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1
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Safavi P, Moghadam KB, Haghighi Z, Ferns GA, Rahmani F. Interplay between LncRNA/miRNA and TGF-β Signaling in the Tumorigenesis of Gynecological Cancer. Curr Pharm Des 2024; 30:352-361. [PMID: 38303530 DOI: 10.2174/0113816128284380240123071409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/29/2023] [Accepted: 01/02/2024] [Indexed: 02/03/2024]
Abstract
Gynecologic cancers are among the most common malignancies with aggressive features and poor prognosis. Tumorigenesis in gynecologic cancers is a complicated process that is influenced by multiple factors, including genetic mutations that activate various oncogenic signaling pathways, including the TGF-β pathway. Aberrant activation of TGF-β signaling is correlated with tumor recurrence and metastasis. It has been shown that non-coding RNAs (ncRNAs) have crucial effects on cancer cell proliferation, migration, and metastasis. Upregulation of various ncRNAs, including long non-coding RNAs (lncRNA) and microRNAs (miRNAs), has been reported in several tumors, like cervical, ovarian, and endometrial cancers, but their cellular mechanisms remain to be investigated. Thus, recognizing the role of ncRNAs in regulating the TGF-β pathway may provide novel strategies for better treatment of cancer patients. The present study summarizes recent findings on the role of ncRNAs in regulating the TGF-β signaling involved in tumor progression and metastasis in gynecologic cancers.
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Affiliation(s)
- Pegah Safavi
- Department of Medical Radiation, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Kimia Behrouz Moghadam
- Department of Medicinal Chemistry, Faculty of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran
| | - Zahra Haghighi
- Department of Clinical Biochemistry, Kashmar School of Medical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Farzad Rahmani
- Department of Clinical Biochemistry, Kashmar School of Medical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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2
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Yu Y, MohamedAl-Sharani H, Zhang B. EZH2-mediated SLC7A11 upregulation via miR-125b-5p represses ferroptosis of TSCC. Oral Dis 2023; 29:880-891. [PMID: 34614259 DOI: 10.1111/odi.14040] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/27/2021] [Accepted: 09/28/2021] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Tongue squamous cell carcinoma is one of the most common carcinomas in oral cancer with a high morbidity and mortality. Ferroptosis is a novel type of cell death involved in various diseases including cancers. Additionally, Enhancer of Zeste homolog 2 (EZH2) is significantly associated with a poor prognosis in esophageal squamous cell carcinoma patients but its role in TSCC is unclear. MATERIALS AND METHODS In this study, we tried to investigate the possible mechanism of EZH2 involved in the ferroptosis of TSCC. Expression of EZH2 and SLC7A11 was determined by RT-qPCR. CCK-8 assays were performed to quantify the cell death rate of TSCC cells. Malondialdehyde (MDA) assays were performed to quantify the lipid accumulation. Western blot was performed to analyze the expression level of SLC7A11. We used dual-luciferase reporter assays to determine the association between EZH2 and miR-125b-5p promoter, and miR-125b-5p and the SLC7A11 3' untranslated region (UTR). RESULT Overexpression of EZH2 and SLC7A11 inhibits erastin-induced ferroptosis in TSCC cells. MiR-125b-5p regulates ferroptosis in TSCC cells by targeting SLC7A11. EZH2 inhibits the ferroptosis of TSCC cells by inhibiting miR-125b-5p and enhancing SLC7A11. CONCLUSION EZH2 inhibits erastin-induced ferroptosis in TSCC cells via miR-125b-5p/SLC7A11 axis.
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Affiliation(s)
- Yue Yu
- Oral and Maxillofacial Surgery Ward, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | | | - Bin Zhang
- Oral and Maxillofacial Surgery Ward, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
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3
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He G, Li W, Zhao W, Men H, Chen Q, Hu J, Zhang J, Zhu H, Wang W, Deng M, Xu Z, Wang G, Zhou L, Qian X, Liang L. Formin-like 2 promotes angiogenesis and metastasis of colorectal cancer by regulating the EGFL6/CKAP4/ERK axis. Cancer Sci 2023; 114:2014-2028. [PMID: 36715549 PMCID: PMC10154862 DOI: 10.1111/cas.15739] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/16/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Increasing evidence indicates that angiogenesis plays a pivotal role in tumor progression. Formin-like 2 (FMNL2) is well-known for promoting metastasis; however, the molecular mechanisms by which FMNL2 promotes angiogenesis in colorectal cancer (CRC) remain unclear. Here, we found that FMNL2 promotes angiogenesis and metastasis of CRC in vitro and in vivo. The GDB/FH3 domain of FMNL2 directly interacts with epidermal growth factor-like protein 6 (EGFL6). Formin-like 2 promotes EGFL6 paracrine signaling by exosomes to regulate angiogenesis in CRC. Cytoskeleton associated protein 4 (CKAP4) is a downstream target of EGFL6 and is involved in CRC angiogenesis. Epidermal growth factor-like protein 6 binds to the N-terminus of CKAP4 to promote the migration of HUVECs by activating the ERK/MMP pathway. These findings suggest that FMNL2 promotes the migration of HUVECs and enhances angiogenesis and tumorigenesis in CRC by regulating the EGFL6/CKAP4/ERK axis. Therefore, the EGFL6/CKAP4/ERK axis could be a candidate therapeutic target for CRC treatment.
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Affiliation(s)
- Guoyang He
- Department of Pathology, Xinxiang Medical University, Xinxiang, China.,Department of Pathology, Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Wei Li
- School of Forensic Medicine, Xinxiang Medical University, Xinxiang, China
| | - Wenli Zhao
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Hui Men
- Department of Pathology, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China.,Department of Pathology, Southern Medical University, Guangzhou, China
| | - Qingqing Chen
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Jinlong Hu
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jingyu Zhang
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Huifang Zhu
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Wenxin Wang
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Meijing Deng
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Zishan Xu
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Gaoxiang Wang
- Department of Colorectal and Anal Surgery, First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Lin Zhou
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinlai Qian
- Department of Pathology, Xinxiang Medical University, Xinxiang, China.,Department of Pathology, Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Li Liang
- Department of Pathology, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
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You G, Zhou C, Wang L, Liu Z, Fang H, Yao X, Zhang X. COMMD proteins function and their regulating roles in tumors. Front Oncol 2023; 13:1067234. [PMID: 36776284 PMCID: PMC9910083 DOI: 10.3389/fonc.2023.1067234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 01/12/2023] [Indexed: 01/27/2023] Open
Abstract
The COMMD proteins are a highly conserved protein family with ten members that play a crucial role in a variety of biological activities, including copper metabolism, endosomal sorting, ion transport, and other processes. Recent research have demonstrated that the COMMD proteins are closely associated with a wide range of disorders, such as hepatitis, myocardial ischemia, cerebral ischemia, HIV infection, and cancer. Among these, the role of COMMD proteins in tumors has been thoroughly explored; they promote or inhibit cancers such as lung cancer, liver cancer, gastric cancer, and prostate cancer. COMMD proteins can influence tumor proliferation, invasion, metastasis, and tumor angiogenesis, which are strongly related to the prognosis of tumors and are possible therapeutic targets for treating tumors. In terms of molecular mechanism, COMMD proteins in tumor cells regulate the oncogenes of NF-κB, HIF, c-MYC, and others, and are related to signaling pathways including apoptosis, autophagy, and ferroptosis. For the clinical diagnosis and therapy of malignancies, additional research into the involvement of COMMD proteins in cancer is beneficial.
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Affiliation(s)
- Guangqiang You
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Jilin University, Jilin University, Changchun, China
| | - Chen Zhou
- Department of General Affairs, First Hospital of Jilin University (the Eastern Division), Jilin University, Changchun, China
| | - Lei Wang
- Department of Pediatric Neurology, First Hospital of Jilin University, Jilin University, Changchun, China
| | - Zefeng Liu
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Jilin University, Jilin University, Changchun, China
| | - He Fang
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Jilin University, Jilin University, Changchun, China
| | - Xiaoxao Yao
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Jilin University, Jilin University, Changchun, China,*Correspondence: Xiaoxao Yao, ; Xuewen Zhang,
| | - Xuewen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Jilin University, Jilin University, Changchun, China,*Correspondence: Xiaoxao Yao, ; Xuewen Zhang,
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Zhang L, Wang C, Lu X, Xu X, Shi T, Chen J. Transcriptome sequencing of hepatocellular carcinoma uncovers multiple types of dysregulated ncRNAs. Front Oncol 2022; 12:927524. [PMID: 36132143 PMCID: PMC9484539 DOI: 10.3389/fonc.2022.927524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Transcriptome profiling of hepatocellular carcinoma (HCC) by next-generation sequencing (NGS) technology has been broadly performed by previous studies, which facilitate our understanding of the molecular mechanisms of HCC formation, progression, and metastasis. However, few studies jointly analyze multiple types of noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and micro-RNAs (miRNAs), and further uncover their implications in HCC. In this study, we observed that the circRNA cZRANB1 and lncRNA DUXAP10 were not only significantly upregulated in tumor tissues, but also higher expressed in blood exosomes of HCC as compared with healthy donors. From the analysis of subclass-associated dysregulated ncRNAs, we observed that DLX6-AS1, an antisense RNA of DLX6, and the sense gene DLX6 were highly expressed in S1, a subclass with a more invasive/disseminative phenotype. High correlation between DLX6-AS1 and DLX6 suggested that DLX6-AS1 may function via promoting the transcription of DLX6. Integrative analysis uncovers circRNA–miRNA, lncRNA–miRNA, and competing endogenous RNA networks (ceRNAs). Specifically, cZRANB1, LINC00501, CTD-2008L17.2, and SLC7A11-AS1 may function as ceRNAs that regulate mRNAs by competing the shared miRNAs. Further prognostic analysis demonstrated that the dysregulated ncRNAs had the potential to predict HCC patients’ overall survival. In summary, we identified some novel circRNAs and miRNAs, and dysregulated ncRNAs that could participate in HCC tumorigenesis and progression by inducing transcription of their neighboring genes, increasing their derived miRNAs, or acting as miRNA sponges. Moreover, our systematic analysis provides not only rich data resources for related researchers, but also new insights into the molecular basis of how different ncRNAs coordinately or antagonistically participate in the pathogenesis process of diseases.
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Affiliation(s)
- Li Zhang
- Department of Gastroenterology, Affiliated Sixth People’s Hospital South Campus of Shanghai Jiaotong University, Shanghai, China
- Center for Bioinformatics and Computational Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China
| | - Chunmei Wang
- Department of Gastroenterology, Affiliated Sixth People’s Hospital South Campus of Shanghai Jiaotong University, Shanghai, China
- Department of Gastroenterology, Affiliated Fengxian Hospital of Southern Medical University, Shanghai, China
| | - Xiaojie Lu
- Department of Gastroenterology, Affiliated Sixth People’s Hospital South Campus of Shanghai Jiaotong University, Shanghai, China
| | - Xiao Xu
- The First Affiliated Hospital, Zhejiang University, Hangzhou, China
- *Correspondence: Jinlian Chen, ; Tieliu Shi, ; Xiao Xu,
| | - Tieliu Shi
- Center for Bioinformatics and Computational Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China
- *Correspondence: Jinlian Chen, ; Tieliu Shi, ; Xiao Xu,
| | - Jinlian Chen
- Department of Gastroenterology, Affiliated Sixth People’s Hospital South Campus of Shanghai Jiaotong University, Shanghai, China
- Department of Gastroenterology, Affiliated Fengxian Hospital of Southern Medical University, Shanghai, China
- Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- *Correspondence: Jinlian Chen, ; Tieliu Shi, ; Xiao Xu,
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Teng D, Xia S, Hu S, Yan Y, Liu B, Yang Y, Du X. miR-887-3p Inhibits the Progression of Colorectal Cancer via Downregulating DNMT1 Expression and Regulating P53 Expression. COMPUTATIONAL INTELLIGENCE AND NEUROSCIENCE 2022; 2022:7179733. [PMID: 35795731 PMCID: PMC9252659 DOI: 10.1155/2022/7179733] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/19/2022] [Accepted: 06/07/2022] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) is the third most diagnosed cancer worldwide and the second leading cause of cancer-related deaths. Many researchers have reported that abnormal microRNAs (miRs) were expressed in CRC and participated in the occurrence and progression of CRC. However, there are few reports of miR-887-3p regulating CRC development. In the current study, we investigated the abnormal expression of miR-887-3p and also demonstrated its regulatory role and detailed molecular mechanism in CRC. Initially, miRNA expression data were obtained from TCGA-COAD that consisted of 453 CRC samples and 8 normal tissue samples. These were downloaded and analyzed to compare the expression level of miR-887-3p in CRC tissues to that in normal tissues. Moreover, 32 pairs of surgically resected CRC tumors and para-cancer tissues from our hospital were collected. Quantitative real-time PCR (qRT-PCR) was performed to detect miR-887-3p expression levels in CRC tissues, para-cancer tissues, several CRC cell lines, and an intestinal epithelial cell line. Following miR-887-3p mimic transfection in colon cancer SW480 cell line, the regulatory roles of miR-887-3p on cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT) were detected through CCK-8, flow cytometry, transwell assay, and Western blot. After potential targeting protein was predicted by bioinformatic websites, the luciferase reporter assay and Western blot were used to confirm the target of miR-887-3p. The targeting protein expressions were detected by Western blot and qRT-PCR. The relationship between miR-887-3p level and the effect of miR-887-3p on P53 expression was evaluated by Western blot and qRT-PCR. The effects of miR-887-3p on CRC cell growth in vivo by xenograft tumor experiments were investigated, and Ki-67 in tumor tissue was determined by immunohistochemistry. Results. The COAD data demonstrated that the expression levels of miR-887-3p in CRC clinical sample tissues and cell line cultures were remarkably lower than para-cancer normal tissues and NCM460 cells (normal colonic epithelial cell line). Functional experiments demonstrated that overexpression of miR-887-3p in SW480 cells significantly reduced proliferation, migration, invasion, and EMT, and promoted cancer cell apoptosis. Additionally, Western blot, qRT-PCR, and luciferase reporter assays confirmed that DNMT1 was a downstream target of miR-887-3p. Moreover, the blocking of DNMT1 by miR-887-3p mimics also promoted P53 expression. Finally, overexpression of DNMT1 in SW480 cells could partially reverse the regulatory effect of miR-887-3p mimics on CRC cell development. From in vivo experiments, overexpression of miR-887-3p could inhibit tumor growth in CRC xenograft mice and reduce the Ki-67 level. Conclusion. The microRNA miR-887-3p is a potential biomarker of CRC. It inhibited CRC cell proliferation, invasion, and EMT, and promoted cell apoptosis through targeting and downregulating DNMT1 and promoting P53 expression. Therefore, miR-887-3p may be a good biomarker and therapeutic target for CRC treatment.
