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1
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Cheng YC, Fan Z, Liang C, Peng CJ, Li Y, Wang LN, Luo JS, Zhang XL, Liu Y, Zhang LD. miR-133a and miR-135a Regulate All-Trans Retinoic Acid-Mediated Differentiation in Pediatric Acute Myeloid Leukemia by Inhibiting CDX2 Translation and Serve as Prognostic Biomarkers. Technol Cancer Res Treat 2024; 23:15330338241248576. [PMID: 38693824 PMCID: PMC11067685 DOI: 10.1177/15330338241248576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 03/13/2024] [Accepted: 03/26/2024] [Indexed: 05/03/2024] Open
Abstract
Background: Acute myeloid leukemia (AML) is a type of blood cancer characterized by excessive growth of immature myeloid cells. Unfortunately, the prognosis of pediatric AML remains unfavorable. It is imperative to further our understanding of the mechanisms underlying leukemogenesis and explore innovative therapeutic approaches to enhance overall disease outcomes for patients with this condition. Methods: Quantitative reverse-transcription PCR was used to quantify the expression levels of microRNA (miR)-133a and miR-135a in 68 samples from 59 pediatric patients with AML. Dual-luciferase reporter transfection assay, Cell Counting Kit-8 assay, and western blot analysis were used to investigate the functions of miR-133a and miR-135a. Results: Our study found that all-trans-retinoic acid (ATRA) promoted the expression of miR-133a and miR-135a in AML cells, inhibited caudal type homeobox 2 (CDX2) expression, and subsequently inhibited the proliferation of AML cells. Additionally, miR-133a and miR-135a were highly expressed in patients with complete remission and those with better survival. Conclusions: miR-133a and miR-135a may play an antioncogenic role in pediatric AML through the ATRA-miRNA133a/135a-CDX2 pathway. They hold promise as potentially favorable prognostic indicators and novel therapeutic targets for pediatric AML.
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MESH Headings
- Adolescent
- Child
- Child, Preschool
- Female
- Humans
- Infant
- Male
- Biomarkers, Tumor/genetics
- Cell Differentiation/genetics
- Cell Line, Tumor
- Cell Proliferation
- Gene Expression Regulation, Leukemic/drug effects
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/metabolism
- MicroRNAs/genetics
- Prognosis
- Tretinoin/pharmacology
- Tretinoin/therapeutic use
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Affiliation(s)
- Yu-Cai Cheng
- Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Zhong Fan
- Department of Pediatrics, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Cong Liang
- Department of Pediatrics, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chun-Jin Peng
- Department of Pediatrics, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yu Li
- Department of Pediatrics, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Li-Na Wang
- Department of Pediatrics, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jie-Si Luo
- Department of Pediatrics, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiao-Li Zhang
- Department of Pediatrics, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yong Liu
- Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Li-Dan Zhang
- Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
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2
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Tariq L, Arafah A, Sehar N, Ali A, Khan A, Rasool I, Rashid SM, Ahmad SB, Beigh S, Dar TUH, Rehman MU. Novel insights on perils and promises of miRNA in understanding colon cancer metastasis and progression. Med Oncol 2023; 40:282. [PMID: 37639075 DOI: 10.1007/s12032-023-02099-2] [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: 05/23/2023] [Accepted: 06/19/2023] [Indexed: 08/29/2023]
Abstract
Colorectal cancer (CRC) is the third highest frequent malignancy and ultimate critical source of cancer-associated mortality around the world. Regardless of latest advances in molecular and surgical targeted medicines that have increased remedial effects in CRC patients, the 5-year mortality rate for CRC patients remains dismally low. Evidence suggests that microRNAs (miRNAs) execute an essential part in the development and spread of CRC. The miRNAs are a type of short non-coding RNA that exhibited to control the appearance of tumor suppressor genes and oncogenes. miRNA expression profiling is already being utilized in clinical practice as analytical and prognostic biomarkers to evaluate cancer patients' tumor genesis, advancement, and counteraction to drugs. By modulating their target genes, dysregulated miRNAs are linked to malignant characteristics (e.g., improved proliferative and invasive capabilities, cell cycle aberration, evasion of apoptosis, and promotion of angiogenesis). This review presents an updated summary of circulatory miRNAs, tumor-suppressive and oncogenic miRNAs, and the potential reasons for dysregulated miRNAs in CRC. Further we will explore the critical role of miRNAs in CRC drug resistance.
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Affiliation(s)
- Lubna Tariq
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Azher Arafah
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Nouroz Sehar
- Centre for Translational and Clinical Research, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Aarif Ali
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, 45142, Jazan, Saudi Arabia
| | - Iyman Rasool
- Department of Pathology, Government Medical College (GMC-Srinagar), Karanagar, Srinagar, Jammu and Kashmir, 190006, India
| | - Shahzada Mudasir Rashid
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Sheikh Bilal Ahmad
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Saba Beigh
- Department of Public Health, Faculty of Applied Medical Science, Al Baha University, 65431, Al Baha, Saudi Arabia
| | - Tanveer Ul Hassan Dar
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Muneeb U Rehman
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia.
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3
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Elrebehy MA, Abdelghany TM, Elshafey MM, Gomaa MH, Doghish AS. miR-509-5p promotes colorectal cancer cell ferroptosis by targeting SLC7A11. Pathol Res Pract 2023; 247:154557. [PMID: 37229918 DOI: 10.1016/j.prp.2023.154557] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/05/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND/AIM Colorectal cancer (CRC), is characterized by aberrant microRNA (miRNA) expression during their development and progression. Recently, miR-509-5p's role as a regulator of several malignancies has been highlighted. Its function in CRC, however, is exposed. This research aimed to determine the relative abundance of miR-509-5p and its biological function in colorectal cancer. METHODS The expression of miR-509-5p in CRC cell lines and tissues, as well as neighboring normal tissues, was evaluated using real-time quantitative polymerase chain reaction (RT-PCR). 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyl-2 H-tetrazolium bromide (MTT) was used to assess cell viability. The association between miR-509-5p and its predicted target in CRC cells was analyzed using bioinformatics tools. The levels of Solute carrier family seven number 11 (SLC7A11) were assessed using enzyme-linked immunosorbent assay (ELISA), while malondialdehyde (MDA) and iron content levels were determined colorimetrically. RESULTS Compared to adjacent normal tissue and normal colorectal cell, there was a significant reduction in miR-509-5p expression in both CRC tissues and cells. miR-509-5p upregulation inhibited Caco-2 cell viability. SLC7A11 was predicted to be the cellular target of miR-509-5p. Interestingly, miR-509-5p's overexpression suppressed both mRNA and protein levels of SLC7A11, whereas its downregulation boosted SLC7A11 gene expression. Finally, overexpressing miR-509-5p resulted in increased MDA and iron levels. CONCLUSION Our results demonstrate that miR-509-5p has CRC tumor suppressor functions through controlling the expression of SLC7A11 and promotion of ferroptosis providing a new therapeutic target for the treatment of CRC.
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Affiliation(s)
- Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
| | - Tamer M Abdelghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11231, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mostafa M Elshafey
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Maher H Gomaa
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
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4
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Wani TA, Zargar S. Molecular Spectroscopy Evidence of 1,3,5-Tris(4-carboxyphenyl)benzene Binding to DNA: Anticancer Potential along with the Comparative Binding Profile of Intercalation via Modeling Studies. Cells 2023; 12:cells12081120. [PMID: 37190029 DOI: 10.3390/cells12081120] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 05/17/2023] Open
Abstract
One of medicinal chemistry's top priorities is the discovery of new molecules with anticancer potential. Compounds that interact with DNA are an intriguing family of chemotherapeutic medications used to treat cancer. Studies in this area have uncovered a plethora of potential anticancer medicines, such as groove binding, alkylating, and intercalator compounds. The anticancer activity of DNA intercalators (molecules that intercalate between DNA base pairs) has drawn special interest. The current study investigated the promising anticancer drug 1,3,5-Tris(4-carboxyphenyl)benzene (H3BTB) against breast and cervical cancer cell lines. In addition, 1,3,5-Tris(4-carboxyphenyl)benzene binds to DNA by groove binding. The binding of H3BTB to DNA was found to be significant which unwinds the DNA helix. Considerable electrostatic and non-electrostatic contributions were present in the binding's free energy. The cytotoxic potential of H3BTB is effectively demonstrated by the computational study outcomes, which include molecular docking and molecular dynamics (MD) simulations. The minor groove binding for the H3BTB-DNA complex is supported by molecular docking research. This study will promote empirical investigation into the synthesis of metallic and non-metallic H3BTB derivatives and their potential use as bioactive molecules for the treatment of cancer.
