and mechanisms for exploring GBM progression.
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Affiliation(s)
- Kuo-Hao Ho
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Xinyi District, Taipei, 11031, Taiwan
| | - Peng-Hsu Chen
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Xinyi District, Taipei, 11031, Taiwan
| | - Chwen-Ming Shih
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Xinyi District, Taipei, 11031, Taiwan
| | - Yi-Ting Lee
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Xinyi District, Taipei, 11031, Taiwan
| | - Chia-Hsiung Cheng
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Xinyi District, Taipei, 11031, Taiwan
| | - Ann-Jeng Liu
- Department of Neurosurgery, Taipei City Hospital Ren-Ai Branch, Taipei, Taiwan
| | - Chin-Cheng Lee
- Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen Chang Road, Shih Lin District, Taipei, 111, Taiwan.
| | - Ku-Chung Chen
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Xinyi District, Taipei, 11031, Taiwan.
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Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Pirsalehi A, Safaroghli-Azar A, Zali MR, Bashash D. The PI3K/Akt/mTOR signaling pathway in gastric cancer; from oncogenic variations to the possibilities for pharmacologic interventions. Eur J Pharmacol 2021; 898:173983. [PMID: 33647255 DOI: 10.1016/j.ejphar.2021.173983] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/13/2021] [Accepted: 02/23/2021] [Indexed: 12/24/2022]
Abstract
Genetic and epigenetic alterations have been under concentrated investigations for many years in order to unearth the molecules regulating human cancer pathogenesis. However, the identification of a wide range of dysregulated genes and their protein products has raised a question regarding how the results of this large collection of alterations could converge into a formation of one malignancy. The answer may be found in the signaling cascades that regulate the survival and metabolism of the cells. Aberrancies of each participant molecule of such cascades may well result in augmented viability and unlimited proliferation of cancer cells. Among various signaling pathways, the phosphatidylinositol-3-kinase (PI3K) axis has been shown to be activated in about one-third of human cancers. One of the malignancies that is mostly affected by this axis is gastric cancer (GC), one of the most fatal cancers worldwide. In the present review, we aimed to illustrate the significance of the PI3K/Akt/mTOR axis in the pathogenesis of GC and also provided a wide perspective about the application of the inhibitors of this axis in the therapeutic strategies of this malignancy.
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Affiliation(s)
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Pirsalehi
- Department of Internal Medicine, School of Medicine, Ayatollah Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo. Cancers (Basel) 2020; 12:cancers12123640. [PMID: 33291663 PMCID: PMC7761932 DOI: 10.3390/cancers12123640] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/24/2020] [Accepted: 12/02/2020] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Growth hormone (GH) action is strongly implicated in the progression and therapy resistance in several types of solid tumors which overexpress the GH receptor (GHR). The aim of our study was to characterize the effects of GH and its downstream effector insulin-like growth factor 1 (IGF-1) on melanoma using in vitro and in vivo models. We confirmed an IGF-1-independent role of elevated circulating GH in upregulating key mechanisms of therapy resistance and malignancy with analyses conducted at the molecular and cellular level. We identified that GH upregulates key mechanisms of therapy resistance and metastases in melanoma tumors in an IGF-1 dependent and independent manner by upregulating multidrug efflux pumps and EMT transcription factors. Our study reveals that GH action renders an intrinsic drug resistance phenotype to the melanoma tumors—a clinically crucial property of GH verifiable in other human cancers with GHR expression. Abstract Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH; high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO; high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.
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Yang C, Wang Y, Xue W, Xie Y, Dong Q, Zhu C. Competing Endogenous RNA (ceRNA) Network Analysis of Autophagy-Related Genes in Hepatocellular Carcinoma. Pharmgenomics Pers Med 2020; 13:445-462. [PMID: 33116760 PMCID: PMC7568685 DOI: 10.2147/pgpm.s267563] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 09/07/2020] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Autophagy plays an important role in the occurrence and development of hepatocellular carcinoma (HCC). We aimed to develop an autophagy-related genes signature predicting the prognosis of HCC and to depict a competing endogenous RNA (ceRNA) network. METHODS Differentially expressed autophagy-related genes (DE-ATGs), miRNAs and lncRNAs and clinical data of HCC patients were extracted from TCGA. The GO and KEGG analysis were performed to investigate the gene function. Univariate and multivariate Cox regression analysis were used to identify a prognostic signature with the DE-ATGs. And a nomogram, adapted to the clinical characteristics, was established. Then, we established a ceRNA network related to autophagy genes. RESULTS We screened out 27 differentially expressed genes which were enriched in GO and KEGG pathways related to autophagy and cancers. In univariate and multivariate Cox regression analysis, BIRC5, HSPB8, and SQSTM1 were screened out to establish a prognostic risk score model (AUC=0.749, p<0.01). Kaplan-Meier survival analysis showed that the overall survival of high-risk patients was significantly worse. Furthermore, the signature was validated in the other two independent databases. The nomogram, including the autophagy-related risk signature, gender, stage and TNM, was constructed and validated (C-index=0.736). Finally, the ceRNA network was established based on DE-ATGs, differentially expressed miRNAs and lncRNAs. CONCLUSION We constructed a reliable prognostic model of HCC with autophagy-related genes and depicted a ceRNA network of DE-ATGs in HCC which provides a basis for the study of post-transcriptional modification and regulation of autophagy-related genes in HCC.