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Affiliation(s)
- Da Teng
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Shaoyou Xia
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Shidong Hu
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Yang Yan
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Boyan Liu
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Yu Yang
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Xiaohui Du
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
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7
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HMGA1 Has Predictive Value in Response to Chemotherapy in Gastric Cancer. Curr Oncol 2021; 29:56-67. [PMID: 35049679 PMCID: PMC8774981 DOI: 10.3390/curroncol29010005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/17/2021] [Accepted: 12/21/2021] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer is a serious health problem worldwide. Although its incidence is decreasing, the five-year survival rate remains low. Thus, it is essential to identify new biomarkers that could promote better diagnosis and treatment of patients with gastric cancer. High-mobility group AT-hook 1 (HMGA1) is a non-histone, chromatin-binding protein that has been found overexpressed in several tumor types. It has been correlated with invasion, metastasis, and drug resistance, leading to worse patient survival. The aim of this work was to evaluate the clinical value of HMGA1 in gastric cancer. HMGA1 expression was analyzed by immunohistochemistry in a single hospital series (n = 323) of gastric adenocarcinoma cases (stages I to IV) with clinicopathological and treatment data. In this series, HMGA1 expression showed no significant relevance as a prognostic biomarker. Nevertheless, a significantly better overall survival was observed in cases with high levels of HMGA1 when they were treated with chemotherapy, compared to the nontreated ones, implying that they can benefit more from treatment than patients with low expression of HMGA1. We thereby show for the first time that HMGA1 expression has a substantial value as a biomarker of response to chemotherapy in gastric cancer.
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8
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Zhao Y, Zhang H, Wang H, Ye M, Jin X. Role of formin INF2 in human diseases. Mol Biol Rep 2021; 49:735-746. [PMID: 34698992 DOI: 10.1007/s11033-021-06869-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 10/21/2021] [Indexed: 01/08/2023]
Abstract
Formin proteins catalyze actin nucleation and microfilament polymerization. Inverted formin 2 (INF2) is an atypical diaphanous-related formin characterized by polymerization and depolymerization of actin. Accumulating evidence showed that INF2 is associated with kidney disease focal segmental glomerulosclerosis and cancers, such as colorectal and thyroid cancer where it functions as a tumor suppressor, glioblastoma, breast, prostate, and gastric cancer, via its oncogenic function. However, studies on the underlying molecular mechanisms of the different roles of INF2 in diverse cancers are limited. This review comprehensively describes the structure, biochemical features, and primary pathogenic mutations of INF2.
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Affiliation(s)
- Yiting Zhao
- Department of Hepato-Biliary-Pancreatic Surgery, The Affiliated Ningbo Medical Center of LiHuiLi Hospital of Medical School of Ningbo University, Ningbo, 315048, China.,The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China
| | - Hui Zhang
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, 315211, China.,The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China
| | - Haibiao Wang
- Department of Hepato-Biliary-Pancreatic Surgery, The Affiliated Ningbo Medical Center of LiHuiLi Hospital of Medical School of Ningbo University, Ningbo, 315048, China. .,Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, 315211, China.
| | - Meng Ye
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, 315211, China. .,The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China.
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, 315211, China. .,The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China.
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Dai W, Liu S, Zhang J, Pei M, Xiao Y, Li J, Hong L, Lin J, Wang J, Wu X, Liu G, Chen Y, Wang Y, Lin Z, Yang Q, Zhi F, Li G, Tang W, Li A, Xiang L, Wang J. Vorinostat triggers miR-769-5p/3p-mediated suppression of proliferation and induces apoptosis via the STAT3-IGF1R-HDAC3 complex in human gastric cancer. Cancer Lett 2021; 521:196-209. [PMID: 34481934 DOI: 10.1016/j.canlet.2021.09.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 08/04/2021] [Accepted: 09/01/2021] [Indexed: 12/23/2022]
Abstract
Previous reports have shown that histone deacetylase inhibitors (HDACi) can alter miRNA expression in a range of cancers. Both the 5p-arm and 3p-arm of mature miRNAs can be expressed from the same precursor and involved in cancer progress. Nevertheless, the detailed mechanism by which vorinostat (SAHA), a HDACi, triggers miR-769-5p/miR-769-3p-mediated suppression of proliferation and induces apoptosis in gastric cancer (GC) cells remains elusive. Here, we showed that the miRNA-seq analysis of GC cells treated with SAHA identified seven differentially expressed miRNAs with both strands of the miRNA duplex. miR-769-5p/miR-769-3p expression was downregulated in GC tissues compared with normal tissues. Functionally, high expression of miR-769-5p/miR-769-3p blocked the malignant abilities of GC cells. Mechanistically, miR-769-5p/miR-769-3p targeted IGF1R and IGF1R overexpression rescued the effects of miR-769-5p/miR-769-3p on GC cells growth and metastasis. Moreover, STAT3 bound to the promoter of miR-769. Furthermore, miR-769-5p/miR-769-3p expression was negatively regulated by the STAT3-IGF1R-HDAC3 complex. Besides, miR-769-5p/miR-769-3p synergized with SAHA to promote GC cells apoptosis. Our studies suggest that miR-769-5p/miR-769-3p acts as a tumor suppressor by the STAT3-IGF1R-HDAC3 complex. Moreover, SAHA triggers miR-769-5p/miR-769-3p-mediated inhibition of proliferation and induces apoptosis in GC cells.
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Affiliation(s)
- Weiyu Dai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Gastroenterology, Longgang District People's Hospital, Shenzhen, 518172, China
| | - Jieming Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Miaomiao Pei
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yizhi Xiao
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jiaying Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Linjie Hong
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jianjiao Lin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Gastroenterology, Longgang District People's Hospital, Shenzhen, 518172, China
| | - Jing Wang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xiaosheng Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Guangnan Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yaying Chen
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Yusi Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Zhizhao Lin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Qiong Yang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Gastroenterology, The Second Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Fachao Zhi
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Gastroenterology, Longgang District People's Hospital, Shenzhen, 518172, China
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Weimei Tang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Aimin Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Li Xiang
- Department of Gastroenterology, Longgang District People's Hospital, Shenzhen, 518172, China.
| | - Jide Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Gastroenterology, Longgang District People's Hospital, Shenzhen, 518172, China.
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10
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Yang Q, Wang Y, Li M, Wang Z, Zhang J, Dai W, Pei M, Hong L, Xiao Y, Hu H, Li J, Lin J, Wu X, Chen Y, Huang M, Li A, Liu S, Tang W, Xiang L, Wang J. HMGA1 promotes gastric cancer growth and metastasis by transactivating SUZ12 and CCDC43 expression. Aging (Albany NY) 2021; 13:16043-16061. [PMID: 34167089 PMCID: PMC8266323 DOI: 10.18632/aging.203130] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 05/13/2021] [Indexed: 12/12/2022]
Abstract
HMGA1 protein is an architectural transcription factor that has been implicated in the progression of multiple malignant tumors. However, the role of HMGA1 in the growth and metastasis of gastric cancer (GC) has not yet been elucidated. Here, we show that HMGA1 is overexpressed in GC cells and the high expression of HMGA1 was correlated with worse survival in GC patients using a bioinformatics assay. Functionally, HMGA1 affected the EdU incorporation, colony formation, migration and invasion of GC cells by exogenously increasing or decreasing the expression of HMGA1. Mechanistically, HMGA1 directly bound to the SUZ12 and CCDC43 promoter and transactivated its expression in GC cells. Inhibition of SUZ12 and CCDC43 attenuated the proliferation, migration and invasiveness of HMGA1-overexpressing GC cells in vitro. Moreover, both HMGA1 and SUZ12/CCDC43 were highly expressed in cancer cells but not in normal gastric tissues, and their expressions were positively correlated. Finally, a tail vein metastatic assay showed that HMGA1 promoted SUZ12/CCDC43-mediated GC cell metastasis in vivo. Our findings suggest that HMGA1 promotes GC growth and metastasis by transactivating SUZ12 and CCDC43 expression, highlighting HMGA1 as a potential prognostic biomarker in the treatment of GC.
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Affiliation(s)
- Qiong Yang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.,The Second Affiliated Hospital of University of South China, Hengyang 421001, China
| | - Yusi Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Mengshu Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhi Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jieming Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Weiyu Dai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Miaomiao Pei
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Linjie Hong
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yizhi Xiao
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hongsong Hu
- Department of Gastroenterology, Longgang District People's Hospital, Shenzhen 518172, China
| | - Jiaying Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jianjiao Lin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.,Department of Gastroenterology, Longgang District People's Hospital, Shenzhen 518172, China
| | - Xiaosheng Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yaying Chen
- Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Miaojuan Huang
- Department of Gastroenterology, Longgang District People's Hospital, Shenzhen 518172, China
| | - Aimin Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.,Department of Gastroenterology, Longgang District People's Hospital, Shenzhen 518172, China
| | - Weimei Tang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Li Xiang
- Department of Gastroenterology, Longgang District People's Hospital, Shenzhen 518172, China
| | - Jide Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.,Department of Gastroenterology, Longgang District People's Hospital, Shenzhen 518172, China
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11
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Liu D, Chen C, Cui M, Zhang H. miR-140-3p inhibits colorectal cancer progression and its liver metastasis by targeting BCL9 and BCL2. Cancer Med 2021; 10:3358-3372. [PMID: 33838016 PMCID: PMC8124101 DOI: 10.1002/cam4.3840] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 12/24/2022] Open
Abstract
Recent studies have identified microRNAs (miRNAs) as a compelling novel class of biomarker in colorectal cancer (CRC) development and metastasis. Here, we demonstrated that the level of plasma exosomal miR‐140‐3p in CRC patients was lower than that in healthy controls. The decreased miR‐140‐3p level was also observed in CRC patients with liver metastasis. The expression of miR‐140‐3p in CRC tissues were significantly lower than that in matched normal tissues. Functionally, miR‐140‐3p overexpression suppressed proliferation, migration, invasion, and β‐catenin nuclear translocation, as well as promoted apoptosis in LoVo cells, while inhibition of miR‐140‐3p reversed these cellular processes in HCT 116 cells. Notably, BCL9 and BCL2 were recognized as direct targets of miR‐140‐3p. BCL9 knockdown abrogated miR‐140‐3p inhibitor‐induced effects on HCT 116 cells with decreased proliferation, migration, and invasion. BCL2 knockdown increased apoptosis of miR‐140‐3p inhibitor‐transfected HCT 116 cells. In vivo experiments revealed that miR‐140‐3p overexpression inhibited tumor growth in LoVo xenograft model and diminished metastatic nodules in nude mice liver. Taken together, this work supports that miR‐140‐3p exerts as a tumor suppressor in CRC progression via targeting BCL9 and BCL2, and suggests miR‐140‐3p‐BCL9/BCL2 axis may be applied in miRNA‐based therapy and prognostication of CRC.
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Affiliation(s)
- Dingsheng Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Chunsheng Chen
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Mingming Cui
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Hong Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
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12
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Chen W, Du J, Li X, Zhi Z, Jiang S. microRNA-137 downregulates MCL1 in ovarian cancer cells and mediates cisplatin-induced apoptosis. Pharmacogenomics 2021; 21:195-207. [PMID: 31967512 DOI: 10.2217/pgs-2019-0122] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Aim: miR-137 is downregulated in various cancers; however, its function in ovarian cancer remains unclear. Methods: The roles of miR-137 in apoptosis were accessed through IC50 values and DAPI assay. The regulation of MCL1 by miR-137 was investigated through luciferase reporter assay and immunoblot. Results: miR-137 mimic could decrease the IC50 value of cisplatin and promote apoptosis in OVCAR3 ovarian cancer cells. Using luciferase assay, results on a panel of anti-apoptotic proteins, we identified MCL1 as a target for miR-137 and the results were confirmed using immunoblot. Finally, the underlying pathway in which miR-137 may be involved was investigated by transcriptome sequencing. Conclusion: These results suggest that miR-137 downregulates MCL1 in ovarian cancer cells and mediates cisplatin-induced apoptosis.