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Affiliation(s)
- Tanveer A Wani
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Seema Zargar
- Department of Biochemistry, College of Science, King Saud University, P.O. Box 22452, Riyadh 11451, Saudi Arabia
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5
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Duca RB, Massillo C, Farré PL, Graña KD, Moro J, Gardner K, Lacunza E, De Siervi A. Hsa-miR-133a-3p, miR-1-3p, GOLPH3 and JUP combination results in a good biomarker to distinguish between prostate cancer and non-prostate cancer patients. Front Oncol 2022; 12:997457. [PMID: 36387263 PMCID: PMC9641240 DOI: 10.3389/fonc.2022.997457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 10/04/2022] [Indexed: 11/02/2023] Open
Abstract
The incidence and mortality of Prostate Cancer (PCa) worldwide correlate with age and bad dietary habits. Previously, we investigated the mRNA/miRNA role on PCa development and progression using high fat diet (HFD) fed mice. Here our main goal was to investigate the effect of HFD on the expression of PCa-related miRNAs and their relevance in PCa patients. We identified 6 up- and 18 down-regulated miRNAs in TRAMP-C1 mice prostate tumors under HFD conditions using miRNA microarrays. Three down-regulated miRNAs: mmu-miR-133a-3p, -1a-3p and -29c-3p were validated in TRAMP-C1 mice prostate tumor by stem-loop RT-qPCR. Hsa-miR-133a-3p/1-3p expression levels were significantly decreased in PCa compared to normal tissues while hsa-miR-133a-3p was found to be further decreased in metastatic prostate cancer tumors compared to non-metastatic PCa. We examined the promoter region of hsa-miR-133a-3p/1-3p genes and compared methylation at these loci with mature miRNA expression. We found that hsa-miR-1-2/miR-133a-1 cluster promoter hypermethylation decreased hsa-miR-133a-3p/1-3p expression in PCa. GOLPH3 and JUP, two hsa-miR-133a-3p and miR-1-3p predicted target genes, were up-regulated in PCa. ROC analysis showed that the combination of hsa-miR-133a-3p, miR-1-3p, GOLPH3 and JUP is a promising panel biomarker to distinguish between PCa and normal adjacent tissue (NAT). These results link PCa aggressiveness to the attenuation of hsa-miR-133a-3p and miR-1-3p expression by promoter hypermethylation. Hsa-miR-133a-3p and miR-1-3p down-regulation may enhance PCa aggressiveness in part by targeting GOLPH3 and JUP.
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Affiliation(s)
- Rocío Belén Duca
- Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Cintia Massillo
- Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Paula Lucía Farré
- Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Karen Daniela Graña
- Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Juana Moro
- Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Kevin Gardner
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, United States
| | - Ezequiel Lacunza
- Centro de Investigaciones Inmunológicas Básicas y Aplicadas (CINIBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Buenos Aires, Argentina
| | - Adriana De Siervi
- Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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6
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Li T, Liu H, Dong C, Lyu J. Application of miRNA Biomarkers in Predicting Overall Survival Outcomes for Lung Adenocarcinoma. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5249576. [PMID: 36147635 PMCID: PMC9485713 DOI: 10.1155/2022/5249576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/25/2022] [Accepted: 09/01/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND With the development of research, the importance of microRNAs (miRNAs) in the occurrence, metastasis, and prognosis of lung adenocarcinoma (LUAD) has attracted extensive attention. This study is aimed at predicting overall survival (OS) results through bioinformatics to identify novel miRNA biomarkers and hub genes. MATERIALS AND METHODS The data of LUAD-related miRNA and mRNA samples was downloaded from The Cancer Genome Atlas (TCGA) database. Upon screening and pretreatment of initial data, TCGA data were analyzed using R platform and a series of analytical tools to identify biomarkers with high specificity and sensitivity. RESULTS 7 miRNAs and 13 hub genes that had strong relation to the overall surviving status were identified in patients with LUAD. The expression of seven miRNAs (hsa-miR-19a-3p, hsa-miR-126-5p, hsa-miR-556-3p, hsa-miR-671-5p, hsa-miR-937-3p, hsa-miR-4664-3p, and hsa-miR-4746-5p) could apparently improve the OS rate of patient with LUAD. The 13 hub genes, namely, CCT6A, CDK5R1, CEP55, DNAJB4, EGLN3, HDGF, HOXC8, LIMD1, MKI67, PCP4L1, PPIL1, SCAI, and STK32A, showed a correlation with the OS status. CONCLUSION 7 miRNAs were identified as novel biomarkers for the prognosis of patients with LUAD. This study offered a deeper comprehension of LUAD treatment and prognosis from the molecular level and helped enhance the understanding of the pathogenesis and potential molecular events of LUAD.
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Affiliation(s)
- Tingting Li
- Department of Pharmacy, Xi'an Chest Hospital, Xi'an, Shaanxi, China
| | - Huanqing Liu
- Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Chunsheng Dong
- School of Computer Science, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Jun Lyu
- Northwestern Polytechnical University, Xi'an, Shaanxi, China
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
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Elrebehy MA, Al-Saeed S, Gamal S, El-Sayed A, Ahmed AA, Waheed O, Ismail A, El-Mahdy HA, Sallam AAM, Doghish AS. miRNAs as cornerstones in colorectal cancer pathogenesis and resistance to therapy: A spotlight on signaling pathways interplay - A review. Int J Biol Macromol 2022; 214:583-600. [PMID: 35768045 DOI: 10.1016/j.ijbiomac.2022.06.134] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/18/2022] [Accepted: 06/19/2022] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the world's third most prevalent cancer and the main cause of cancer-related mortality. A lot of work has been put into improving CRC patients' clinical care, including the development of more effective methods and wide biomarkers variety for prognostic, and diagnostic purposes. MicroRNAs (miRNAs) regulate a variety of cellular processes and play a significant role in the CRC progression and spread via controlling their target gene expression by translation inhibition or mRNA degradation. Consequently, dysregulation and disruption in their function, miRNAs are linked to CRC malignant pathogenesis by controlling several cellular processes involved in the CRC. These cellular processes include increased proliferative and invasive capacity, cell cycle aberration, evasion of apoptosis, enhanced EMT, promotion of angiogenesis and metastasis, and decreased sensitivity to major treatments. The miRNAs control cellular processes in CRC via regulation of pathways such as Wnt/β-catenin signaling, PTEN/AKT/mTOR axis, KRAS, TGFb signaling, VEGFR, EGFR, and P53. Hence, the goal of this review was to review miRNA biogenesis and present an updated summary of oncogenic and tumor suppressor (TS) miRNAs and their potential implication in CRC pathogenesis and responses to chemotherapy and radiotherapy. We also summarise the biological importance and clinical applications of miRNAs in the CRC.
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Affiliation(s)
- Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Sarah Al-Saeed
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Sara Gamal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Asmaa El-Sayed
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Alshaimaa A Ahmed
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Omnia Waheed
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry Department, Faculty of Pharmacy, Ain-Shams University, Abassia, Cairo 11566, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
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8
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Zhang Z, Wang Y, Zeng L, Yu K, Wang Y, Luo Y, Liu F, Yang B, Zou Y, Wang L, Huang O. miR-218-5p in endometrial microenvironment prevents the migration of ectopic endometrial stromal cells by inhibiting LASP1. Reprod Biol Endocrinol 2022; 20:64. [PMID: 35379225 PMCID: PMC8978357 DOI: 10.1186/s12958-022-00928-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 03/13/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Our previous two-dimensional electrophoresis experiment showed that the expression of LASP1 in patients with endometriosis was significantly higher than that of control endometrium. However, the molecular mechanism by which LASP1 is regulated in endometriosis/adenomyosis is unknown. METHODS Herein, qPCR was performed to analyze the expression levels of LASP1 and miR-218-5p between endometriosis (Ems) cells and control cells. Fluorescence in situ hybridization was carried out to measure the expression level of miR-218-5p in ectopic endometrium versus normal endometrium. After miR-218-5p mimic or inhibitor were transfected, the transwell experiment was carried out to see the effect of miR-218-5p on the migration of endometrial stromal cells (ESCs). EdU was used to measure cell proliferation rate. Dual-luciferase reporter assay was used to verify the binding of hsa-miR-218-5p to the 3'UTR of LASP1. Western blot and immunofluorescence analysis were carried out to identify the protein expression pattern of LASP1 and EMT markers in endometrial tissue. RESULTS The miR-218-5p is mainly secreted from blood vessels and expressed in the muscle layer around the endometrium, which inhibits the expression level of LASP1 by binding the 3'UTR region of LASP1 in normal ESCs. Overexpression of miR-218-5p impedes the epithelial-to-mesenchymal transition (EMT) and prevents the migration of ESCs and the expression of Vimentin in Ems. CONCLUSIONS Our findings revealed that miR-218-5p in endometrial microenvironment prevents the migration of ectopic endometrial stromal cells by inhibiting LASP1.