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Affiliation(s)
- Chenyu Yang
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao266003, People’s Republic of China
- Shandong Provincial Key Laboratory of Digital Medicine and Computer-Assisted Surgery, Qingdao266003, People’s Republic of China
| | - Yixiu Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao266003, People’s Republic of China
| | - Weijie Xue
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao266003, People’s Republic of China
| | - Yuwei Xie
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao266003, People’s Republic of China
| | - Qian Dong
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao266003, People’s Republic of China
- Shandong Provincial Key Laboratory of Digital Medicine and Computer-Assisted Surgery, Qingdao266003, People’s Republic of China
| | - Chengzhan Zhu
- Shandong Provincial Key Laboratory of Digital Medicine and Computer-Assisted Surgery, Qingdao266003, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao266003, People’s Republic of China
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Peng Y, Li F, Zhang P, Wang X, Shen Y, Feng Y, Jia Y, Zhang R, Hu J, He A. IGF-1 promotes multiple myeloma progression through PI3K/Akt-mediated epithelial-mesenchymal transition. Life Sci 2020; 249:117503. [PMID: 32142767 DOI: 10.1016/j.lfs.2020.117503] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 02/23/2020] [Accepted: 03/02/2020] [Indexed: 12/26/2022]
Abstract
AIMS To investigate the role and mechanism of insulin-like growth factor 1(IGF-1)-mediated EMT on multiple myeloma (MM) growth and metastasis. MATERIALS AND METHODS The expression data from GEO datasets were utilized to explore the expression levels of IGF-1 and epithelial-mesenchymal transition (EMT) markers in MM. Western blotting and flow cytometry analysis were performed to detect the protein levels of EMT markers as well as key components of the PI3K/Akt pathway. Cell proliferation ability was assessed using colony formation assay and EdU incorporation assays. Transwell migration and invasion assays were performed to assess cell metastasis properties. Vimentin was knocked down by using electro-transfection with small interfering RNA (siRNA) to detect the effect of IGF-1-mediated EMT on MM cell growth and metastasis. KEY FINDINGS First of all, the analysis of GEO database revealed that IGF-1 was excessively expressed and closely correlated with the expression of the EMT markers in MM patients. Furthermore, we demonstrated that IGF-1 enhanced the acquisition of mesenchymal features in a time-dependent manner. Additionally, in vitro studies revealed that IGF-1-mediated mesenchymal phenotype promoted MM migration, invasion and colony formation. Finally, the mechanism study showed PI3K/Akt signaling pathway was involved in the IGF-1-induced EMT in MM cells. SIGNIFICANCE IGF-1-induced mesenchymal phenotype contributed to MM progression via the PI3K/Akt pathway regulation.
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Affiliation(s)
- Yue Peng
- Xi'an Jiaotong University Health Science Center, Xi'An City, Shaanxi Province, China
| | - Fangmei Li
- Xi'an Jiaotong University Health Science Center, Xi'An City, Shaanxi Province, China
| | - Peihua Zhang
- Xi'an Jiaotong University Health Science Center, Xi'An City, Shaanxi Province, China
| | - Xiaman Wang
- Xi'an Jiaotong University Health Science Center, Xi'An City, Shaanxi Province, China
| | - Ying Shen
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'An City, Shaanxi Province, China
| | - Yuandong Feng
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'An City, Shaanxi Province, China
| | - Yachun Jia
- Xi'an Jiaotong University Health Science Center, Xi'An City, Shaanxi Province, China
| | - Ru Zhang
- Xi'an Jiaotong University Health Science Center, Xi'An City, Shaanxi Province, China
| | - Jinsong Hu
- Xi'an Jiaotong University Health Science Center, Xi'An City, Shaanxi Province, China.
| | - Aili He
- Xi'an Jiaotong University Health Science Center, Xi'An City, Shaanxi Province, China.