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Affiliation(s)
- Wei Chen
- Department of Gynecology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
| | - Jingjie Du
- Department of Biological Sciences & Technology, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Xiaodi Li
- Department of Biological Sciences & Technology, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Ziming Zhi
- Department of Gynecology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
| | - Songshan Jiang
- Department of Biological Sciences & Technology, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
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13
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Grzywa TM, Klicka K, Włodarski PK. Regulators at Every Step-How microRNAs Drive Tumor Cell Invasiveness and Metastasis. Cancers (Basel) 2020; 12:E3709. [PMID: 33321819 PMCID: PMC7763175 DOI: 10.3390/cancers12123709] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/03/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Tumor cell invasiveness and metastasis are the main causes of mortality in cancer. Tumor progression is composed of many steps, including primary tumor growth, local invasion, intravasation, survival in the circulation, pre-metastatic niche formation, and metastasis. All these steps are strictly controlled by microRNAs (miRNAs), small non-coding RNA that regulate gene expression at the post-transcriptional level. miRNAs can act as oncomiRs that promote tumor cell invasion and metastasis or as tumor suppressor miRNAs that inhibit tumor progression. These miRNAs regulate the actin cytoskeleton, the expression of extracellular matrix (ECM) receptors including integrins and ECM-remodeling enzymes comprising matrix metalloproteinases (MMPs), and regulate epithelial-mesenchymal transition (EMT), hence modulating cell migration and invasiveness. Moreover, miRNAs regulate angiogenesis, the formation of a pre-metastatic niche, and metastasis. Thus, miRNAs are biomarkers of metastases as well as promising targets of therapy. In this review, we comprehensively describe the role of various miRNAs in tumor cell migration, invasion, and metastasis.
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Affiliation(s)
- Tomasz M. Grzywa
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Klaudia Klicka
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Paweł K. Włodarski
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
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14
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Liu H, Zhang X, Jin X, Yang Y, Liang G, Ma Y, Wang B. Long Noncoding RNA VPS9D1-AS1 Sequesters microRNA-525-5p to Promote the Oncogenicity of Colorectal Cancer Cells by Upregulating HMGA1. Cancer Manag Res 2020; 12:9915-9928. [PMID: 33116849 PMCID: PMC7553769 DOI: 10.2147/cmar.s273687] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 09/03/2020] [Indexed: 12/24/2022] Open
Abstract
Background The long noncoding RNA VPS9D1 antisense RNA 1 (VPS9D1-AS1) has emerged as a critical regulator in non-small-cell lung, gastric, and prostate cancers. In this study, we measured the expression levels of VPS9D1-AS1 in colorectal cancer (CRC) and determined the role of VPS9D1-AS1 in regulating the biological activities of CRC cells. In addition, we thoroughly elucidated the molecular mechanism mediating the oncogenic activities of VPS9D1-AS1 in CRC. Methods The expression levels of VPS9D1-AS1 in CRC tissues and cell lines were detected via quantitative reverse transcription-polymerase chain reaction. Loss-of-function experiments were performed to detect the effects of VPS9D1-AS1 silencing on CRC cell proliferation, apoptosis, migration, and invasion as well as on tumor growth in vivo. Bioinformatics analysis predicted the potential microRNAs (miRNAs) interacting with VPS9D1-AS1, and this prediction was further confirmed via RNA immunoprecipitation and luciferase reporter assays. Results Our results demonstrated the upregulated expression of VPS9D1-AS1 in CRC tissues and cell lines. Functionally, VPS9D1-AS1 interference suppressed CRC cell proliferation, migration, and invasion and promoted cell apoptosis in vitro. In addition, the loss of VPS9D1-AS1 hindered tumor growth in vivo. Mechanistic studies identified VPS9D1-AS1 as a competing endogenous RNA in CRC cells, in which VPS9D1-AS1 acted as a molecular sponge of miR-525-5p and consequently increased the expression of high-mobility group AT-hook 1 (HMGA1). Moreover, rescue experiments revealed that the regulatory effects of VPS9D1-AS1 deficiency on CRC cells were abolished after miR-525-5p inhibition or HMGA1 restoration. Conclusion The newly identified competing endogenous RNA pathway involving VPS9D1-AS1, miR-525-5p, and HMGA1 is implicated in the control of CRC progression and may provide an effective target for CRC diagnosis and therapy.
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Affiliation(s)
- Hairui Liu
- Department of Abdominal Surgery, Jilin Cancer Hospital, Changchun, Jilin 130021, People's Republic of China
| | - Xueying Zhang
- Department of Oncology Medicine, Jilin Cancer Hospital, Changchun, Jilin 130021, People's Republic of China
| | - Xianmei Jin
- Department of Childhood Solid Tumor, First Hospital of Jilin University, Changchun, Jilin 130021, People's Republic of China
| | - Yubo Yang
- Department of Abdominal Surgery, Jilin Cancer Hospital, Changchun, Jilin 130021, People's Republic of China
| | - Guodong Liang
- Department of Abdominal Surgery, Jilin Cancer Hospital, Changchun, Jilin 130021, People's Republic of China
| | - Yuehan Ma
- Department of Abdominal Surgery, Jilin Cancer Hospital, Changchun, Jilin 130021, People's Republic of China
| | - Bing Wang
- Department of Radiotherapy, Jilin Cancer Hospital, Changchun, Jilin 130021, People's Republic of China
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15
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Huerta M, Reyes L, García-Rivera G, Bañuelos C, Betanzos A, Díaz-Hernández M, Galindo A, Bolaños J, Cárdenas H, Azuara-Liceaga E, Chávez-Munguía B, Orozco E. A noncanonical GATA transcription factor of Entamoeba histolytica modulates genes involved in phagocytosis. Mol Microbiol 2020; 114:1019-1037. [PMID: 32808689 DOI: 10.1111/mmi.14592] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 08/12/2020] [Accepted: 08/14/2020] [Indexed: 12/21/2022]
Abstract
In this paper, we explored the presence of GATA in Entamoeba histolytica and their function as regulators of phagocytosis-related genes. Bioinformatics analyses evidenced a single 579 bp sequence encoding for a protein (EhGATA), smaller than GATA factors of other organisms. EhGATA appeared phylogenetically close to Dictyostelium discoideum and Schistosoma mansoni GATA proteins. Its sequence predicts the presence of a zinc-finger DNA binding domain and an AT-Hook motif; it also has two nuclear localization signals. By transmission electron and confocal microscopy, anti-EhGATA antibodies revealed the protein in the cytoplasm and nucleus, and 65% of nuclear signal was in the heterochromatin. EhGATA recombinant protein and trophozoites nuclear extracts bound to GATA-DNA consensus sequence. By in silico scrutiny, 1,610 gene promoters containing GATA-binding sequences appeared, including Ehadh and Ehvps32 promoters, whose genes participate in phagocytosis. Chromatin immunoprecipitation assays showed that EhGATA interact with Ehadh and Ehvps32 promoters. In EhGATA-overexpressing trophozoites (NeoGATA), the Ehadh and Ehvps32 mRNAs amount was modified, strongly supporting that EhGATA could regulate their transcription. NeoGATA trophozoites exhibited rounded shapes, high proliferation rates, and diminished erythrophagocytosis. Our results provide new insights into the role of EhGATA as a noncanonical transcription factor, regulating genes associated with phagocytosis.
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Affiliation(s)
- Miriam Huerta
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, México
| | - Luz Reyes
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, México
| | - Guillermina García-Rivera
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, México
| | - Cecilia Bañuelos
- Programa de Doctorado Transdisciplinario en Desarrollo Científico y Tecnológico para la Sociedad, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, México
| | - Abigail Betanzos
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, México.,Consejo Nacional de Ciencia y Tecnología, Ciudad de México, México
| | - Mitzi Díaz-Hernández
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, México
| | - Ausencio Galindo
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, México
| | - Jeni Bolaños
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, México
| | - Helios Cárdenas
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Ciudad de México, México
| | - Elisa Azuara-Liceaga
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Ciudad de México, México
| | - Bibiana Chávez-Munguía
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, México
| | - Esther Orozco
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, México
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16
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Zang Y, Zhu J, Li Q, Tu J, Li X, Hu R, Yang D. miR-137-3p Modulates the Progression of Prostate Cancer by Regulating the JNK3/EZH2 Axis. Onco Targets Ther 2020; 13:7921-7932. [PMID: 32884286 PMCID: PMC7434530 DOI: 10.2147/ott.s256161] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 07/22/2020] [Indexed: 01/11/2023] Open
Abstract
Background Prostate cancer (PCa) is one of the most common cancers in men worldwide. Early detection of prostate cancer by prostate-specific antigen (PSA) screening still has limitations. The discovery of new candidates is urgent and can provide insights into the mechanism involved in prostate cancer tumorigenesis. Methods We conducted a cross-sectional study involving prostate cancer cell lines and clinical samples. qPCR and IHC were used to evaluate the expression of miR-137-3p/JNK3/EZH2. Furthermore, cell growth, migration, invasion, cell cycle and apoptosis were analyzed to describe the function of this axis. Moreover, xenograft models, pathology platforms and TCGA data were generated to confirm the role of the miR-137-3p/JNK3/EZH2 axis. Results In this study, we determined that miR-137-3p was significantly reduced in prostate cancer, and low expression of miR-137-3p was correlated with tumor stage . The overexpression of miR-137-3p suppressed cell proliferation, migration and invasion in prostate cancer by enhancing cell apoptosis. We also validated JNK3 (MAPK10) as a direct target gene of miR-137-3p. Down-regulation of JNK3 in prostate cancer also inhibited cell proliferation and invasion and promoted apoptosis. Moreover, JNK3 expression was up-regulated and negatively correlated with miR-137-3p in prostate cancer tissues. Furthermore, JNK3 modulated EZH2 expression, which is a key oncogene in prostate cancer. Survival data indicated that patients with high levels of JNK3 and EZH2 had a worse prognosis. Conclusion Collectively, the identification of miR-137-3p and the JNK3/EZH2 pathway might facilitate the development of biomarkers and therapeutic targets for prostate cancer.
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Affiliation(s)
- Yachen Zang
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, People's Republic of China
| | - Jin Zhu
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, People's Republic of China
| | - Qin Li
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China.,GenePharma-Deakin University Joint Laboratory of Aptamer Medicine, Suzhou 215123, People's Republic of China
| | - Jian Tu
- Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou 215006, People's Republic of China
| | - Xiaoqing Li
- Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215001, People's Republic of China
| | - Rongkuan Hu
- GenePharma-Deakin University Joint Laboratory of Aptamer Medicine, Suzhou 215123, People's Republic of China
| | - Dongrong Yang
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, People's Republic of China
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17
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Nie H, Mei J, Zhang Q, An F, Zhan Q. Systematic Characterization of the Expression and Prognostic Values of Formin-Like Gene Family in Gastric Cancer. DNA Cell Biol 2020; 39:1664-1677. [PMID: 32551946 DOI: 10.1089/dna.2020.5508] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Formin-like genes (FMNLs) are members of formins family and have been implicated to the development and progression of multiple cancers. This research aims to analyze the expression profiles, prognostic values, and immune infiltrating associations of FMNLs in gastric cancer (GC) using multiple online bioinformatics website, including Oncomine, UALCAN, Kaplan-Meier Plotter, TIMER, GeneMANIA, DAVID, and LinkedOmics databases. The mRNA levels of FMNL1/2/3 were higher in GC tissues than normal. Meanwhile, FMNLs expressions tend to be upregulated in advanced and poorly differentiated GC. Prognostic value analysis suggested that high transcription levels of FMNL1/3 were associated with poor overall survival in GC patients. Correlation analysis between FMNLs expressions and immune infiltrating GC revealed that the expressions of FMNLs were significantly associated with immune infiltrating. Protein-protein interaction network and enrichment analysis of FMNLs in GC showed that FMNLs coexpressed genes mainly participated in organizing actin cytoskeleton through affecting small G proteins activity. Moreover, Gene Set Enrichment Analysis (GSEA) analysis uncovered FMNLs and their coexpressed genes was tightly associated with immune-related cellular functions. These findings demonstrate that FMNLs might play significant immunomodulatory roles in tumor immunity and could be novel therapeutic targets and potential prognostic biomarkers in GC.