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Affiliation(s)
- Ziyu Zhang
- Department of Pathology, Jiangxi Maternal & Child Health Hospital, Nanchang, Jiangxi, 330006, PR China
- Central Laboratory, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Yaoqing Wang
- Department of Reproductive Health, Jiangxi Maternal & Child Health Hospital, Nanchang, Jiangxi, 330006, PR China
| | - Liqin Zeng
- The College of Medicine, Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Kaihui Yu
- The College of Medicine, Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Yuanqin Wang
- The College of Medicine, Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Yong Luo
- Central Laboratory, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Faying Liu
- Central Laboratory, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Bicheng Yang
- Jiangxi Provincial Key Laboratory of Birth Defect for Prevention and Control, Jiangxi Maternal & Child Health Hospital, Nanchang, Jiangxi, 330006, PR China
| | - Yang Zou
- Central Laboratory, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.
| | - Liqun Wang
- Department of Reproductive Health, Jiangxi Maternal & Child Health Hospital, Nanchang, Jiangxi, 330006, PR China.
| | - Ouping Huang
- Central Laboratory, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.
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9
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Golla U, Sesham K, Dallavalasa S, Manda NK, Unnam S, Sanapala AK, Nalla S, Kondam S, Kumar R. ABHD11-AS1: An Emerging Long Non-Coding RNA (lncRNA) with Clinical Significance in Human Malignancies. Noncoding RNA 2022; 8:ncrna8020021. [PMID: 35314614 PMCID: PMC8938790 DOI: 10.3390/ncrna8020021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/27/2022] [Accepted: 02/28/2022] [Indexed: 12/24/2022] Open
Abstract
The aberrant expression of lncRNAs has been linked to the development and progression of different cancers. One such lncRNA is ABHD11 antisense RNA 1 (ABHD11-AS1), which has recently gained attention for its significant role in human malignancies. ABHD11-AS1 is highly expressed in gastric, lung, breast, colorectal, thyroid, pancreas, ovary, endometrium, cervix, and bladder cancers. Several reports highlighted the clinical significance of ABHD11-AS1 in prognosis, diagnosis, prediction of cancer progression stage, and treatment response. Significantly, the levels of ABHD11-AS1 in gastric juice had been exhibited as a clinical biomarker for the assessment of gastric cancer, while its serum levels have prognostic potential in thyroid cancers. The ABHD11-AS1 has been reported to exert oncogenic effects by sponging different microRNAs (miRNAs), altering signaling pathways such as PI3K/Akt, epigenetic mechanisms, and N6-methyladenosine (m6A) RNA modification. In contrast, the mouse homolog of AHD11-AS1 (Abhd11os) overexpression had exhibited neuroprotective effects against mutant huntingtin-induced toxicity. Considering the emerging research reports, the authors attempted in this first review on ABHD11-AS1 to summarize and highlight its oncogenic potential and clinical significance in different human cancers. Lastly, we underlined the necessity for future mechanistic studies to unravel the role of ABHD11-AS1 in tumor development, prognosis, progression, and targeted therapeutic approaches.
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Affiliation(s)
- Upendarrao Golla
- Department of Medicine, Division of Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
- Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
- Correspondence:
| | - Kishore Sesham
- Department of Anatomy, All India Institute of Medical Sciences (AIIMS), Mangalagiri 522503, India;
| | - Siva Dallavalasa
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, Mysuru 570015, India;
| | - Naresh Kumar Manda
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India;
| | - Sambamoorthy Unnam
- Faculty of Pharmacy, Sree Dattha Institute of Pharmacy, Ibrahimpatnam 501510, India; (S.U.); (A.K.S.)
| | - Arun Kumar Sanapala
- Faculty of Pharmacy, Sree Dattha Institute of Pharmacy, Ibrahimpatnam 501510, India; (S.U.); (A.K.S.)
| | - Sharada Nalla
- Faculty of Pharmacy, University College of Pharmaceutical Sciences, Palamuru University, Mahabubnagar 509001, India; (S.N.); (S.K.)
| | - Susmitha Kondam
- Faculty of Pharmacy, University College of Pharmaceutical Sciences, Palamuru University, Mahabubnagar 509001, India; (S.N.); (S.K.)
| | - Rajesh Kumar
- Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India;
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10
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Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives. Cancers (Basel) 2022; 14:cancers14010245. [PMID: 35008407 PMCID: PMC8750728 DOI: 10.3390/cancers14010245] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/30/2021] [Accepted: 01/01/2022] [Indexed: 12/20/2022] Open
Abstract
Simple Summary In recent years, aspartate has been increasingly acknowledged as a critical player in the metabolism of cancer cells which use this metabolite for nucleotide and protein synthesis and for redox homeostasis. Most intracellular aspartate derives from the mitochondrial catabolism of glutamine. To date at least four mitochondrial transporters have been involved in this metabolic pathway. Their involvement appears to be cancer type-specific and dependent on glutamine availability. Targeting these mitochondrial transporters may represent a new attractive strategy to fight cancer. The aim of this review is to dissect the role of each of these transporters in relation to the type of cancer and the availability of nutrients in the tumoral microenvironment. Abstract Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspartate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the aspartate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention.
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11
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Liao Q, Ren Y, Yang Y, Zhu X, Zhi Y, Zhang Y, Chen Y, Ding Y, Zhao L. CCT8 recovers WTp53-suppressed cell cycle evolution and EMT to promote colorectal cancer progression. Oncogenesis 2021; 10:84. [PMID: 34862361 PMCID: PMC8642402 DOI: 10.1038/s41389-021-00374-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 11/11/2021] [Accepted: 11/22/2021] [Indexed: 11/09/2022] Open
Abstract
LIM and SH3 protein 1 (LASP1) is a metastasis-related protein reported to enhance tumor progression in colorectal cancer (CRC). However, the underlying mechanism is still elusive. The chaperonin protein containing TCP1 (CCT) is a cellular molecular chaperone complex, which is necessary for the correct folding of many proteins. It contains eight subunits, CCT1-8. CCT8 is overexpressed in many cancers, however, studies on CCT8 are limited and its role on CRC development and progression remains elusive. In this study, we confirmed that CCT8 and LASP1 can interact with each other and express positively in CRC cells. CCT8 could recover the ability of LASP1 to promote the invasion of CRC; CCT8 could significantly promote the proliferation, invasion, and metastasis of colorectal cells in vivo and in vitro. Mechanically, CCT8 inhibited the entry of WTp53 into the nucleus, and there was a negative correlation between the expression of CCT8 and the nuclear expression of WTp53 in clinical colorectal tissues. CCT8 promoted the cell cycle evolution and EMT progression of CRC by inhibiting the entry of WTp53 into the nucleus. Clinically, CCT8 was highly expressed in CRC. More importantly, the overall survival of CRC patients with high expression of CCT8 was worse than that of patients with low expression of CCT8. These findings indicate that as LASP1-modulated proteins, CCT8 plays a key role in promoting the progression of colorectal cancer, which provides a potential target for clinical intervention in patients with colorectal cancer.
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Affiliation(s)
- Qing Liao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China.,Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong province, People's Republic of China
| | - Yun Ren
- Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong province, People's Republic of China.,Department of Pathology, Affiliated Tumor Hospital of Guangzhou, Medical University, Guangzhou, China
| | - Yuyi Yang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China.,The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China
| | - Xiaohui Zhu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China.,Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong province, People's Republic of China
| | - Yunfei Zhi
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China.,Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong province, People's Republic of China
| | - Yujie Zhang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China.,Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong province, People's Republic of China
| | - Yi Chen
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China.,Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong province, People's Republic of China
| | - Yanqing Ding
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China. .,Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong province, People's Republic of China.
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China. .,Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong province, People's Republic of China.