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Cevenini A, Orrù S, Mancini A, Alfieri A, Buono P, Imperlini E. Molecular Signatures of the Insulin-like Growth Factor 1-mediated Epithelial-Mesenchymal Transition in Breast, Lung and Gastric Cancers. Int J Mol Sci 2018; 19:ijms19082411. [PMID: 30111747 PMCID: PMC6122069 DOI: 10.3390/ijms19082411] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 08/13/2018] [Accepted: 08/14/2018] [Indexed: 02/07/2023] Open
Abstract
The insulin-like growth factor (IGF) system, which is constituted by the IGF-1 and IGF-2 peptide hormones, their corresponding receptors and several IGF binding proteins, is involved in physiological and pathophysiological processes. The IGF system promotes cancer proliferation/survival and its signaling induces the epithelial-mesenchymal transition (EMT) phenotype, which contributes to the migration, invasiveness, and metastasis of epithelial tumors. These cancers share two major IGF-1R signaling transduction pathways, PI3K/AKT and RAS/MEK/ERK. However, as far as we could review at this time, each type of cancer cell undergoes EMT through tumor-specific routes. Here, we review the tumor-specific molecular signatures of IGF-1-mediated EMT in breast, lung, and gastric cancers.
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Affiliation(s)
- Armando Cevenini
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Via S. Pansini 5, 80131 Napoli, Italy.
- CEINGE-Biotecnologie Avanzate S.c.a r.l., Via G. Salvatore 486, 80145 Napoli, Italy.
| | - Stefania Orrù
- Dipartimento di Scienze Motorie e del Benessere, Università degli Studi di Napoli "Parthenope", Via Medina 40, 80133 Napoli, Italy.
- IRCCS SDN, Via Francesco Crispi 8, 80121 Napoli, Italy.
| | - Annamaria Mancini
- CEINGE-Biotecnologie Avanzate S.c.a r.l., Via G. Salvatore 486, 80145 Napoli, Italy.
- Dipartimento di Scienze Motorie e del Benessere, Università degli Studi di Napoli "Parthenope", Via Medina 40, 80133 Napoli, Italy.
| | - Andreina Alfieri
- CEINGE-Biotecnologie Avanzate S.c.a r.l., Via G. Salvatore 486, 80145 Napoli, Italy.
- Dipartimento di Scienze Motorie e del Benessere, Università degli Studi di Napoli "Parthenope", Via Medina 40, 80133 Napoli, Italy.
| | - Pasqualina Buono
- Dipartimento di Scienze Motorie e del Benessere, Università degli Studi di Napoli "Parthenope", Via Medina 40, 80133 Napoli, Italy.
- IRCCS SDN, Via Francesco Crispi 8, 80121 Napoli, Italy.
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Underrated enemy - from nonalcoholic fatty liver disease to cancers of the gastrointestinal tract. Clin Exp Hepatol 2018; 4:55-71. [PMID: 29904722 PMCID: PMC6000748 DOI: 10.5114/ceh.2018.75955] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 04/17/2018] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is intrahepatic ectopic lipid deposition which is present despite a lack of other causes of secondary hepatic fat accumulation. It is the most common chronic liver disorder in the welldeveloped countries. NAFLD is a multidisciplinary disease that affects various systems and organs and is inextricably linked to simple obesity, metabolic syndrome, insulin resistance and overt diabetes mellitus type 2. The positive energy balance related to obesity leads to a variety of systemic changes including modified levels of insulin, insulin- like growth factor-1, adipokines, hepatokines and cytokines. It is strongly linked to carcinogenesis and new evidence proves that NAFLD is associated with higher risk of all-cause mortality and cancer-specific mortality among cancer survivors. This article focuses on the association between NAFLD and extrahepatic gastrointestinal tract cancers, aiming to shed light on the pathomechanism of changes leading to the development of tumors.