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Affiliation(s)
- He Nie
- Department of Gastroenterology and Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Jie Mei
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Qinglin Zhang
- Department of Gastroenterology and Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Fangmei An
- Department of Gastroenterology and Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Qiang Zhan
- Department of Gastroenterology and Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
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18
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Shi T, Fujita K, Gong J, Nakahara M, Iwama H, Liu S, Yoneyama H, Morishita A, Nomura T, Tani J, Takuma K, Tadokoro T, Himoto T, Oura K, Tsutsui K, Kobara H, Masaki T. Aspirin inhibits hepatocellular carcinoma cell proliferation in vitro and in vivo via inducing cell cycle arrest and apoptosis. Oncol Rep 2020; 44:457-468. [PMID: 32627038 PMCID: PMC7336451 DOI: 10.3892/or.2020.7630] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 03/10/2020] [Indexed: 12/24/2022] Open
Abstract
Aspirin, a nonsteroidal anti‑inflammatory drug (NSAID), is known to inhibit cell proliferation in a variety of cancers. However, the underlying mechanism of this inhibition remains unknown. We investigated the effects of aspirin on hepatocellular carcinoma (HCC) cells using in vitro and in vivo models. Six HCC cell lines and a liver cancer cell line including Huh‑7 were used in assays that evaluated cell proliferation, cell cycle, and apoptosis. Flow cytometry, enzyme‑linked immunosorbent assay (ELISA), western blot analysis, and phosphorylated receptor tyrosine kinase array were used to evaluate the effects of aspirin on the cells, and microRNAs (miRNAs) were analyzed by a miRNA array chip. The results were validated in vivo using a nude mouse model of Huh‑7‑xenografted tumors. Our results showed that aspirin exhibited an antiproliferative effect on all cell lines. Moreover, aspirin induced G0/G1 cell cycle arrest and modulated the levels of cell cycle‑related molecules such as cyclin E, cyclin D1, and cyclin‑dependent kinase 2 (Cdk2). In addition, aspirin upregulated the levels of caspase‑cleaved cytokeratin 18, increased the proportion of early apoptotic cells, decreased the levels of clusterin and heat shock protein 70 (HSP 70), upregulated the levels of miRNA‑137 and inhibited epidermal growth factor receptor (EGFR) activation. In addition, we observed that aspirin suppressed cell proliferation partially through the miRNA‑137/EGFR pathway. Our in vivo results showed that aspirin reduced the growth of xenograft tumors in nude mice. In conclusion, aspirin was able to inhibit the growth of HCC cells by cell cycle arrest, apoptosis, and alteration of miRNA levels in in vitro and in vivo models.
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Affiliation(s)
- Tingting Shi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Jian Gong
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Shi Liu
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Takashi Himoto
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Kunihiko Tsutsui
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa 761‑0793, Japan
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19
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Liu X, Zhou Z, Wang Y, Zhu K, Deng W, Li Y, Zhou X, Chen L, Li Y, Xie A, Zeng T, Wang G, Fu B. Downregulation of HMGA1 Mediates Autophagy and Inhibits Migration and Invasion in Bladder Cancer via miRNA-221/TP53INP1/p-ERK Axis. Front Oncol 2020; 10:589. [PMID: 32477928 PMCID: PMC7235162 DOI: 10.3389/fonc.2020.00589] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 03/31/2020] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) have been implicated in regulating the development and metastasis of human cancers. MiR-221 is reported to be an oncogene in multiple cancers, including bladder cancer (BC). Deregulation of autophagy is associated with multiple human malignant cancers. Whether and how miR-221 regulates autophagy and how miR-221 has been regulated in BC are poorly understood. This study explored the potential functions and mechanisms of miR-221 in the autophagy and tumorigenesis of BC. We showed that the downregulation of miR-221 induces autophagy via increasing TP53INP1 (tumor protein p53 inducible nuclear protein 1) and inhibits migration and invasion of BC cells through suppressing activation of extracellular signal-regulated kinase (ERK). Furthermore, the expression of miR-221 is regulated by high-mobility group AT-hook 1 (HMGA1) which is overexpressed in BC. And both miR-221 and HMGA1 are correlated with poor patient survival in BC. Finally, the downregulation of HMGA1 suppressed the proliferative, migrative, and invasive property of BC by inducing toxic autophagy via miR-221/TP53INP1/p-ERK axis. Collectively, our findings demonstrate that the downregulation of miR-221 and HMGA1 mediates autophagy in BC, and both of them are valuable therapeutic targets for BC.
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Affiliation(s)
- Xiaoqiang Liu
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Institute of Urology, Nanchang, China
| | - Zhengtao Zhou
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yibing Wang
- Department of Emergency, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ke Zhu
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Institute of Urology, Nanchang, China
| | - Wen Deng
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yulei Li
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaochen Zhou
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Luyao Chen
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yu Li
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - An Xie
- Jiangxi Institute of Urology, Nanchang, China
| | - Tao Zeng
- Department of Urology, The People's Hospital of Jiangxi Province, Nanchang, China
| | - Gongxian Wang
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Institute of Urology, Nanchang, China
| | - Bin Fu
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Institute of Urology, Nanchang, China
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20
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Wu X, Xiao Y, Ma J, Wang A. Circular RNA: A novel potential biomarker for skin diseases. Pharmacol Res 2020; 158:104841. [PMID: 32404296 DOI: 10.1016/j.phrs.2020.104841] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 04/02/2020] [Accepted: 04/16/2020] [Indexed: 02/07/2023]
Abstract
Circular RNA (circRNA) has been classified as noncoding RNA with a covalent closed continuous loop, the 3'and 5' ends of which are normally joined together to increase its own stability. More recently, circRNA has been shown to encode proteins and may be involved in the regulation of gene transcription. This provides more evidence for the involvement of circRNA in disease progression. Accumulating investigations have found that the expression of many circRNAs is abnormal in plenty of skin diseases such as malignant melanoma, psoriasis, and abnormal wound healing. Herein, in addition to the summary of recent studies on the nuclear export, N6-methyladenosine (m6A) modification, degradation, and other biogenesis and properties of circRNA, we highlight the importance of circRNAin skin diseases. Although their exact roles and mechanisms in most skin disease remain preliminary, circRNAs have potential applications as diagnostic biomarkers and novel therapeutic targets for skin diseases due to its structural and functional properties (stability, specificity and sensitivity), which is worthy of deeper exploration and greater research efforts.
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Affiliation(s)
- Xiaoting Wu
- Department of Dermatology, The Second Hospital of Dalian Medical University, Dalian, China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Yanwei Xiao
- Department of Dermatology, The Second Hospital of Dalian Medical University, Dalian, China
| | - Jingxin Ma
- Department of Cell Biology, Dalian Medical University, Dalian, China
| | - Aoxue Wang
- Department of Dermatology, The Second Hospital of Dalian Medical University, Dalian, China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China.
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21
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Liu M, Xiao Y, Tang W, Li J, Hong L, Dai W, Zhang W, Peng Y, Wu X, Wang J, Chen Y, Bai Y, Lin J, Yang Q, Wang Y, Lin Z, Liu S, Xiong J, Wang J, Xiang L. HOXD9 promote epithelial-mesenchymal transition and metastasis in colorectal carcinoma. Cancer Med 2020; 9:3932-3943. [PMID: 32281284 PMCID: PMC7286477 DOI: 10.1002/cam4.2967] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 02/06/2020] [Accepted: 02/21/2020] [Indexed: 12/26/2022] Open
Abstract
Background HOXD9, a Hox family member, is involved in cancer growth and metastasis. But, its regulation mechanism at the molecular level particularly in colorectal cancer (CRC), is mostly unknown. Methods The HOXD9 protein expression levels were analyzed using immunofluorescence, immunohistochemistry (IHC) assays, and western blot. The in vivo and in vitro roles of HOXD9 in CRC were determined using colony formation and EdU incorporation, CCK‐8, wound scratch and transwell invasion assay, and animal models. Results Expression of HOXD9 was higher in CRC than in matched healthy tissues. High expression of HOXD9 has significantly associated with the American Joint Committee on Cancer (AJCC) stages, tumor differentiation, lymph node metastasis, and other serious invasions, and it had a poor prognosis. In vitro, HOXD9 encouraged proliferation, movement and EMT processes in cells of CRC. Also, TGF‐β1 promoted the expression of HOXD9 and this effect was dependent on the dose and downregulation of HOXD9 repressed TGF‐β1 ‐induced EMT. In vivo, HOXD9 promoted the invasive and metastasis of CRC cells via orthotopic implantation. Conclusions The ectopic expression of HOXD9 promoted the invasion metastasis in cells of the colorectal tumor by induction of EMT in vitro and vivo.
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Affiliation(s)
- Mengwei Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yizhi Xiao
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weimei Tang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiaying Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Linjie Hong
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weiyu Dai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenjing Zhang
- Department of Medical Oncology, The First people's Hospital of Yunnan Province, Medical School of Kunming University of Science and Technology, Kunming, China
| | - Ying Peng
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaosheng Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jing Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yaying Chen
- Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yang Bai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jianjiao Lin
- Department of Gastroenterology, Longgang District Peopl, Hospital, Shenzhen, China
| | - Qiong Yang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,The Second Affiliated Hospital of University of South China, Hengyang, China
| | - Yusi Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhizhao Lin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Gastroenterology, Longgang District Peopl, Hospital, Shenzhen, China
| | - Jing Xiong
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jide Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Gastroenterology, Longgang District Peopl, Hospital, Shenzhen, China
| | - Li Xiang
- Department of Gastroenterology, Longgang District Peopl, Hospital, Shenzhen, China
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Yan Y, Su M, Qin B. CircHIPK3 promotes colorectal cancer cells proliferation and metastasis via modulating of miR-1207-5p/FMNL2 signal. Biochem Biophys Res Commun 2020; 524:839-846. [PMID: 32046858 DOI: 10.1016/j.bbrc.2020.01.055] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 01/11/2020] [Indexed: 12/14/2022]
Abstract
Increasing evidences demonstrate that circular RNAs (circRNAs) are extensively implicated in various cancers including colorectal cancer (CRC). In the present study, we found that circRNA HIPK3 (circPIK3) was upregulated in CRC. We identified that circHIPK3 was closely related with unfavorable clinicopathological features in patients with CRC. Functional transwell assay and proliferation assay indicated that circHIPK3 served as an oncogene and promoted CRC cells migration, invasion and proliferation. Meanwhile, we found that formin like 2 (FMNL2) was a key downstream molecule in circHIPK3-induced metastasis and proliferation in CRC cells. We further verified that circHIPK3 was mainly located at cytoplasm through an immunofluorescence assay. An online bioinformatics screening and a GEO datasets analysis showed that microRNA 1207-5p (miR-1207-5p) was downregulated in CRC. Also, we found that miR-1207-5p shared a similar miR-1207-5p response elements (MREs-1207-5p). Meanwhile, we showed that miR-1207-5p suppressed CRC cells migration, invasion and proliferation via directly targeting of FMNL2. Even further, via a constructed luciferase assay, we indicated that circHIPK3 was another target of miR-1207-5p. Functionally, we proved that circHIPK3 enhanced FMNL2 mediated promotion of migration, invasion and proliferation by sponging of miR-1207-5p in CRC cells. In summary, the outcomes of this study illustrated that circHIPK3 promoted CRC cells migration, invasion and proliferation modulating of FMNL2 by sponging of miR-1207-5p. Our findings indicated that circHIPK3/miR-1207-5p/FMNL2 axis might be a new strategy in molecular treatment of CRC.
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Affiliation(s)
- Yan Yan
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, PR China.
| | - Meng Su
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, PR China.
| | - Baoli Qin
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, PR China.
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23
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The POU2F1/miR-4490/USP22 axis regulates cell proliferation and metastasis in gastric cancer. Cell Oncol (Dordr) 2020; 43:1017-1033. [PMID: 32857323 PMCID: PMC7716863 DOI: 10.1007/s13402-020-00553-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/18/2020] [Indexed: 12/30/2022] Open
Abstract
PURPOSE Growing evidence indicates that aberrant expression of microRNAs contributes to tumor development. However, the biological role of microRNA-4490 (miR-4490) in gastric cancer (GC) remains to be clarified. METHODS To explore the function of miR-4490 in GC, we performed colony formation, EdU incorporation, qRT-PCR, Western blotting, in situ hybridization (ISH), immunohistochemistry (IHC), flow cytometry, ChIP and dual-luciferase reporter assays. In addition, the growth, migration and invasion capacities of GC cells were evaluated. RESULTS We found that miR-4490 was significantly downregulated in primary GC samples and in GC-derived cell lines compared with normal controls, and that this expression level was negatively correlated with GC malignancy. Exogenous miR-4490 expression not only reduced cell cycle progression and proliferation, but also significantly inhibited GC cell migration, invasion and epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, we found that miR-4490 directly targets USP22, which mediates inhibition of GC cell proliferation and EMT-induced metastasis in vitro and in vivo. Moreover, we found through luciferase and ChIP assays that transcription factor POU2F1 can directly bind to POU2F1 binding sites within the miR-4490 and USP22 promoters and, by doing so, modulate their transcription. Spearman's correlation analysis revealed a positive correlation between USP22 and POU2F1 expression and negative correlations between miR-4490 and USP22 as well as miR-4490 and POU2F1 expression in primary GC tissues. CONCLUSION Based on our results we conclude that miR-4490 acts as a tumor suppressor, and that the POU2F1/miR-4490/USP22 axis plays an important role in the regulation of growth, invasion and EMT of GC cells.