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12
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Alterations of non-coding RNA expression and mitochondrial biogenesis in colorectal cancer tissue: Possible crosstalk with macrophage polarization. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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13
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Xie L, Huang H, Zheng Z, Yang Q, Wang S, Chen Y, Yu J, Cui C. MYO1B enhances colorectal cancer metastasis by promoting the F-actin rearrangement and focal adhesion assembly via RhoA/ROCK/FAK signaling. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1543. [PMID: 34790749 PMCID: PMC8576704 DOI: 10.21037/atm-21-4702] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022]
Abstract
Background Colorectal cancer (CRC) has a high worldwide incidence and mortality. Tumor metastasis is one of the primary reasons for the poor prognosis of CRC patients. However, the mechanism underlying CRC metastasis is still unclear. Myosin 1B (MYO1B) is important for cell migration and motility and is part of the myosin superfamily that contains various myosins. Studies of prostate, cervical, and head and neck cancer have revealed preliminary findings concerning the effect of MYO1B on tumor metastasis. However, the role of MYO1B in CRC metastasis, as well as its underlying mechanism, remains unknown. Methods Quantitative real-time PCR and immunohistochemical staining methods were used to analyze the expression of MYO1B in human CRC and normal mucosa tissues. Lentivirus vector-based MYO1B oligonucleotides and short hairpin RNA (shRNA) were used to examine the functional relevance of MYO1B in CRC cells. Co-immunoprecipitation, western blotting, and immunofluorescence assays were used to investigate the underlying mechanism of MYO1B-mediated cell migration. Results The expression of MYO1B was increased in most CRC tissues and was positively associated with a greater risk of tumor metastasis and poor prognosis for patients. MYO1B was significantly associated with the migration and invasion properties of CRC cells in vitro and in vivo. MYO1B promoted F-actin rearrangement through the ROCK2/LIMK/Cofilin axis by enhancing the activation of RhoA. MYO1B also promoted the assembly of focal adhesions by targeting RhoA. Conclusions MYO1B plays a vital role in CRC metastasis by promoting the activation of RhoA. MYO1B may not only be a valid biomarker for predicting the risk of metastasis and poor prognosis in CRC but may also be a potential therapeutic target for patients with a high risk of tumor metastasis.
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Affiliation(s)
- Lang Xie
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Hongyun Huang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zheng Zheng
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Qian Yang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Shubo Wang
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Yaoxu Chen
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Jinlong Yu
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Chunhui Cui
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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14
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Li R, Hao Y, Wang Q, Meng Y, Wu K, Liu C, Xu L, Liu Z, Zhao L. ECHS1, an interacting protein of LASP1, induces sphingolipid-metabolism imbalance to promote colorectal cancer progression by regulating ceramide glycosylation. Cell Death Dis 2021; 12:911. [PMID: 34615856 PMCID: PMC8494735 DOI: 10.1038/s41419-021-04213-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 09/14/2021] [Accepted: 09/23/2021] [Indexed: 01/30/2023]
Abstract
Sphingolipid metabolic dysregulation has increasingly been considered to be a drug-resistance mechanism for a variety of tumors. In this study, through an LC-MS assay, LIM and SH3 protein 1 (LASP1) was identified as a sphingolipid-metabolism-involved protein, and short-chain enoyl-CoA hydratase (ECHS1) was identified as a new LASP1-interacting protein through a protein assay in colorectal cancer (CRC). Gain- and loss-of-function analyses demonstrated the stimulatory role played by ECHS1 in CRC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistic studies of the underlying tumor-supportive oncometabolism indicate that ECHS1 enables altering ceramide (Cer) metabolism that increases glycosphingolipid synthesis (HexCer) by promoting UDP-glucose ceramide glycosyltransferase (UGCG). Further analysis showed that ECHS1 promotes CRC progression and drug resistance by releasing reactive oxygen species (ROS) and interfering mitochondrial membrane potential via the PI3K/Akt/mTOR-dependent signaling pathway. Meanwhile, the phenomenon of promoting the survival and drug resistance of CRC cells caused by ECHS1 could be reversed by Eliglustat, a specific inhibitor of UCCG, in vitro and in vivo. IHC assay showed that ECHS1 was overexpressed in CRC tissues, which was related to the differentiation and poor prognosis of CRC patients. This study provides new insight into the mechanism by which phospholipids promote drug resistance in CRC and identifies potential targets for future therapies.
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Affiliation(s)
- Rui Li
- Department of Pathology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
- Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yanyu Hao
- Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Qiuhan Wang
- Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yuan Meng
- Department of Pathology, The Second People's Hospital of Longgang District, Shenzhen, China
| | - Kunhe Wu
- Department of Pathology, Guangdong Women and Children Hospital, Guangzhou, Guangdong, 511442, China
| | - Chaoqun Liu
- Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Lijun Xu
- Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Ziguang Liu
- Department of Pathology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Liang Zhao
- Department of Pathology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China.
- Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
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15
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Caporali S, Calabrese C, Minieri M, Pieri M, Tarantino U, Marini M, D’Ottavio S, Angeletti S, Mauriello A, Cortese C, Bernardini S, Terrinoni A. The miR-133a, TPM4 and TAp63γ Role in Myocyte Differentiation Microfilament Remodelling and Colon Cancer Progression. Int J Mol Sci 2021; 22:ijms22189818. [PMID: 34575979 PMCID: PMC8472330 DOI: 10.3390/ijms22189818] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/01/2021] [Accepted: 09/05/2021] [Indexed: 01/16/2023] Open
Abstract
MicroRNAs (miRNAs) play an essential role in the regulation of a number of physiological functions. miR-133a and other muscular miRs (myomiRs) play a key role in muscle cell growth and in some type of cancers. Here, we show that miR133a is upregulated in individuals that undertake physical exercise. We used a skeletal muscle differentiation model to dissect miR-133a's role and to identify new targets, identifying Tropomyosin-4 (TPM4). This protein is expressed during muscle differentiation, but importantly it is an essential component of microfilament cytoskeleton and stress fibres formation. The microfilament scaffold remodelling is an essential step in cell transformation and tumour progression. Using the muscle system, we obtained valuable information about the microfilament proteins, and the knowledge on these molecular players can be transferred to the cytoskeleton rearrangement observed in cancer cells. Further investigations showed a role of TPM4 in cancer physiology, specifically, we found that miR-133a downregulation leads to TPM4 upregulation in colon carcinoma (CRC), and this correlates with a lower patient survival. At molecular level, we demonstrated in myocyte differentiation that TPM4 is positively regulated by the TA isoform of the p63 transcription factor. In muscles, miR-133a generates a myogenic stimulus, reducing the differentiation by downregulating TPM4. In this system, miR-133a counteracts the differentiative TAp63 activity. Interestingly, in CRC cell lines and in patient biopsies, miR-133a is able to regulate TPM4 activity, while TAp63 is not active. The downregulation of the miR leads to TPM4 overexpression, this modifies the architecture of the cell cytoskeleton contributing to increase the invasiveness of the tumour and associating with a poor prognosis. These results add data to the interesting question about the link between physical activity, muscle physiology and protection against colorectal cancer. The two phenomena have in common the cytoskeleton remodelling, due to the TPM4 activity, that is involved in stress fibres formation.
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Affiliation(s)
- Sabrina Caporali
- Department of Industrial Engineering, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Cosimo Calabrese
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
| | - Marilena Minieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
| | - Massimo Pieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
| | - Umberto Tarantino
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (U.T.); (S.D.)
| | - Mario Marini
- Centre of Space Biomedicine and Department of Systems Medicine of the University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Stefano D’Ottavio
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (U.T.); (S.D.)
| | - Silvia Angeletti
- Unit of Clinical Laboratory Science, University Campus Bio-Medico of Rome, Via Alvaro del Portillo, 00128 Rome, Italy;
| | - Alessandro Mauriello
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
| | - Claudio Cortese
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
| | - Sergio Bernardini
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
| | - Alessandro Terrinoni
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
- Correspondence:
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16
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Li M, Zhuang J, Kang D, Chen Y, Song W. Identification of circRNA circ-CSPP1 as a potent driver of colorectal cancer by directly targeting the miR-431/LASP1 axis. Open Life Sci 2021; 16:523-536. [PMID: 34124372 PMCID: PMC8165258 DOI: 10.1515/biol-2021-0053] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/27/2020] [Accepted: 12/29/2020] [Indexed: 12/28/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy worldwide. Circular RNAs (circRNAs) have been implicated in cancer biology. The purpose of the current work is to investigate the precise parts of circRNA centrosome and spindle pole-associated protein 1 (circ-CSPP1) in the progression of CRC. Our data showed that circ-CSPP1 was significantly overexpressed in CRC tissues and cells. The knockdown of circ-CSPP1 attenuated cell proliferation, migration, invasion and promoted apoptosis in vitro and weakened tumor growth in vivo. circ-CSPP1 directly targeted miR-431, and circ-CSPP1 knockdown modulated CRC cell progression in vitro via upregulating miR-431. Moreover, LIM and SH3 protein 1 (LASP1) was a functional target of miR-431 in modulating CRC cell malignant progression. Furthermore, circ-CSPP1 in CRC cells functioned as a posttranscriptional regulator on LASP1 expression by targeting miR-431. Our present study identified the oncogenic role of circ-CSPP1 in CRC partially by the modulation of the miR-431/LASP1 axis, providing evidence for circ-CSPP1 as a promising biomarker for CRC management.