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Zhao C, Wang Q, Wang B, Sun Q, He Z, Hong J, Kuehn F, Liu E, Zhang Z. IGF-1 induces the epithelial-mesenchymal transition via Stat5 in hepatocellular carcinoma. Oncotarget 2017; 8:111922-111930. [PMID: 29340101 PMCID: PMC5762369 DOI: 10.18632/oncotarget.22952] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 11/17/2017] [Indexed: 01/10/2023] Open
Abstract
It has been reported that the epithelial-mesenchymal transition (EMT) plays an important role in hepatocellular carcinoma (HCC). However, the relationship between the insulin-like growth factor-1 (IGF-1) and EMT of HCC was not fully elucidated. In the present work, we found that the expression of N-cadherin, Vimentin, Snail1, Snail2, and Twist1 was positively associated with IGF-1R expression, while E-cadherin expression was negatively associated with IGF-1 expression in human HCC samples. Furthermore, we observed that IGF-1 up-regulated the expression of N-cadherin, Vimentin, Snail1, Snail2 and Twist1, and down-regulated the expression of E-cadherin. In addition, Stat5 was induced in IGF-1-treated HepG2 and Hep3B cells, and Stat5 inhibition or siRNA significantly affected IGF-1-induced EMT in HepG2 and Hep3B cells. In conclusion, IGF-1 induces EMT of HCC via Stat5 signaling pathway. Thus, IGF-1/Stat5 can be recommended as a potential and novel therapeutic strategy for HCC patients.
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Affiliation(s)
- Chuanzong Zhao
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, P.R. China
| | - Qian Wang
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, P.R. China
| | - Ben Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, P.R. China
| | - Qi Sun
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, P.R. China
| | - Zhaobin He
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, P.R. China
| | - Jianguo Hong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, P.R. China
| | - Florian Kuehn
- Department of General, Thoracic, Vascular and Transplantation Surgery, University of Rostock, Rostock, Germany
| | - Enyu Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, P.R. China
| | - Zongli Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, P.R. China
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IGF1/IGF1R/STAT3 signaling-inducible IFITM2 promotes gastric cancer growth and metastasis. Cancer Lett 2017; 393:76-85. [PMID: 28223169 DOI: 10.1016/j.canlet.2017.02.014] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 01/20/2017] [Accepted: 02/11/2017] [Indexed: 01/06/2023]
Abstract
Interferon-induced transmembrane proteins (IFITMs) are expressed in some types of cancer. However, their precise roles in tumor progression remain unclear. The present study investigated the function of IFITM2 in gastric cancer (GC) progression. A retrospective analysis of a public database and 167 GC patients revealed that IFITM2 expression was upregulated in gastric tumor samples, which was positively correlated with disease progression, more frequent postoperative recurrence, and higher mortality rate. IFITM2 knockdown decreased GC cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition in vitro. We also found that IFITM2 expression was in part induced by insulin-like growth factor (IGF) 1 via IGF1 receptor/signal transducer and activator of transcription 3 signaling. Furthermore, IFITM2 regulated interleukin-6 expression and secretion, which in turn increased IFITM2 expression. Silencing of IFITM2 expression suppressed tumor growth and lung metastasis in vivo. These results suggest that IFITM2 is a novel prognostic biomarker and regulator of GC progression.
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Li H, Batth IS, Qu X, Xu L, Song N, Wang R, Liu Y. IGF-IR signaling in epithelial to mesenchymal transition and targeting IGF-IR therapy: overview and new insights. Mol Cancer 2017; 16:6. [PMID: 28137302 PMCID: PMC5282886 DOI: 10.1186/s12943-016-0576-5] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 12/19/2016] [Indexed: 01/06/2023] Open
Abstract
The insulin-like growth factor-I (IGF-I) signaling induces epithelial to mesenchymal transition (EMT) program and contributes to metastasis and drug resistance in several subtypes of tumors. In preclinical studies, targeting of the insulin-like growth factor-I receptor (IGF-IR) showed promising anti-tumor effects. Unfortunately, high expectations for anti-IGF-IR therapy encountered challenge and disappointment in numerous clinical trials. This review summarizes the regulation of EMT by IGF-I/IGF-IR signaling pathway and drug resistance mechanisms of targeting IGF-IR therapy. Most importantly, we address several factors in the regulation of IGF-I/IGF-IR-associated EMT progression that may be potential predictive biomarkers in targeted therapy.
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Affiliation(s)
- Heming Li
- Department of Medical Oncology, the First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang City, 110001, China.,Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, People's Republic of China
| | - Izhar Singh Batth
- Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiujuan Qu
- Department of Medical Oncology, the First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Ling Xu
- Department of Medical Oncology, the First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Na Song
- Department of Medical Oncology, the First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Ruoyu Wang
- Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, People's Republic of China.
| | - Yunpeng Liu
- Department of Medical Oncology, the First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang City, 110001, China.
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