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24
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Naeli P, Pourhanifeh MH, Karimzadeh MR, Shabaninejad Z, Movahedpour A, Tarrahimofrad H, Mirzaei HR, Bafrani HH, Savardashtaki A, Mirzaei H, Hamblin MR. Circular RNAs and gastrointestinal cancers: Epigenetic regulators with a prognostic and therapeutic role. Crit Rev Oncol Hematol 2020; 145:102854. [PMID: 31877535 PMCID: PMC6982584 DOI: 10.1016/j.critrevonc.2019.102854] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 11/28/2019] [Accepted: 11/29/2019] [Indexed: 02/06/2023] Open
Abstract
Both environmental and genetic factors are involved in the initiation and development of gastrointestinal cancer. Covalent closed circular RNAs (circRNAs) are produced by a mechanism called "back-splicing" from mRNAs. They are highly stable and show cell and tissue specific expression patterns. Although some functions such as "microRNA sponge" and "RNA binding protein sponge" have been reported for a small number of circRNAs, the function of thousands of other circRNAs is still unknown. Dysregulation of circRNAs has been reported in many GI cancers and are involved in metastasis and invasion. CircRNAs have been reported to be useful as prognostic markers and targets for developing new treatments. We first describe the properties and biogenesis of circRNAs. We then summarize recent reports about circRNA functions, expression status, and their potential to be used as biomarkers in GI cancers including, gastric cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, gallbladder cancer and pancreatic cancer.
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Affiliation(s)
- Parisa Naeli
- Department of Biological Sciences, Faculty of Genetics, Tarbiat Modares University, Tehran, Iran.
| | | | - Mohammad Reza Karimzadeh
- Department of Medical Genetics, School of Medicine, Bam University of Medical Sciences, Bam, Iran.
| | - Zahra Shabaninejad
- Department of Nanobiotechnology, School of Basic Sciences, TarbiatModares University, Tehran, Iran; Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Ahmad Movahedpour
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Hossein Tarrahimofrad
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.
| | - Hamid Reza Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Hassan Hassani Bafrani
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Amir Savardashtaki
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences Shiraz, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 40 Blossom Street, Boston, MA, 02114, USA.
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Yan L, You WQ, Sheng NQ, Gong JF, Hu LD, Tan GW, Chen HQ, Wang ZG. A CREB1/miR-433 reciprocal feedback loop modulates proliferation and metastasis in colorectal cancer. Aging (Albany NY) 2019; 10:3774-3793. [PMID: 30523220 PMCID: PMC6326693 DOI: 10.18632/aging.101671] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 11/15/2018] [Indexed: 12/28/2022]
Abstract
Increasing evidence has indicated the prognostic value of miR-433 across a series of malignancy types. However, the underlying mechanisms involved in cancer progression haven’t been sufficiently elucidated. In the present work, we found that miR-433 was downregulated in CRC tissues and cell lines. Ectopic expression of miR-433 obviously suppressed the proliferation, invasion and metastasis activity of CRC cells in vitro and in vivo. CREB1, CCAR1 and JNK1 were highly expressed and negatively correlated with miR-433 expression in CRC. CRC patients with higher expression of CREB1, CCAR1 or JNK1 presented a worse outcome relative to those with lower expression. CREB1 transactivated the expression of miR-433, and CREB1, CCAR1 and JNK1 simultaneously served as its targets, which in turn composed a feedback loop between CREB1 and miR-433. miR-433 blocked cell cycle progression and abolished EMT. Collectively, our study demonstrated the CREB1/miR-433 reciprocal feedback loop restrained the propagation, invasion and metastasis activities of CRC cells through abrogation of cell cycle progression and constraint of EMT.
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Affiliation(s)
- Li Yan
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wei-Qiang You
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Neng-Quan Sheng
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jian-Feng Gong
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Lan-Dian Hu
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Ge-Wen Tan
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Hong-Qi Chen
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhi-Gang Wang
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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26
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Xu C, Liu T, Liu H, Chen G, Guo Y. Panax notoginseng saponins radiosensitize colorectal cancer cells by regulating the SNHG6/miR-137 axis. RSC Adv 2019; 9:38558-38567. [PMID: 35540209 PMCID: PMC9075843 DOI: 10.1039/c9ra07622k] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/11/2019] [Indexed: 01/14/2023] Open
Abstract
Panax notoginseng saponins (PNS) have recently attracted great attention for their anti-cancer activity in colorectal cancer (CRC). The aim of this study was to explore the functional role and underlying mechanisms of PNS on CRC radiosensitivity. Cell viability was assessed by a Cell Counting kit-8 assay. Cell survival and apoptosis were determined using colony formation assay and flow cytometry, respectively. Quantitative real-time PCR was used to quantify the levels of SNHG6 and miR-137. The targeted correlation between SNHG6 and miR-137 was validated by dual-luciferase reporter and RNA immunoprecipitation assays. Our data supported that PNS weakened the viability of CRC cells. Moreover, PNS promoted the radiosensitivity of CRC cells. Mechanistically, PNS enhanced CRC cell radiosensitivity by upregulating SNHG6. SNHG6 directly targeted miR-137 and inhibited miR-137 expression. MiR-137 was involved in the regulatory effect of SNHG6 on CRC cell radiosensitivity. Furthermore, PNS increased miR-137 expression through SNHG6 in CRC cells. Our study suggested that PNS promoted radiosensitivity in CRC cells at least partly through regulating the SNHG6/miR-137 axis, providing a novel understanding of the anti-cancer mechanism of PNS in CRC.
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Affiliation(s)
- Caihui Xu
- Department of Oncology, Shangqiu First People's Hospital No. 292, South Kaixuan Road, Suiyang District Shangqiu 476100 Henan China +86-0370-3255630
| | - Teng Liu
- Xinxiang Medical University Hongqi District Xinxiang Henan China
| | - Haiyan Liu
- Department of Oncology, Shangqiu First People's Hospital No. 292, South Kaixuan Road, Suiyang District Shangqiu 476100 Henan China +86-0370-3255630
| | - Gongbin Chen
- Department of Oncology, Shangqiu First People's Hospital No. 292, South Kaixuan Road, Suiyang District Shangqiu 476100 Henan China +86-0370-3255630
| | - Yinmou Guo
- Department of Oncology, Shangqiu First People's Hospital No. 292, South Kaixuan Road, Suiyang District Shangqiu 476100 Henan China +86-0370-3255630
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27
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A strategy to identify protein-N-myristoylation-dependent phosphorylation reactions of cellular proteins by using Phos-tag SDS-PAGE. PLoS One 2019; 14:e0225510. [PMID: 31751425 PMCID: PMC6872159 DOI: 10.1371/journal.pone.0225510] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 11/06/2019] [Indexed: 11/21/2022] Open
Abstract
To establish a strategy for identifying protein-N-myristoylation-dependent phosphorylation of cellular proteins, Phos-tag SDS-PAGE was performed on wild-type (WT) and nonmyristoylated mutant (G2A-mutant) FMNL2 and FMNL3, phosphorylated N-myristoylated model proteins expressed in HEK293 cells. The difference in the banding pattern in Phos-tag SDS-PAGE between the WT and G2A-mutant FMNL2 indicated the presence of N-myristoylation-dependent phosphorylation sites in FMNL2. Phos-tag SDS-PAGE of FMNL2 mutants in which the putative phosphorylation sites listed in PhosphoSitePlus (an online database of phosphorylation sites) were changed to Ala revealed that Ser-171 and Ser-1072 are N-myristoylation-dependent phosphorylation sites in FMNL2. Similar experiments with FMNL3 demonstrated that N-myristoylation-dependent phosphorylation occurs at a single Ser residue at position 174, which is a Ser residue conserved between FMNL2 and FMNL3, corresponding to Ser-171 in FMNL2. The facts that phosphorylation of Ser-1072 in FMNL2 has been shown to play a critical role in integrin β1 internalization mediated by FMNL2 and that Ser-171 in FMNL2 and Ser-174 in FMNL3 are novel putative phosphorylation sites conserved between FMNL2 and FMNL3 indicate that the strategy used in this study is a useful tool for identifying and characterizing physiologically important phosphorylation reactions occurring on N-myristoylated proteins.
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28
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Propofol weakens hypoxia-aroused apoptosis and autophagy via elevating microRNA-137 in neurocytes. Exp Mol Pathol 2019; 112:104327. [PMID: 31678238 DOI: 10.1016/j.yexmp.2019.104327] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 10/28/2019] [Accepted: 10/30/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hypoxia was proven to cause brain cell apoptosis and autophagy. Herein, we tested the influences of propofol, a commonly used intravenous sedative hypnotic drug, on apoptosis and autophagy aroused by hypoxia stimulation in PC-12 and HT-22 cells. METHODS Followed by hypoxia and/or propofol treatment, cell viability of PC-12 and HT-22 cells, apoptosis and autophagy, along with microRNA-137 (miR-137) expression were measured, respectively. Then, miR-137 inhibitor was transfected to silence miR-137. Whether miR-137 took part in the impacts of propofol on hypoxia-exposed cells was explored. Finally, the activities of PI3K/AKT/mTOR and ERK pathways were measured. RESULTS Hypoxia stimulation aroused cell apoptosis and elevated cell autophagy in PC-12 and HT-22 cells. Propofol weakened the apoptosis and autophagy of PC-12 and HT-22 cells aroused by hypoxia. Moreover, propofol elevated the miR-137 level in PC-12 and HT-22 cells. Silencing miR-137 declined the influences of propofol on hypoxia-induced injuries. Besides, propofol promoted PI3K/AKT/mTOR and ERK pathways activation in hypoxia-exposed cells through raising miR-137. CONCLUSION Propofol weakened hypoxia-aroused apoptosis and autophagy of PC-12 and HT-22 cells might be through raising miR-137 level and thereby promoting PI3K/AKT/mTOR and ERK pathways activation.
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29
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Savardashtaki A, Shabaninejad Z, Movahedpour A, Sahebnasagh R, Mirzaei H, Hamblin MR. miRNAs derived from cancer-associated fibroblasts in colorectal cancer. Epigenomics 2019; 11:1627-1645. [PMID: 31702390 PMCID: PMC7132634 DOI: 10.2217/epi-2019-0110] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 09/24/2019] [Indexed: 02/07/2023] Open
Abstract
Currently, the incidence of colorectal cancer (CRC) is increasing across the world. The cancer stroma exerts an impact on the spread, invasion and chemoresistance of CRC. The tumor microenvironment involves a complex interaction between cancer cells and stromal cells, for example, cancer-associated fibroblasts (CAFs). CAFs can promote neoplastic angiogenesis and tumor development in CRC. Mounting evidence suggests that many miRNAs are overexpressed (miR-21, miR-329, miR-181a, miR-199a, miR-382 and miR-215) in CRC CAFs, and these miRNAs can influence the spread, invasiveness and chemoresistance in neighboring tumor cells via paracrine signaling. Herein, we summarize the pathogenic roles of miRNAs and CAFs in CRC. Moreover, for first time, we highlight the miRNAs derived from CRC-associated CAFs and their roles in CRC pathogenesis.
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Affiliation(s)
- Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences … Technologies, Shiraz University of Medical Sciences Shiraz, Iran
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Shabaninejad
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ahmad Movahedpour
- Department of Medical Biotechnology, School of Advanced Medical Sciences … Technologies, Shiraz University of Medical Sciences Shiraz, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Roxana Sahebnasagh
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 40 Blossom Street, Boston, MA 02114, USA
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HOXD9 promotes the growth, invasion and metastasis of gastric cancer cells by transcriptional activation of RUFY3. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:412. [PMID: 31547840 PMCID: PMC6755711 DOI: 10.1186/s13046-019-1399-1] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 08/28/2019] [Indexed: 12/12/2022]
Abstract
Background The transcription factor HOXD9 is one of the members of the HOX family, which plays an important role in neoplastic processes. However, the role of HOXD9 in the growth and metastasis of gastric cancer (GC) remains to be elucidated. Methods In vitro functional role of HOXD9 and RURY3 in GC cells was determined using the TMA-based immunohistochemistry, western blot, EdU incorporation, gelatin zymography, luciferase, chromatin Immunoprecipitation (ChIP) and cell invasion assays. In vivo tumor growth and metastasis were conducted in nude mice. Results HOXD9 is overexpressed in GC cells and tissues. The high expression of HOXD9 was correlated with poor survival in GC patients. Functionally, HOXD9 expression significantly promoted the proliferation, invasion and migration of GC cells. Mechanically, HOXD9 directly associated with the RUFY3 promoter to increase the transcriptional activity of RUFY3. Inhibition of RUFY3 attenuated the proliferation, migration and invasiveness of HOXD9-overexpressing GC cells in vitro and in vivo. Moreover, both HOXD9 and RUFY3 were highly expressed in cancer cells but not in normal gastric tissues, with their expressions being positively correlated. Conclusions The evidence presented here suggests that the HOXD9-RUFY3 axis promotes the development and progression of human GC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1399-1) contains supplementary material, which is available to authorized users.