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Affiliation(s)
- Minghao Li
- Department of Gastrointestinal Anorectal Surgery, Tianjin Third Central Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China
| | - Jianbin Zhuang
- Department of Gastrointestinal Anorectal Surgery, Tianjin Third Central Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China
| | - Di Kang
- Department of Gastrointestinal Anorectal Surgery, Tianjin Third Central Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China
| | - Yuzhuo Chen
- Department of Gastrointestinal Anorectal Surgery, Tianjin Third Central Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China
| | - Weiliang Song
- Department of Gastrointestinal Anorectal Surgery, Tianjin Third Central Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China
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Meng X, Zhong J, Zeng C, Yung KKL, Zhang X, Wu X, Qu S. MiR-30a-5p Regulates GLT-1 Function via a PKCα-Mediated Ubiquitin Degradation Pathway in a Mouse Model of Parkinson's Disease. ACS Chem Neurosci 2021; 12:1578-1592. [PMID: 33882234 DOI: 10.1021/acschemneuro.1c00076] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Glutamate excitotoxicity is caused by dysfunctional glutamate transporters and plays an important role in the pathogenesis of Parkinson's disease (PD); however, the mechanisms that underlie the regulation of glutamate transporters in PD are still not fully elucidated. MicroRNAs(miRNA), which are abundant in astrocytes and neurons, have been reported to play key roles in regulating the translation of glutamate-transporter mRNA. In this study, we hypothesized that the miR-30a-5p contributes to the pathogenesis of PD by regulating the ubiquitin-mediated degradation of glutamate transporter 1 (GLT-1). We demonstrated that short-hairpin RNA-mediated knockdown of miR-30a-5p ameliorated motor deficits and pathological changes like astrogliosis and reactive microgliosis in a mouse model of PD (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice). Western blotting and immunofluorescent labeling revealed that miR-30a-5p suppressed the expression and function of GLT-1 in MPTP-treated mice and specifically in astrocytes treated with 1-methyl-4-phenylpyridinium (MPP+) (cell model of PD). Both in vitro and in vivo, we found that miR-30a-5p knockdown promoted glutamate uptake and increased GLT-1 expression by hindering GLT-1 ubiquitination and subsequent degradation in a PKCα-dependent manner. Therefore, we conclude that miR-30a-5p represents a potential therapeutic target for the treatment of PD.
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Affiliation(s)
- Xingjun Meng
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
- Central Laboratory and Department of Neurology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde Foshan), Foshan, Guangdong 528300, China
- Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, Guangdong 510515, China
- Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Jianping Zhong
- Department of Neurology, Shunde Hospital of Southern Medical University (The First People’s Hospital of Shunde Foshan), Foshan, Guangdong 528300, China
| | - Chong Zeng
- Central Laboratory and Department of Neurology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde Foshan), Foshan, Guangdong 528300, China
| | - Ken Kin Lam Yung
- Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong, China
| | - Xiuping Zhang
- Teaching Center of Experimental Medicine, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Xiaojuan Wu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Shaogang Qu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
- Central Laboratory and Department of Neurology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde Foshan), Foshan, Guangdong 528300, China
- Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, Guangdong 510515, China
- Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, Guangdong 510515, China
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18
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Du G, Yu X, Chen Y, Cai W. MiR-1-3p Suppresses Colorectal Cancer Cell Proliferation and Metastasis by Inhibiting YWHAZ-Mediated Epithelial-Mesenchymal Transition. Front Oncol 2021; 11:634596. [PMID: 33718221 PMCID: PMC7952857 DOI: 10.3389/fonc.2021.634596] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 01/21/2021] [Indexed: 12/24/2022] Open
Abstract
Background Colorectal cancer (CRC) is regarded as one of the most common malignancies in the world. MiR-1-3p was reported to be a tumor suppressor in CRC. However, the mechanisms have not been fully elucidated. Methods To identify CRC-associated miRNA, microarray data set GSE30454 was downloaded from the Gene Expression Omnibus database (GEO), and miR-1-3p was screened out as a candidate. The expression of miR-1-3p was detected using quantitative real-time polymerase chain reaction (qRT-PCR) in CRC cell lines and tissues. CCK-8 assay and transwell invasion assay were performed to determine CRC cell line proliferation and invasion, respectively. The levels of YWHAZ and EMT-associated proteins were detected using western blotting. Results Bioinformatic analysis showed that miR-1-3p was downregulated in CRC tissues, which is verified by our experimental validation. The overexpression of miR-1-3p significantly suppressed CRC cell proliferation and invasion. Further studies showed that YWHAZ was a direct target of miR-1-3p and mediated epithelial-mesenchymal transition (EMT) modulated by miR-1-3p. Conclusion Our results demonstrated that miR-1-3p suppresses colorectal cancer cell proliferation and metastasis through regulating YWHAZ-mediated EMT, which may support a novel therapeutic strategy for CRC patients.
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Affiliation(s)
- Guanghong Du
- Department of Geriatrics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xuelian Yu
- Department of Geriatrics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yun Chen
- Department of Geriatrics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Wangting Cai
- Organ transplant center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
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19
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Zhu T, Chen Y, Liu Z, Leng Y, Tian Y. Expression profiles and prognostic significance of AFTPH in different tumors. FEBS Open Bio 2020; 10:2666-2677. [PMID: 33090728 PMCID: PMC7714068 DOI: 10.1002/2211-5463.13003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/24/2020] [Accepted: 09/23/2020] [Indexed: 01/16/2023] Open
Abstract
Aftiphilin (AFTPH) plays an important role in regulating intracellular trafficking, exocytosis, and the pro‐inflammatory response. However, the potential prognostic role of AFTPH in cancers remains unclear. Here, we examined the expression profiles and prognostic significance of AFTPH in breast invasive carcinoma (BRCA), diffuse large B‐cell lymphoma (DLBC), lung squamous cell carcinoma (LUSC), and pancreatic adenocarcinoma (PADD) using the GEPIA and UALCAN databases. AFTPH expression was observed to be higher in cancer tissues than in normal tissues, but expression did not differ significantly between tumor stages for the four cancer types. AFTPH expression in cancer cell lines was investigated using the CCLE database; AFTPH was found to be highly expressed in four cancer cell lines. The relationship between AFTPH expression and patient prognosis was analyzed using GEPIA, LinkedOmics, and Kaplan–Meier plotter databases. Low expression of AFTPH was associated with improved prognosis for BRCA, DLBC, LUSC, and PAAD. Genetic alterations of AFTPH in cancers were explored using the cBioPortal website, revealing that gene copy number gains and amplification are common in BRCA, DLBC, LUSC, and PAAD. Related genes and markers associated with AFTPH were discovered using the LinkedOmics database. Furthermore, transfection of cells with AFTPH siRNA demonstrated that AFTPH exerts positive effects on cell proliferation in BRCA, LUSC, and PAAD cells. In conclusion, AFTPH may be a potential therapeutic target and prognostic biomarker for BRCA, DLBC, LUSC, and/or PAAD.
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Affiliation(s)
- Tengjiao Zhu
- Third Hospital of Peking University, Beijing, China
| | | | - Zhongjun Liu
- Third Hospital of Peking University, Beijing, China
| | - Yuxin Leng
- Third Hospital of Peking University, Beijing, China
| | - Yun Tian
- Third Hospital of Peking University, Beijing, China
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20
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MicroRNAs as regulators of ERK/MAPK pathway: A comprehensive review. Biomed Pharmacother 2020; 132:110853. [PMID: 33068932 DOI: 10.1016/j.biopha.2020.110853] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/19/2020] [Accepted: 10/04/2020] [Indexed: 02/07/2023] Open
Abstract
The ERK/MAPK cascade is one the four distinctive MAPK cascades which transmit extracellular signals to intracellular targets. This cascade has an important role in the regulation of several fundamental processes such as proliferation, differentiation and cell response to diverse extrinsic stresses. Moreover, several studies have shown participation of this cascade in the pathogenesis of cancer. Recent investigations have unraveled interaction between microRNAs (miRNAs) and ERK/MAPK cascade. These transcripts reside in both upstream and downstream of this cascade, regulating or being regulated by ERK/MAPK proteins. In the current review, we summarize the role of miRNAs in the regulation of ERK/MAPK and their contribution in the pathogenesis of human disorders with particular focus on cancers.
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21
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Wu L, Lin W, Liao Q, Wang H, Lin C, Tang L, Lian W, Chen Z, Li K, Xu L, Zhou R, Ding Y, Zhao L. Calcium Channel Blocker Nifedipine Suppresses Colorectal Cancer Progression and Immune Escape by Preventing NFAT2 Nuclear Translocation. Cell Rep 2020; 33:108327. [PMID: 33113363 DOI: 10.1016/j.celrep.2020.108327] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 08/17/2020] [Accepted: 10/07/2020] [Indexed: 12/15/2022] Open
Abstract
Abnormal activation of calcium channels has been shown to play crucial roles in tumor occurrence and development. However, the role of inhibitors targeting calcium channels in tumor progression and immune regulation remains unclear, and their clinical applications are still limited. We show that nifedipine (NIFE), a calcium channel blocker, inhibits calcium influx to impair nuclear factor of activated T cell 2 (NFAT2) dephosphorylation, activation, and nuclear translocation, thus preventing transcriptional activation of downstream signaling molecules to suppress colorectal cancer (CRC) proliferation and metastasis. In addition, NIFE decreases expression of programmed death-ligand 1 (PD-L1) on CRC cells and programmed death-1 (PD-1) on CD8+ T cells and reactivates tumor immune monitoring, which may stimulate or enhance PD-1-based antitumor immunotherapy. Our findings provide direct evidence that NIFE is a promising clinical therapy to treat patients with advanced CRC by affecting the tumor itself and tumor immunity. NIFE may be a promising therapeutic option to enhance effectiveness of immune checkpoint blockade therapy in CRC.
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Affiliation(s)
- Ling Wu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China
| | - Weihao Lin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China
| | - Qing Liao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China
| | - Hui Wang
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou, China
| | - Chuang Lin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lihua Tang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China
| | - Weidong Lian
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China
| | - Zetao Chen
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China
| | - Kaitao Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China
| | - Lijun Xu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China
| | - Rui Zhou
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China
| | - Yanqing Ding
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China.
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, China.
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22
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Targeting protein tyrosine kinase 6 in cancer. Biochim Biophys Acta Rev Cancer 2020; 1874:188432. [PMID: 32956764 DOI: 10.1016/j.bbcan.2020.188432] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 07/27/2020] [Accepted: 09/04/2020] [Indexed: 11/21/2022]
Abstract
Protein tyrosine kinase 6 (PTK6) is the most well studied member of the PTK6 family of intracellular tyrosine kinases. While it is expressed at highest levels in differentiated cells in the regenerating epithelial linings of the gastrointestinal tract and skin, induction and activation of PTK6 is detected in several cancers, including breast and prostate cancer where high PTK6 expression correlates with worse outcome. PTK6 expression is regulated by hypoxia and cell stress, and its kinase activity is induced by several growth factor receptors implicated in cancer including members of the ERBB family, IGFR1 and MET. Activation of PTK6 at the plasma membrane has been associated with the epithelial mesenchymal transition and tumor metastasis. Several lines of evidence indicate that PTK6 has context dependent functions that depend on cell type, intracellular localization and kinase activation. Systemic disruption of PTK6 has been shown to reduce tumorigenesis in mouse models of breast and prostate cancer, and more recently small molecule inhibitors of PTK6 have exhibited efficacy in inhibiting tumor growth in animal models. Here we review data that suggest targeting PTK6 may have beneficial therapeutic outcomes in some cancers.
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23
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Ahadi A. The significance of microRNA deregulation in colorectal cancer development and the clinical uses as a diagnostic and prognostic biomarker and therapeutic agent. Noncoding RNA Res 2020; 5:125-134. [PMID: 32954092 PMCID: PMC7476809 DOI: 10.1016/j.ncrna.2020.08.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/19/2020] [Accepted: 08/19/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most widely recognized and deadly malignancies worldwide. Although death rates have declined over the previous decade, mainly because of enhanced screening or potential treatment alternatives, CRC remains the third leading cause of cancer-related mortality globally, with an estimated incidence of over 1 million new cases and approximately 600 000 deaths estimated yearly. Therefore, many scientific efforts are put into the development of new diagnostic biomarkers for CRC. MicroRNAs (miRNAs), one of the epigenetics categories, have demonstrated significant roles in carcinogenesis and progression through regulating epithelial-mesenchymal transition (EMT), oncogenic signaling pathways, and metastasis. Dysregulation of miRNAs expression has been reported in many cancers, including CRC. The expression profile of miRNAs is reproducibly altered in CRC, and their expression patterns are associated with diagnosis, prognosis, and therapeutic outcomes in CRC. Recently, many studies were conducted on the dysregulation of miRNAs as a diagnostic and prognostic biomarker in CRC. Among them, some miRNAs, which include miR-21, miR-34 family, miR-155, miR-224, and miR-378, have been more studied in CRC with more prominent roles in diagnosis, prognosis, and therapy. In the present review, we summarized the latest information regarding the dysregulated miRNAs in CRC and the advantages of using miRNAs as a biomarker for CRC diagnosis, treatment, and their function in different signaling pathways involved in CRC progression. Moreover, we described the translation of miRNA research to potential therapeutic applications in the management of CRC in clinical settings.
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Affiliation(s)
- Alireza Ahadi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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24
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Pidíkova P, Reis R, Herichova I. miRNA Clusters with Down-Regulated Expression in Human Colorectal Cancer and Their Regulation. Int J Mol Sci 2020; 21:E4633. [PMID: 32610706 PMCID: PMC7369991 DOI: 10.3390/ijms21134633] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/24/2020] [Accepted: 06/27/2020] [Indexed: 02/07/2023] Open
Abstract
Regulation of microRNA (miRNA) expression has been extensively studied with respect to colorectal cancer (CRC), since CRC is one of the leading causes of cancer mortality worldwide. Transcriptional control of miRNAs creating clusters can be, to some extent, estimated from cluster position on a chromosome. Levels of miRNAs are also controlled by miRNAs "sponging" by long non-coding RNAs (ncRNAs). Both types of miRNA regulation strongly influence their function. We focused on clusters of miRNAs found to be down-regulated in CRC, containing miR-1, let-7, miR-15, miR-16, miR-99, miR-100, miR-125, miR-133, miR-143, miR-145, miR-192, miR-194, miR-195, miR-206, miR-215, miR-302, miR-367 and miR-497 and analysed their genome position, regulation and functions. Only evidence provided with the use of CRC in vivo and/or in vitro models was taken into consideration. Comprehensive research revealed that down-regulated miRNA clusters in CRC are mostly located in a gene intron and, in a majority of cases, miRNA clusters possess cluster-specific transcriptional regulation. For all selected clusters, regulation mediated by long ncRNA was experimentally demonstrated in CRC, at least in one cluster member. Oncostatic functions were predominantly linked with the reviewed miRNAs, and their high expression was usually associated with better survival. These findings implicate the potential of down-regulated clusters in CRC to become promising multi-targets for therapeutic manipulation.
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Affiliation(s)
- Paulína Pidíkova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia;
| | - Richard Reis
- First Surgery Department, University Hospital, Comenius University in Bratislava, 811 07 Bratislava, Slovakia;
| | - Iveta Herichova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia;
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25
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Shang T, Zhou X, Chen W. LINC01123 Promotes Progression of Colorectal Cancer via miR-625-5p/LASP1 Axis. Cancer Biother Radiopharm 2020; 36:765-773. [PMID: 32423238 DOI: 10.1089/cbr.2020.3740] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background: Evidence from previous investigations points to a rising trend in the incidence of colorectal cancer (CRC) worldwide. The mortality resulting from this cancer is high. Unlike nonsmall cell lung cancer for which LINC01123 has been investigated, there are few reports on how this long noncoding RNA (lncRNA) regulates CRC. Materials and Methods: The authors evaluated the expression of LINC01123 in CRC tissues by quantitative real-time polymerase chain reaction. Its impact on cancer cell behavior was analyzed with cell counting kit-8 (CCK-8), colony formation, and Transwell invasion assays. To establish the mechanisms of LINC01123 in CRC they carried out RIP and luciferase reporter assays. Results: The results show that LINC01123 expression is abnormally elevated in CRC tissues and cell lines. High LINC01123 expression closely correlates with poor prognosis, advanced TNM stage, and lymph-node metastasis. The authors also show that knockdown of LINC01123 inhibits proliferation and invasion in CRC cells. In mechanism, it is revealed that LINC01123 may function as competitive endogenous RNA (ceRNA) against miR-625-5p to promote LIM and SH3 protein 1 (LASP1) expression. Conclusions: The data indicate that high LINC01123 exerts its oncogenic roles by regulating the miR-625-5p/LASP1 axis in CRC progression.