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Wang J, Chen W, Lin H, Zhang J. [Role of miRNA-340 in modulating gastric cancer cell proliferation and bioinformatic analysis]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2019; 39:784-790. [PMID: 31340910 DOI: 10.12122/j.issn.1673-4254.2019.07.06] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE To investigate the mechanism of miRNA-340 for regulating the proliferation of gastric cancer (GC) cells and predict its interacting circular RNAs (circRNAs), its downstream target genes and the involved signaling pathways. METHODS The differentially expressed miRNAs in GC cell lines were analyzed and screened using miRNA microarrays. The expression level of miRNA-340 in 21 pairs of GC tissues and adjacent normal tissues was detected using real-time PCR. MTT and EdU assays were performed to examine the effect of miRNA-340 on the proliferation ability of HFE145 and BGC-823 cells. We also tested the effect of miRNA-340 inhibition on subcutaneous tumorigenesis of GC cells in a nude mouse model. The downstream target genes of miRNA-340 and the probable signal pathways were predicted online using Targetscan and DAVID database, respectively. The interacting circRNAs of miRNA-340 were analyzed using starBase platform. RESULTS Among the differentially expressed miRNAs, miRNA-340 was significantly down-regulated in GC cell lines. Real-time PCR results showed that the expression of miRNA-340 was significantly lower in GC tissues than in the adjacent tissues (P < 0.05). MTT and EdU cell proliferation assays showed that miRNA-340 overexpression inhibited the proliferation of GC cells in vitro. In the nude mouse models, the proliferation of GC cells transfected with miRNA-340 inhibitor was obviously enhanced. Bioinformatics analysis suggested that miRNA-340 had 21 target genes with 3 or more conserved sites, and these genes were involved in tumorigenesis and invasion. The top 10 circRNAs were selected as the most powerful sponge circRNAs interacting with miRNA-340. CONCLUSIONS miRNA-340 may play the role of a tumor suppressor in tumorigenesis and progression. Overexpression of miRNA-340 suppress the proliferation of GC cells, suggesting its involvement in the development of GC along with multiple circRNAs.
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Affiliation(s)
- Jian Wang
- Department of Pathology, Guangdong Women and Children's Hospital Affiliated to Guangzhou Medical University, Guangzhou 510000, China
| | - Wenjing Chen
- Department of Pathology, Guangdong Women and Children's Hospital Affiliated to Guangzhou Medical University, Guangzhou 510000, China
| | - Huijuan Lin
- Department of Pathology, Guangdong Women and Children's Hospital Affiliated to Guangzhou Medical University, Guangzhou 510000, China
| | - Jiangyu Zhang
- Department of Pathology, Guangdong Women and Children's Hospital Affiliated to Guangzhou Medical University, Guangzhou 510000, China
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Li Y, Zhang Q, Liu F, Zhang Z, Zou Y, Yang B, Luo Y, Wang L, Huang O. Inhibition of formin like 2 promotes the transition of ectopic endometrial stromal cells to epithelial cells in adenomyosis through a MET-like process. Gene 2019; 710:186-192. [PMID: 31175924 DOI: 10.1016/j.gene.2019.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 05/10/2019] [Accepted: 06/04/2019] [Indexed: 12/11/2022]
Abstract
EMT (Epithelial-Mesenchymal Transition) is one of the factors in the pathogenesis of adenomyosis. FMNL2 induced invasion of cancer cell through promoting EMT, but it is unclear the role of FMNL2 in the adenomyosis. By IHC staining, we found the expression level of FMNL2 was significantly higher in the ectopic endometrial stromal cells from women with adenomyosis when compared with normal endometrial stromal cells. Knockdown of FMNL2 inhibited the invasion and migration of ectopic endometrial stromal cells and promoted the protein levels of E-cadherin and Vimentin. Meanwhile, inhibition of FMNL2 could induce the cell membrane localization of E-cadherin. Our findings reveal that the aberrant activation of FMNL2 promotes the pathogenesis of adenomyosis through inducing the EMT process. On the contrary, inhibition of FMNL2 promotes the transition of ectopic endometrial stromal cells to epithelial cells in adenomyosis through a MET-like process.
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Affiliation(s)
- You Li
- The College of Medicine, Nanchang University, Nanchang, Jiangxi 330006, PR China; Reproductive Medicine Center, Jiangxi Maternal & Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Quan Zhang
- The College of Medicine, Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Faying Liu
- Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Maternal & Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Ziyu Zhang
- Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Maternal & Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Yang Zou
- Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Maternal & Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Bicheng Yang
- Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Maternal & Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Yong Luo
- Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Maternal & Child Health Hospital, Nanchang, Jiangxi 330006, PR China
| | - Liqun Wang
- Division of Obstetrics, Jiangxi Maternal & Child Health Hospital, Nanchang, Jiangxi 330006, PR China.
| | - Ouping Huang
- Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Maternal & Child Health Hospital, Nanchang, Jiangxi 330006, PR China.
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García-Cárdenas JM, Guerrero S, López-Cortés A, Armendáriz-Castillo I, Guevara-Ramírez P, Pérez-Villa A, Yumiceba V, Zambrano AK, Leone PE, Paz-y-Miño C. Post-transcriptional Regulation of Colorectal Cancer: A Focus on RNA-Binding Proteins. Front Mol Biosci 2019; 6:65. [PMID: 31440515 PMCID: PMC6693420 DOI: 10.3389/fmolb.2019.00065] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 07/23/2019] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a major health problem with an estimated 1. 8 million new cases worldwide. To date, most CRC studies have focused on DNA-related aberrations, leaving post-transcriptional processes under-studied. However, post-transcriptional alterations have been shown to play a significant part in the maintenance of cancer features. RNA binding proteins (RBPs) are uprising as critical regulators of every cancer hallmark, yet little is known regarding the underlying mechanisms and key downstream oncogenic targets. Currently, more than a thousand RBPs have been discovered in humans and only a few have been implicated in the carcinogenic process and even much less in CRC. Identification of cancer-related RBPs is of great interest to better understand CRC biology and potentially unveil new targets for cancer therapy and prognostic biomarkers. In this work, we reviewed all RBPs which have a role in CRC, including their control by microRNAs, xenograft studies and their clinical implications.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - César Paz-y-Miño
- Facultad de Ciencias de la Salud Eugenio Espejo, Centro de Investigación Genética y Genómica, Universidad UTE, Quito, Ecuador
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Dong L, Zhang Z, Xu J, Wang F, Ma Y, Li F, Shen C, Liu Z, Zhang J, Liu C, Yi P, Yu J. Consistency analysis of microRNA-arm expression reveals microRNA-369-5p/3p as tumor suppressors in gastric cancer. Mol Oncol 2019; 13:1605-1620. [PMID: 31162777 PMCID: PMC6599845 DOI: 10.1002/1878-0261.12527] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 04/20/2019] [Accepted: 06/03/2019] [Indexed: 01/11/2023] Open
Abstract
The 5p and 3p arms of microRNA (miRNA) are typically generated from the same precursor, and one arm influences protein output, while the other has a short half‐life. However, a few miR‐5p/3p pairs have been reported to co‐exist in cancer cells. Here, we performed a genome‐wide analysis of miRNA expression in gastric cancer (GC) cells to systematically investigate the co‐expression profile of miR‐5p/3p in gastric tumorigenesis. We discovered that only 41 miR‐5p/3p pairs out of 1749 analyzed miRNA were co‐expressed. Specifically, abnormal expression of miR‐369‐5p and miR‐369‐3p was correlated with GC progression. Importantly, both in vitro and in vivo assays revealed that miR‐369‐5p and miR‐369‐3p exhibited tumor‐suppressive roles by regulating jun proto‐oncogene and v‐akt murine thymoma viral oncogene homolog 1 function in GC cells, respectively. Moreover, we observed that miR‐369 was inactivated in GC tissues due to DNA methylation. We also showed that inhibition of miR‐369‐5p/3p attenuated the effect of azacitidine (AZA) treatment on suppressing cell growth and invasion. These results suggest that the therapeutic efficacy of AZA in GC is at least partly attributable to miR‐369 activation. Overall, our findings provide convincing evidence that both the 5p and 3p arms of miRNA co‐expressed in GC and DNA methylation‐induced miR‐369 signaling contribute to GC progression.
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Affiliation(s)
- Lei Dong
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Zhengyi Zhang
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Jiayue Xu
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Fang Wang
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Yanni Ma
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Feng Li
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Chao Shen
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Ziwen Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Junwu Zhang
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Changzheng Liu
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.,NHC Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China
| | - Ping Yi
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jia Yu
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
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Wu Y, Chen X, Zhao Y, Wang Y, Li Y, Xiang C. Genome-wide DNA methylation and hydroxymethylation analysis reveal human menstrual blood-derived stem cells inhibit hepatocellular carcinoma growth through oncogenic pathway suppression via regulating 5-hmC in enhancer elements. Stem Cell Res Ther 2019; 10:151. [PMID: 31151404 PMCID: PMC6544940 DOI: 10.1186/s13287-019-1243-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 03/15/2019] [Accepted: 04/24/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Epigenetic alteration is an important indicator of crosstalk between cancer cells and surrounding microenvironment components including mesenchymal stem cells (MSC). Human menstrual blood-derived stem cells (MenSCs) are novel source of MSCs which exert suppressive effects on cancers via multiple components of microenvironmental paracrine signaling. However, whether MenSCs play a crucial role in the epigenetic regulation of cancer cells remains unknown. METHODS Epigenetic alterations of hepatocellular carcinoma (HCC) mediated by MenSCs were examined by immunofluorescence, ELISA, and RT-PCR assays. The suppressive impact of MenSCs on HCC was investigated in vitro using CCK8, apoptosis, wound healing, and invasion assays and in vivo using a xenograft mice model. MeDIP-seq, hMeDIP-seq, and RNA-seq were used to identify the genome-wide pattern of DNA methylation and hydroxymethylation in HCC cells after MenSC therapy. RESULTS We show that HCC cells display distinct genome-wide alterations in DNA hydroxymethylation and methylation after MenSC therapy. MenSCs exert an inhibitory effect on HCC growth via regulating 5-hmC and 5-mC abundance in the regulatory regions of oncogenic pathways including PI3K/AKT and MAPK signaling, especially in enhancers and promoters. FOXO3 expression is rescued via reversal of 5-hmC and 5-mC levels in its enhancers and contributes to the activation of downstream apoptosis. Inactivation of the MAPK pathway further disrupts c-myc-mediated epithelial-mesenchymal transitions (EMT). Additionally, chemotherapy resistance-associated genes including ID4 and HMGA1 are suppressed via amending 5-hmC and 5-mC abundance at their regulatory regions. HMGA1 and BYSL might be potential targets for gene-modified MSC therapy. CONCLUSIONS Our results confirm that MSCs could regulate the epigenetic mechanism of HCC cells and provide a novel concept for a modified MSC strategy or combination therapy with chemotherapeutics based on epigenetics.
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Affiliation(s)
- Yichen Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xin Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yongjia Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yanling Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
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Yi L, Zhong X, Chen Z, Wang Q, Yan Y, Wang J, Deng X. MicroRNA-147b Promotes Proliferation and Invasion of Human Colorectal Cancer by Targeting RAS Oncogene Family (RAP2B). Pathobiology 2019; 86:173-181. [PMID: 31121595 DOI: 10.1159/000495253] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 11/05/2018] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs), a class of small-regulatory RNA molecules, were closely involved in the pathogenesis of a broad-spectrum of colorectal cancer (CRC). But role of miR-147b in CRC still remains unclear. METHODS Real-time RT-PCR or Western blotting was utilized to detect the expressions of miR-147b and RAP2B in CRC cell lines and tissues. Luciferase reporter assays were conducted to detect the associations between miR-147b and 3'UTRs of RAP2B. A series of assays were performed to evaluate the effect of miR-147b on proliferation, migration, and invasion of CRC in vitro and in vivo. RESULTS We found that the level of miR-147b was significantly lower in CRC tissues than in normal tissues (p = 0.0006). Enforced expression of miR-147b led to suppression of CRC cell proliferation in vitro and tumor growth in vivo. Specifically, miR-147b promoted proliferation by arresting CRC cells in the G1/G0 phase. Mechanically, RAP2B was identified as a direct target gene of miR-147b and RAP2B rescued the suppression of proliferation and invasion reduced by miR-147b in CRC cells. CONCLUSIONS miR-147b not only plays important roles in the regulation of cell proliferation and tumor growth in CRC, which might be a potential prognostic marker or therapeutic target for CRC.
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Affiliation(s)
- Lizhi Yi
- Department of Gastroenterology, People's Hospital of Leshan, Leshan City, China
| | - Xianfei Zhong
- Department of Gastroenterology, People's Hospital of Leshan, Leshan City, China
| | - Zhengyu Chen
- Department of Gastroenterology, People's Hospital of Leshan, Leshan City, China
| | - Qin Wang
- Department of Gastroenterology, People's Hospital of Leshan, Leshan City, China
| | - Yongrong Yan
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jianmei Wang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, China,
| | - Xuejie Deng
- Department of Gastroenterology, People's Hospital of Leshan, Leshan City, China
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Miao H, Wang N, Shi LX, Wang Z, Song WB. Overexpression of mircoRNA-137 inhibits cervical cancer cell invasion, migration and epithelial-mesenchymal transition by suppressing the TGF-β/smad pathway via binding to GREM1. Cancer Cell Int 2019; 19:147. [PMID: 31143092 PMCID: PMC6533679 DOI: 10.1186/s12935-019-0852-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 05/10/2019] [Indexed: 01/05/2023] Open
Abstract
Background Accumulating evidence has highlighted the tumor suppressive roles of microRNA (miRNAs) in cervical cancer (CC). In the present study, we aim to delineate the functional relevance of microRNA-137 (miR-137) in influencing epithelial-mesenchymal transition (EMT), and other CC cell biological activities via the TGF-β/smad pathway by binding to GREM1. Methods Microarray analysis was initially adopted to predict the differentially expressed genes and the miRNAs related to CC, followed by the measurement of the expression patterns of GREM1, EMT-related factors in the CC tissues and the adjacent tissues. Dual luciferase reporter gene assay was conducted to determine the relationship between miR-137 and GREM1. Gain-of- and loss-of-function experiments were conducted to characterize the effects of miR-137 and GREM1 on the colony formation, proliferation, apoptosis, migration, and invasion of CC cells in vitro, and the tumorigenicity of the CC cells in nude mice. The TGF-β/smad pathway was subsequently blocked with si-TGF-β to investigate its involvement. Results Reduced miR-137 expression and increased GREM1 expression were predicted in CC, which was subsequently observed in the CC tissues and cells. Notably, GREM1 was a target gene of miR-137. The overexpressed miR-137 was found to inhibit EMT, cell proliferation, colony formation, invasion, migration and tumorigenesis in nude mice. In addition, miR-137 was noted to inhibit the activation of the TGF-β/smad pathway by binding to GREM1. The silencing of TGF-β1 was shown to reverse the effects induced by downregulated expression of miR-137. Conclusions This study suggests that upregulated miR-137 suppresses the tumor progression in CC via blocking the TGF-β/smad pathway by binding to and negatively regulating GREM1.
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Affiliation(s)
- Hui Miao
- 1Department of Radiotherapy, Xuzhou Cancer Hospital, Xuzhou, 221000 People's Republic of China
| | - Nuan Wang
- 2Department of Neurology, Xuzhou No. 1 People's Hospital, Xuzhou, 221002 People's Republic of China
| | - Lin-Xin Shi
- 1Department of Radiotherapy, Xuzhou Cancer Hospital, Xuzhou, 221000 People's Republic of China
| | - Zheng Wang
- 3Clinical Medical College, Yangzhou University, Yangzhou, 225001 People's Republic of China
| | - Wen-Bo Song
- Department of Radiotherapy, Jiangdu People's Hospital of Yangzhou, No. 9, Dongfanghong Road, Yangzhou, 225200 Jiangsu People's Republic of China
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Rezapour S, Hosseinzadeh E, Marofi F, Hassanzadeh A. Epigenetic-based therapy for colorectal cancer: Prospect and involved mechanisms. J Cell Physiol 2019; 234:19366-19383. [PMID: 31020647 DOI: 10.1002/jcp.28658] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/21/2019] [Accepted: 03/25/2019] [Indexed: 12/15/2022]
Abstract
Epigenetic modifications are heritable variations in gene expression not encoded by the DNA sequence. According to reports, a large number of studies have been performed to characterize epigenetic modification during normal development and also in cancer. Epigenetics can be regarded more widely to contain all of the changes in expression of genes that make by adjusted interactions between the regulatory portions of DNA or messenger RNAs that lead to indirect variation in the DNA sequence. In the last decade, epigenetic modification importance in colorectal cancer (CRC) pathogenesis was demonstrated powerfully. Although developments in CRC therapy have been made in the last years, much work is required as it remains the second leading cause of cancer death. Nowadays, epigenetic programs and genetic change have pivotal roles in the CRC incidence as well as progression. While our knowledge about epigenetic mechanism in CRC is not comprehensive, selective histone modifications and resultant chromatin conformation together with DNA methylation most likely regulate CRC pathogenesis that involved genes expression. Undoubtedly, the advanced understanding of epigenetic-based gene expression regulation in the CRC is essential to make epigenetic drugs for CRC therapy. The major aim of this review is to deliver a summary of valuable results that represent evidence of principle for epigenetic-based therapeutic approaches employment in CRC with a focus on the advantages of epigenetic-based therapy in the inhibition of the CRC metastasis and proliferation.
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Affiliation(s)
- Saleheh Rezapour
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Hosseinzadeh
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faroogh Marofi
- Division of Hematology, Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Hassanzadeh
- Division of Hematology, Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Hernández R, Sánchez-Jiménez E, Melguizo C, Prados J, Rama AR. Downregulated microRNAs in the colorectal cancer: diagnostic and therapeutic perspectives. BMB Rep 2019. [PMID: 30158023 PMCID: PMC6283029 DOI: 10.5483/bmbrep.2018.51.11.116] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Colorectal cancer (CRC), the third most common cancer in the world, has no specific biomarkers that facilitate its diagnosis and subsequent treatment. The miRNAs, small single-stranded RNAs that repress the mRNA translation and trigger the mRNA degradation, show aberrant levels in the CRC, by which these molecules have been related with the initiation, progression, and drug-resistance of this cancer type. Numerous studies show the microRNAs influence the cellular mechanisms related to the cell cycle, differentiation, apoptosis, and migration of the cancer cells through the post-transcriptionally regulated gene expression. Specific patterns of the upregulated and down-regulated miRNA have been associated with the CRC diagnosis, prognosis, and therapeutic response. Concretely, the downregulated miRNAs represent attractive candidates, not only for the CRC diagnosis, but for the targeted therapies via the tumor-suppressing microRNA replacement. This review shows a general overview of the potential uses of the miRNAs in the CRC diagnosis, prognosis, and treatment with a special focus on the downregulated ones. [BMB Reports 2018; 51(11): 563-571].
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Affiliation(s)
- Rosa Hernández
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100; Biosanitary Institute of Granada (ibs. GRANADA), SAS-Universidad de Granada, Granada 18100; Department of Human Anatomy and Embryology, School of Medicine, University of Granada, Granada 18100, Spain
| | - Ester Sánchez-Jiménez
- Proteomics Laboratory CSIC/UAB, Institute of Biomedical Research, Barcelona 08036, Spain
| | - Consolación Melguizo
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100; Biosanitary Institute of Granada (ibs. GRANADA), SAS-Universidad de Granada, Granada 18100; Department of Human Anatomy and Embryology, School of Medicine, University of Granada, Granada 18100, Spain
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100; Biosanitary Institute of Granada (ibs. GRANADA), SAS-Universidad de Granada, Granada 18100; Department of Human Anatomy and Embryology, School of Medicine, University of Granada, Granada 18100, Spain
| | - Ana Rosa Rama
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100; Department of Health Science, University of Jaén, Jaén 23071, Spain
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40
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Wang Y, Hu L, Zheng Y, Guo L. HMGA1 in cancer: Cancer classification by location. J Cell Mol Med 2019; 23:2293-2302. [PMID: 30614613 PMCID: PMC6433663 DOI: 10.1111/jcmm.14082] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 07/19/2018] [Accepted: 11/16/2018] [Indexed: 12/23/2022] Open
Abstract
The high mobility group A1 (HMGA1) gene plays an important role in numerous malignant cancers. HMGA1 is an oncofoetal gene, and we have a certain understanding of the biological function of HMGA1 based on its activities in various neoplasms. As an architectural transcription factor, HMGA1 remodels the chromatin structure and promotes the interaction between transcriptional regulatory proteins and DNA in different cancers. Through analysis of the molecular mechanism of HMGA1 and clinical studies, emerging evidence indicates that HMGA1 promotes the occurrence and metastasis of cancer. Within a similar location or the same genetic background, the function and role of HMGA1 may have certain similarities. In this paper, to characterize HMGA1 comprehensively, research on various types of tumours is discussed to further understanding of the function and mechanism of HMGA1. The findings provide a more reliable basis for classifying HMGA1 function according to the tumour location. In this review, we summarize recent studies related to HMGA1, including its structure and oncogenic properties, its major functions in each cancer, its upstream and downstream regulation associated with the tumourigenesis and metastasis of cancer, and its potential as a biomarker for clinical diagnosis of cancer.
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Affiliation(s)
- Yuhong Wang
- The First Affiliated Hospital of Soochow University Department of Pathology, Suzhou, Jiangsu, China
| | - Lin Hu
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Yushuang Zheng
- The First Affiliated Hospital of Soochow University Department of Pathology, Suzhou, Jiangsu, China
| | - Lingchuan Guo
- The First Affiliated Hospital of Soochow University Department of Pathology, Suzhou, Jiangsu, China
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41
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Yan Y, Wang Z, Qin B. A novel long noncoding RNA, LINC00483 promotes proliferation and metastasis via modulating of FMNL2 in CRC. Biochem Biophys Res Commun 2018; 509:441-447. [PMID: 30594388 DOI: 10.1016/j.bbrc.2018.12.090] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 12/12/2018] [Indexed: 02/07/2023]
Abstract
Long non-coding RNAs (lncRNAs) are extensively involved in multiple malignancies including colorectal cancer (CRC). In the present study, we found a novel lncRNA, long intergenic non-protein coding RNA 483 (LINC00483), which was upregulated in CRC. We also illustrated that upregulated LINC00483 was correlated with poor clinicopathological features of patients with CRC. Functionally, we displayed that a knockdown of LINC00483 suppressed LOVO and HT29 cells proliferation and metastatic ability. We further illustrated that miR-204-3p was involved in LINC00483 induced proliferation and metastasis. An overexpression of miR-204-3p could attenuate the facilitative effect which LINC00483 presented. Through a luciferase assay, we showed the direct binding effect between LINC00483 and miR-204-3p. Even further, we revealed that LINC00483 and formin like 2 (FMNL2) shared a similar miR-204-3p response elements (MREs-204-3p). FMNL2 was a direct target of miR-204-3p. FMNL2 was a downstream gene of LINC00483 and participated in LINC00483 mediated proliferation and metastasis. Lastly, we proved that LINC00483 promoted proliferation and metastasis via modulating of FMNL2 in LOVO and HT29 cells. In summary, the outcomes of this study illustrated that LINC00483 promoted CRC cells proliferation and metastasis via modulating of FMNL2 by acting as a ceRNA of miR-204-3p. LINC00483/miR-204-3p/FMNL2 axial might be a novel target in molecular treatment of CRC.
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Affiliation(s)
- Yan Yan
- Department of Internal Medicine, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, PR China.
| | - Zhongmiao Wang
- Department of Internal Medicine, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, PR China.
| | - Baoli Qin
- Department of Internal Medicine, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, PR China.
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42
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Khan MI, Hamid A, Rath S, Ateeq B, Khan Q, Siddiqui IA, Adhami VM, Choudhry H, Zamzami MA, Mukhtar H. AKT Inhibition Modulates H3K4 Demethylase Levels in PTEN-Null Prostate Cancer. Mol Cancer Ther 2018; 18:356-363. [PMID: 30446585 DOI: 10.1158/1535-7163.mct-18-0141] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 09/24/2018] [Accepted: 11/12/2018] [Indexed: 12/21/2022]
Abstract
Hyperactivated AKT kinase due to loss of its negative regulator PTEN influences many aspects of cancer biology, including chromatin. AKT primarily regulates acetyl-CoA production and phosphorylates many histone-modulating enzymes, resulting in their activation or inhibition. Therefore, understanding the therapeutic impact of AKT inhibition on chromatin-related events is essential. Here, we report that AKT inhibition in prostate-specific PTEN knockout mice significantly induces di- and trimethylation of H3K4 with concomitant reduction in H3K9 acetylation. Mechanistically, we observed that AKT inhibition reduces expression of the H3K4 methylation-specific histone demethylases KDM5 family, especially KDM5B expression at transcriptional levels. Furthermore, we observed that AKT negatively regulates miR-137 levels, which transcriptionally represses KDM5B expression. Overexpression of miR-137 significantly reduced KDM5B and increased H3K4 methylation levels but failed to change AKT phosphorylation. Overall, we observed that AKT transcriptionally regulates KDM5B mainly via repression of miR-137. Our data identify a mechanism by which AKT kinase modulates the prostate cancer epigenome through regulating H3K4 methylation. Additional studies on AKT inhibition-mediated induction of H3K4 methylation will help in designing strategies to enhance the therapeutic efficacy of PI3K/AKT inhibitors.
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Affiliation(s)
- Mohammad Imran Khan
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia. .,Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Abid Hamid
- Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.,Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, India
| | - Suvasmita Rath
- Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Bushra Ateeq
- Molecular Oncology Lab, Department of Biological Sciences & Bioengineering, Indian Institute of Technology-Kanpur (IIT-K) Kanpur, India
| | - Qateeb Khan
- Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Imtiaz A Siddiqui
- Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Vaqar Mustafa Adhami
- Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Hani Choudhry
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.,Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mazin A Zamzami
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.,Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hasan Mukhtar
- Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
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Wang H, Deng G, Ai M, Xu Z, Mou T, Yu J, Liu H, Wang S, Li G. Hsp90ab1 stabilizes LRP5 to promote epithelial-mesenchymal transition via activating of AKT and Wnt/β-catenin signaling pathways in gastric cancer progression. Oncogene 2018; 38:1489-1507. [PMID: 30305727 PMCID: PMC6372478 DOI: 10.1038/s41388-018-0532-5] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 08/29/2018] [Accepted: 09/10/2018] [Indexed: 12/23/2022]
Abstract
Hsp90ab1 is upregulated in numerous solid tumors, which is thought to induce the angiogenesis and promote cancer metastasis. However, it’s actions in gastric cancer (GC) has not been exhibited. In this study, Hsp90ab1 was demonstrated to be overexpressed and correlated with the poor prognosis, proliferation and invasion of GC. Ectopic expression of Hsp90ab1 promoted the proliferation and metastasis of GC cells both in vitro in cell line models of GC and in vivo using two different xenograft mouse models, while opposite effects were observed in Hsp90ab1 silenced cells. Moreover, the underlining molecular mechanism was explored by the co-immunoprecipitation, immunofluorescence, GST pull-down and in vitro ubiquitination assay. Namely, Hsp90ab1 exerted these functions via the interaction of LRP5 and inhibited ubiquitin-mediated degradation of LRP5, an indispensable coreceptor of the Wnt/β-catenin signaling pathway. In addition, the crosstalk between Hsp90ab1 and LRP5 contributed to the upregulation of multiple mesenchymal markers, which are also targets of Wnt/β-catenin. Collectively, this study uncovers the details of the Hsp90ab1-LRP5 axis, providing novel insights into the role and mechanism of invasion and metastasis in GC.