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Affiliation(s)
- Tao Shang
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Colorectal Surgery, Zhejiang Provincial Hospital of Chinese Traditional Medicine, Hangzhou, China
| | - Xiukou Zhou
- Department of Colorectal Surgery, Zhejiang Provincial Hospital of Chinese Traditional Medicine, Hangzhou, China
| | - Wenbin Chen
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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26
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Chen H, Luo J, Guo J. Development and validation of a five-immune gene prognostic risk model in colon cancer. BMC Cancer 2020; 20:395. [PMID: 32375704 PMCID: PMC7204296 DOI: 10.1186/s12885-020-06799-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 03/27/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Colon cancer is a common and highly malignant cancer. Its morbidity is rapidly increasing, and its prognosis is poor. Currently, immunotherapy is a rapidly developing therapeutic modality of colon cancer. This study aimed to construct a prognostic risk model based on immune genes for the early diagnosis and accurate prognostic prediction of colon cancer. METHODS Transcriptomic data and clinical data were downloaded from The Cancer Genome Atlas database. Immune genes were obtained from the ImmPort database. Differentially expressed (DE) immune genes between 473 colon cancer and 41 adjacent normal tissues were identified. The entire cohort was randomly divided into the training and testing cohort. The training cohort was used to construct the prognostic model. The testing and entire cohorts were used to validate the model. The clinical utility of the model and its correlation with immune cell infiltration were analyzed. RESULTS A total of 333 DE immune genes (176 up-regulated and 157 down-regulated) were detected. We developed and validated a five-immune gene model of colon cancer, including LBP, TFR2, UCN, UTS2, and MC1R. This model was approved to be an independent prognostic variable, which was more accurate than age and the pathological stage for predicting overall survival at five years. Besides, as the risk score increased, the content of CD8+ T cells in colon cancer was decreased. CONCLUSIONS We developed and validated a five-immune gene model of colon cancer, including LBP, TFR2, UCN, UTS2, and MC1R. This model could be used as an instrumental variable in the prognosis prediction of colon cancer.
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Affiliation(s)
- Haitao Chen
- Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071 China
| | - Jun Luo
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 China
- Wuhan University Center for Pathology and Molecular Diagnostics, Wuhan, 430071 China
| | - Jianchun Guo
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 China
- Wuhan University Center for Pathology and Molecular Diagnostics, Wuhan, 430071 China
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27
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Humphries BA, Wang Z, Yang C. MicroRNA Regulation of the Small Rho GTPase Regulators-Complexities and Opportunities in Targeting Cancer Metastasis. Cancers (Basel) 2020; 12:E1092. [PMID: 32353968 PMCID: PMC7281527 DOI: 10.3390/cancers12051092] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 04/24/2020] [Accepted: 04/25/2020] [Indexed: 02/07/2023] Open
Abstract
The small Rho GTPases regulate important cellular processes that affect cancer metastasis, such as cell survival and proliferation, actin dynamics, adhesion, migration, invasion and transcriptional activation. The Rho GTPases function as molecular switches cycling between an active GTP-bound and inactive guanosine diphosphate (GDP)-bound conformation. It is known that Rho GTPase activities are mainly regulated by guanine nucleotide exchange factors (RhoGEFs), GTPase-activating proteins (RhoGAPs), GDP dissociation inhibitors (RhoGDIs) and guanine nucleotide exchange modifiers (GEMs). These Rho GTPase regulators are often dysregulated in cancer; however, the underlying mechanisms are not well understood. MicroRNAs (miRNAs), a large family of small non-coding RNAs that negatively regulate protein-coding gene expression, have been shown to play important roles in cancer metastasis. Recent studies showed that miRNAs are capable of directly targeting RhoGAPs, RhoGEFs, and RhoGDIs, and regulate the activities of Rho GTPases. This not only provides new evidence for the critical role of miRNA dysregulation in cancer metastasis, it also reveals novel mechanisms for Rho GTPase regulation. This review summarizes recent exciting findings showing that miRNAs play important roles in regulating Rho GTPase regulators (RhoGEFs, RhoGAPs, RhoGDIs), thus affecting Rho GTPase activities and cancer metastasis. The potential opportunities and challenges for targeting miRNAs and Rho GTPase regulators in treating cancer metastasis are also discussed. A comprehensive list of the currently validated miRNA-targeting of small Rho GTPase regulators is presented as a reference resource.
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Affiliation(s)
- Brock A. Humphries
- Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA
| | - Zhishan Wang
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, 1095 V A Drive, Lexington, KY 40536, USA;
| | - Chengfeng Yang
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, 1095 V A Drive, Lexington, KY 40536, USA;
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28
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Li S, Hou X, Wu C, Han L, Li Q, Wang J, Luo S. MiR-645 promotes invasiveness, metastasis and tumor growth in colorectal cancer by targeting EFNA5. Biomed Pharmacother 2020; 125:109889. [PMID: 32036212 DOI: 10.1016/j.biopha.2020.109889] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/26/2019] [Accepted: 01/13/2020] [Indexed: 01/04/2023] Open
Abstract
MicroRNA-645 (miR-645) has been implicated in numerous types of human cancers including colon cancer. However, the effects and mechanisms of action of miR-645 dysregulation on the growth and malignancy of colorectal cancer (CRC) remain unclear. In this study, we demonstrated that miR-645 knockdown significantly diminished CRC cell migration and invasion and repressed epithelial-mesenchymal transition (EMT). Conversely, miR-645 overexpression enhanced CRC cell migration, invasion, and EMT. In vivo assays confirmed that miR-645 knockdown substantially reduced CRC growth and metastasis. Regarding the mechanism, ephrin-A5 (EFNA5) was identified as a direct target gene of miR-645. MiR-645 specifically targeted the 3'-untranslated region of EFNA5 mRNA and hindered its expression. EFNA5 knockdown attenuated the effects of miR-645 knockdown on CRC cell migration and invasion. Additionally, we noted a statistically significant inverse correlation between EFNA5 mRNA and miR-645 levels in tumors from 28 patients with CRC. Hence, miR-645 acts as an oncogenic miRNA that may increase CRC cell migration, invasiveness, and metastasis by targeting EFNA5.
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Affiliation(s)
- Shuai Li
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Xinfang Hou
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Chen Wu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Lili Han
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Qian Li
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Jufeng Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Suxia Luo
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China.
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29
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Li W, Xu Y, Wang X, Cao G, Bu W, Wang X, Fang Z, Xu Y, Dong M, Tao Q. circCCT3 Modulates Vascular Endothelial Growth Factor A and Wnt Signaling to Enhance Colorectal Cancer Metastasis Through Sponging miR-613. DNA Cell Biol 2019; 39:118-125. [PMID: 31859543 DOI: 10.1089/dna.2019.5139] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Colorectal cancer (CRC) has been suggested to be one of the leading cancer types all over the world. Till now, the molecular mechanism by which circCCT3 regulates CRC remains to be clarified. To detect mRNA and protein levels of various genes, Reverse Transcription-quantitative PCR and western blot were used in our study. Luciferase reporter assay was utilized to probe direct interaction between genes. We used transwell assay to assess the invasion ability of CRC cells. For apoptosis detection, immunofluorescence of CRC cells by Annexin V staining was performed. We carried out bioinformatic analysis to show higher expression of circCCT3 in human clinical CRC tumors. Low level of circCCT3 was closely associated with higher disease-free survival of CRC patients. Moreover, we found that circCCT3 was linked to advanced stage of CRC. miR-613 is the target of circCCT3 and responsible for circCCT3-modulated invasion and apoptosis of CRC cells. In addition, we identified WNT3 and vascular endothelial growth factor A (VEGFA) as downstream effectors of miR-613 in CRC cells. WNT3 and VEGFA overexpression resulted in partial rescue of miR-613-mediated phenotypes of CRC cells. In conclusion, we propose that circCCT3 contributes to CRC metastasis via miR-613/WNT3 or miR-613/VEGFA, promoting the development of therapeutical approaches for treating CRC.
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Affiliation(s)
- Weiliang Li
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Youqi Xu
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaodong Wang
- Department of Interventional Therapy, Peking University Cancer Hospital, Beijing, China
| | - Guang Cao
- Department of Interventional Therapy, Peking University Cancer Hospital, Beijing, China
| | - Wenjing Bu
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xia Wang
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhen Fang
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yao Xu
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Mengjia Dong
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Qianyi Tao
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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30
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Soleimani A, Rahmani F, Saeedi N, Ghaffarian R, Khazaei M, Ferns GA, Avan A, Hassanian SM. The potential role of regulatory microRNAs of RAS/MAPK signaling pathway in the pathogenesis of colorectal cancer. J Cell Biochem 2019; 120:19245-19253. [PMID: 31512778 DOI: 10.1002/jcb.29268] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 06/11/2019] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Dysregulation of RAS/MAPK signaling axis is frequently found in CRC patients. The RAS/MAPK axis regulates cancer cell proliferation, apoptosis, inflammation, migration, and metastasis. Oncogenic or tumor-suppressor microRNAs (miRNAs) for RAS/MAPK signaling play a key role in the pathogenesis of CRC and are considered as novel potential biomarkers for diagnosis and prognosis of human malignancies. This review summarizes the current knowledge of mechanisms of action of RAS/MAPK miRNAs in the development and progression of CRC for a better understanding and hence a better management of this disease.