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Affiliation(s)
- Huanan Wang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, 510515, China
| | - Guangxu Deng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, 510515, China
| | - Meiling Ai
- Department of Pathology, Southern Medical University, Nanfang Hospital, Guangzhou, 510515, China.,Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510515, China
| | - Zhijun Xu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, 510515, China
| | - Tingyu Mou
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, 510515, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, 510515, China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, 510515, China
| | - Shuang Wang
- Department of Pathology, Southern Medical University, Nanfang Hospital, Guangzhou, 510515, China. .,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, 510515, China.
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Wang Y, Lu T, Wang Q, Liu J, Jiao W. Circular RNAs: Crucial regulators in the human body (Review). Oncol Rep 2018; 40:3119-3135. [PMID: 30272328 PMCID: PMC6196641 DOI: 10.3892/or.2018.6733] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Accepted: 09/07/2018] [Indexed: 12/14/2022] Open
Abstract
Circular RNAs (circRNAs) belong to a new type of endogenous non‑coding RNAs (ncRNAs) that are derived from exons and/or introns, and are widely distributed in mammals. The majority of circRNAs have a specific expression profile in cells or tissues, as well as during different stages of development. CircRNAs were originally thought to be the products of mis‑splicing. However, with the assistance of bioinformatics tools and the rapid development of high‑throughput sequencing, an increasing body of evidence has suggested that circRNAs bind micro(mi)RNAs, and have a role as miRNA sponges, thereby regulating target mRNA splicing and transcription. Human diseases are closely associated with circRNAs, especially in cancer as their expression is typically altered during the progression of cancer; this may provide a novel type of biomarker for cancer diagnosis and prognosis. CircRNAs are becoming a key area of interest within the field of cancer research. In the present review, we summarize the known molecular mechanisms and biological origin of circRNAs, as well as their functions, especially those related to human tumors.
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Affiliation(s)
- Yuanyong Wang
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao 266003, P.R. China
| | - Tong Lu
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao 266003, P.R. China
| | - Qian Wang
- College of Nursing, Weifang Medical University, Weifang 261053, P.R. China
| | - Jia Liu
- School of Pharmacy, Qingdao University, Qingdao 266003, P.R. China
| | - Wenjie Jiao
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao 266003, P.R. China
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45
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Zeng YF, Xiao YS, Liu Y, Luo XJ, Wen LD, Liu Q, Chen M. Formin-like 3 regulates RhoC/FAK pathway and actin assembly to promote cell invasion in colorectal carcinoma. World J Gastroenterol 2018; 24:3884-3897. [PMID: 30228782 PMCID: PMC6141330 DOI: 10.3748/wjg.v24.i34.3884] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 06/16/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To clarify the underlying mechanism of formin-like 3 (FMNL3) in the promotion of colorectal carcinoma (CRC) cell invasion.
METHODS The in vitro biological function analyses of FMNL3 were performed by gain- and loss-of function approaches. Changes in the F-actin cytoskeleton were detected by the technologies of phalloidin-TRITC labeling and confocal microscopy. The signaling pathway mediated by FMNL3 was explored by western blot, gelatin zymograph assay, co-immunoprecipitation (co-IP), immunofluorescence co-localization, and glutathione S-transferase (GST) pull-down assay.
RESULTS The in vitro experimental results showed that FMNL3 significantly promoted the proliferation, invasion, and migration of CRC cells (P < 0.05 and P < 0.01). Moreover, FMNL3 regulated the remodeling of actin-based protrusions such as filopodia and lamellipodia in a RhoC-dependent manner. The western blot and gelatin zymograph assay results indicated that FMNL3 was involved in the RhoC/ focal adhesion kinase (FAK) pathway and acted as an effector of RhoC to activate the downstream signaling of p-FAK as well as p-MAPK and p-AKT. This resulted in the increased expression of matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9) and vascular endothelial growth factor (VEGF), and the subsequent promotion of CRC cell invasion. The results of TAE226, U0126 or Ly294002 treatment confirmed an essential role of FMNL3 in activation of the RhoC/FAK pathway and the subsequent promotion of CRC invasion. Co-IP, co-localization and GST pull-down assays showed the direct interaction of FMNL3 with RhoC in vivo and in vitro.
CONCLUSION FMNL3 regulates the RhoC/FAK signaling pathway and RhoC-dependent remodeling of actin-based protrusions to promote CRC invasion.
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Affiliation(s)
- Yuan-Feng Zeng
- Department of Pathology, Jiangxi Provincial People’s Hospital, Nanchang 330006, Jiangxi Province, China
| | - Yi-Sheng Xiao
- Teaching and Researching Section of Morphology, College of Basic Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, Jiangxi Province, China
| | - Yong Liu
- Department of Pathology, Jiangxi Provincial People’s Hospital, Nanchang 330006, Jiangxi Province, China
| | - Xiao-Jiang Luo
- Department of General Surgery, Jiangxi Provincial People’s Hospital, Nanchang 330006, Jiangxi Province, China
| | - Li-Dan Wen
- Clinical Medical Sciences Institute, Jiangxi Provincial People’s Hospital, Nanchang 330006, Jiangxi Province, China
| | - Qian Liu
- Department of Pathology, Jiangxi Provincial People’s Hospital, Nanchang 330006, Jiangxi Province, China
| | - Min Chen
- Department of Pathology, Jiangxi Provincial People’s Hospital, Nanchang 330006, Jiangxi Province, China
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46
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Deciphering the Far-Reaching Functions of Non-coding RNA in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2018. [DOI: 10.1007/s11888-018-0408-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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47
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Zhong B, Wang K, Xu H, Kong F. Silencing Formin-like 2 inhibits growth and metastasis of gastric cancer cells through suppressing internalization of integrins. Cancer Cell Int 2018; 18:79. [PMID: 29881327 PMCID: PMC5984784 DOI: 10.1186/s12935-018-0576-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 05/26/2018] [Indexed: 12/21/2022] Open
Abstract
Background Formin-like 2 (FMNL2) is a member of Formin family which governs cytokinesis, cellular polarity and morphogenesis. Dysregulation of FMNL2 has been discovered in cancers and is closely related to cancers. However, the role of FMNL2 in gastric cancer remains unclear. In this study, we aimed to investigate the role of FMNL2 in gastric cancer cells. Methods A FMNL2-specific shRNA was employed to decrease the endogenous expression of FMNL2. Then the degree of proliferation, apoptosis, migration and invasion of gastric cancer cells was assessed by MTT assay, flow cytometry, wound healing assay and transwell assay, respectively. The expression and distribution of FMNL2 and protein kinase C (PKC) α was detected by immunofluorescence. The internalization of integrins was detected by enzyme-linked immunosorbent assay. Results Our results showed that silencing FMNL2 suppressed proliferation, migration and invasion, and induced apoptosis of gastric cancer cells. The integrin internalization induced by PKC was declined by FMNL2 silencing. Conclusions Our study reveals that silencing FMNL2 suppresses growth and metastasis of gastric cancer cells. Modulation on integrin internalization may be implicated in the role of FMNL2 in growth and migration of gastric cancer cells. Our study indicates that FMNL2 may become a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Banghua Zhong
- Department of Gastric, Intestine and Hernia Surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110001 People's Republic of China
| | - Kewei Wang
- Department of Gastric, Intestine and Hernia Surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110001 People's Republic of China
| | - Hao Xu
- Department of Gastric, Intestine and Hernia Surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110001 People's Republic of China
| | - Fanmin Kong
- Department of Gastric, Intestine and Hernia Surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110001 People's Republic of China
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48
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Fu F, Wang T, Wu Z, Feng Y, Wang W, Zhou S, Ma X, Wang S. HMGA1 exacerbates tumor growth through regulating the cell cycle and accelerates migration/invasion via targeting miR-221/222 in cervical cancer. Cell Death Dis 2018; 9:594. [PMID: 29789601 PMCID: PMC5964147 DOI: 10.1038/s41419-018-0683-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 04/11/2018] [Accepted: 05/03/2018] [Indexed: 12/17/2022]
Abstract
High-mobility group AT-hook1 (HMGA1, formerly HMG-I/Y), an architectural transcription factor, participates in a number of tumor biological processes. However, its effect on cervical cancer remains largely indistinct. In this study, we found that HMGA1 was generally overexpressed in cervical cancer tissues and was positively correlated with lymph node metastasis and advanced clinical stage. Via exogenously increasing or decreasing the expression of HMGA1, we showed that HMGA1 affected the proliferation, colony formation, migration and invasion of cervical cancer cells in vitro. Rescue experiments suggested that miR-221/222 could partly reverse HMGA1-mediated migration and invasion processes. Mechanistically, we discovered that HMGA1 accelerated the G1/S phase transition by regulating the expression of cyclin D1 and cyclin E1, which was consistent with the results of the in vivo experiment. Furthermore, we found that HMGA1 regulated the expression of the miR-221/222 cluster at the transcriptional level and that miR-221/222 targeted the 3'UTR of tissue inhibitor of metalloproteinases 3(TIMP3). We propose a fresh perspective that HMGA1 participates in the migration and invasion process via the miR-221/222-TIMP3-MMP2/MMP9 axis in cervical cancer. In summary, our study identified a critical role played by HMGA1 in the progression of cervical cancer and the potential mechanisms by which exerts its effects, suggesting that targeting HMGA1-related pathways could be conducive to the therapies for cervical cancer.
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Affiliation(s)
- Fangfang Fu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Tian Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Zhangying Wu
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Guizhou Medical University, 55000, Guiyang, Guizhou, China
| | - Yourong Feng
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Wenwen Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Su Zhou
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Xiangyi Ma
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
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Cheng L, Geng L, Dai B, Zheng T, Fu J, Qiao L, Cai W, Wang Y, Yang J. Repression of let-7a cluster prevents adhesion of colorectal cancer cells by enforcing a mesenchymal phenotype in presence of liver inflammation. Cell Death Dis 2018; 9:489. [PMID: 29695839 PMCID: PMC5916926 DOI: 10.1038/s41419-018-0477-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 02/06/2018] [Accepted: 02/14/2018] [Indexed: 01/10/2023]
Abstract
The liver is the most common site of metastasis in patients with colorectal cancer, and colorectal cancer liver metastasis (CRLM) is associated with poor rates of survival. However, CRLM occurs infrequently in livers exhibiting signs of hepatitis or cirrhosis, suggesting a role for inflammation in attenuating CRLM. The molecular mechanisms driving this phenomenon remain unclear. The aim of this study was to confirm the mechanism by which liver inflammation inhibits CRLM. We used BALB/c animal models of inflammatory liver diseases to confirm that liver inflammation inhibits CRLM, and then elucidated the molecular mechanisms governing that process. Out data showed that liver inflammation induces IFN-γ expression, which then downregulates expression of the let-7a cluster through IRF-1 in colorectal cancer cells. Finally, we showed that modulation of let-7a expression regulated the epithelial–mesenchymal transition in colorectal cancer cell lines, and inhibited their capacity to metastasize in vivo. Cumulatively, we clarified the critical role played by the IFN-γ/IRF-1/let-7a cluster/EMT pathway in regulating the spread of circulating colorectal cancer cells to the liver, and highlighted the critical role that the hepatitis microenvironment plays in modulating that process.
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Affiliation(s)
- Lipeng Cheng
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Li Geng
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Binghua Dai
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Tao Zheng
- Department of General Surgery, People's Liberation Army Nanjing General Hospital, Nanjing, 210002, China
| | - Jun Fu
- Department of Hepatobiliary Pancreatic and Spleen Surgery, Xuzhou Central Hospital, Xuzhou, 221000, China
| | - Liang Qiao
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Wenchang Cai
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Yue Wang
- Research Center of Developmental Biology, Second Military Medical University, Shanghai, 200433, China.
| | - Jiamei Yang
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.
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50
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Cortactin recruits FMNL2 to promote actin polymerization and endosome motility in invadopodia formation. Cancer Lett 2018; 419:245-256. [DOI: 10.1016/j.canlet.2018.01.023] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 12/23/2017] [Accepted: 01/08/2018] [Indexed: 01/28/2023]
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