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Affiliation(s)
- Atena Soleimani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzad Rahmani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nikoo Saeedi
- Student Research Committee, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Rana Ghaffarian
- Student Research Committee, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Brighton, Sussex, UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Yang L, Zhang L, Lu L, Wang Y. Long Noncoding RNA SNHG16 Sponges miR-182-5p And miR-128-3p To Promote Retinoblastoma Cell Migration And Invasion By Targeting LASP1. Onco Targets Ther 2019; 12:8653-8662. [PMID: 31806989 PMCID: PMC6855619 DOI: 10.2147/ott.s212352] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 08/21/2019] [Indexed: 12/13/2022] Open
Abstract
Background Long noncoding RNAs (lncRNAs) are dysregulated and play an important role in the tumorigenesis and progression of cancers. However, the potential roles of SNHG16 in retinoblastoma progression still remain largely unclear. Materials and methods The expression levels of SNHG16, miR-182-5p, miR-128-3p and LASP1 in retinoblastoma tissues and cell lines were detected using qRT-PCR. The migratory and invasive abilities of retinoblastoma cells were assessed using Transwell assay. The regulatory relationships among SNHG16, miR-182-5p, miR-128-3p and LASP1 were analyzed through bioinformatics prediction and validated by luciferase reporter assay and Western blot. Results Here, we demonstrated that SNHG16 was frequently up-regulated in retinoblastoma tissue samples and cell lines. Clinicopathological features showed that high levels of SNHG16 were significantly associated with retinoblastoma metastasis and predicted poor overall survival. Functional studies demonstrated that knockdown of SNHG16 suppressed retinoblastoma cell migration and invasion. Mechanistic investigation revealed that SNHG16 exerted its oncogenic activity through increasing LASP1 expression and sponging miR-182-5p and miR-128-3p. Conclusion Taken together, our findings suggest SNHG16 as a novel biomarker and therapeutic target against retinoblastoma.
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Affiliation(s)
- Lidong Yang
- Department of Ocular Fundus Disease, Cangzhou Eye Hospital, Cangzhou Central Hospital, Cangzhou 061001, People's Republic of China
| | - Liyou Zhang
- Department of Ocular Fundus Disease, Cangzhou Eye Hospital, Cangzhou Central Hospital, Cangzhou 061001, People's Republic of China
| | - Lu Lu
- Department of Ocular Fundus Disease, Cangzhou Eye Hospital, Cangzhou Central Hospital, Cangzhou 061001, People's Republic of China
| | - Yan Wang
- Department of Ocular Fundus Disease, Cangzhou Eye Hospital, Cangzhou Central Hospital, Cangzhou 061001, People's Republic of China
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Zheng K, Yang Q, Xie L, Qiu Z, Huang Y, Lin Y, Tu L, Cui C. Overexpression of MAGT1 is associated with aggressiveness and poor prognosis of colorectal cancer. Oncol Lett 2019; 18:3857-3862. [PMID: 31516596 PMCID: PMC6732944 DOI: 10.3892/ol.2019.10710] [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: 11/01/2018] [Accepted: 06/19/2019] [Indexed: 12/18/2022] Open
Abstract
Tumor metastasis and anticancer drug resistance are the major causes of mortality in patients with colorectal cancer (CRC). Due to the limitations of conventional biomarkers, it is urgent to identify novel and valid biomarkers to predict the progression and prognosis of CRC. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect MAGT1 expression in CRC clinical samples or cell lines. Bioinformatics analysis was used to investigate the association between MAGT1 alteration and clinicopathological features of patients with CRC. The present study revealed that the transcription levels of magnesium transporter 1 (MAGT1) were significantly increased in CRC tissues compared with matched adjacent normal tissues. Overexpression of MAGT1 was associated with advanced tumor stage, N and M classification. In addition, for patients who underwent chemotherapy, patients in the MAGT1-low expression group exhibited a longer overall survival (OS) time than patients in the high-expression group. Patients with CRC treated with chemotherapy had a longer OS time than those treated without chemotherapy in the MAGT1-low expression group but not in the MAGT1-high expression group. Furthermore, MAGT1 was a valid but not an independent prognostic factor for CRC. Therefore, the present study highlighted that MAGT1 may serve as a valid biomarker for predicting the development, progression and poor prognosis of CRC.
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Affiliation(s)
- Kehong Zheng
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
- Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Qianqiong Yang
- Department of Pathology, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Lang Xie
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Zhenghua Qiu
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Yongsheng Huang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Yongwei Lin
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Lingjing Tu
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Chunhui Cui
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
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Wang B, Qi X, Liu J, Zhou R, Lin C, Shangguan J, Zhang Z, Zhao L, Li G. MYH9 Promotes Growth and Metastasis via Activation of MAPK/AKT Signaling in Colorectal Cancer. J Cancer 2019; 10:874-884. [PMID: 30854093 PMCID: PMC6400792 DOI: 10.7150/jca.27635] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 01/04/2019] [Indexed: 12/11/2022] Open
Abstract
The contractile protein MYH9 (non-muscle myosin IIA) is an actin-binding protein that plays a fundamental role in cell adhesion, migration, and division. However, its distinct role in colorectal cancer (CRC) still remains unidentified. In this study, we detected significant MYH9 overexpression in CRC samples compared with paired normal tissues using western blotting and tissue microarray immunohistochemistry (IHC). Moreover, analysis of patient clinical information demonstrated that MYH9 overexpression was strongly correlated with lymph node metastasis and poor overall survival. Endogenous overexpression of MYH9 enhanced the ability of cell proliferation and migration in vitro, and accelerated CRC growth in mouse models. Silencing of MYH9 revealed repressive effects on CRC cells in vitro and in vivo. Furthermore, primary biomechanics that involved MAPK/AKT signaling mediated epithelial-mesenchymal transition (EMT) was uncovered underlying MYH9 dependent cell behaviors. Collectively, our data showed that MYH9 significantly promoted tumorigenesis by regulating MAPK/AKT signaling, and was remarkably correlated with poor prognosis in CRC. MYH9 may thus be a novel biomarker and drug target in the diagnosis and treatment of CRC.
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Affiliation(s)
- Bin Wang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaolong Qi
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Jian Liu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P.R. China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, P.R. China
| | - Rui Zhou
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, P.R. China
| | - Chuang Lin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P.R. China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, P.R. China
| | - Junjie Shangguan
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Zhuoli Zhang
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, 60611, USA
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P.R. China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, P.R. China
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
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Yuan YH, Wang HY, Lai Y, Zhong W, Liang WL, Yan FD, Yu Z, Chen JK, Lin Y. Epigenetic inactivation of HOXD10 is associated with human colon cancer via inhibiting the RHOC/AKT/MAPK signaling pathway. Cell Commun Signal 2019; 17:9. [PMID: 30683109 PMCID: PMC6347846 DOI: 10.1186/s12964-018-0316-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 12/28/2018] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND To examine the influence of HOXD10 on the metabolism and growth of colon carcinoma cells by suppressing the RHOC/AKT/MAPK pathway. METHODS Thirty-seven paired colon cancer and its adjacent samples from The Cancer Genome Atlas (TCGA) were analyzed. Chip Analysis Methylation Pipeline (ChAMP) analysis was employed for differential methylated points (DMPs) and the differential methylation regions (DMRs) screening. The HOXD10 mRNA expression and DNA methylation levels were detected by RT-PCR. The Cell proliferation, migration, invasion and apoptosis were respectively measured by MTT assay, transwell assay, wound healing assay and flow cytometry assay in carcinoma cell lines after treated with 5-aza-2'-deoxycytidine (5-Aza-dC) or transfected with HOXD10-expressing plasmid. The expression of HOXD10 and RHOC was revealed by immunohistochemistry in disparate differentiation colon carcinoma tissues, and the dephosphorylation of AKT and MAPK pathways were detected by RT-PCR and western blot. RESULTS The bioinformatics analysis demonstrated that HOXD10 was hypermethylated and low-expressed in colorectal cancer tissues. The detection of RT-PCR indicated the similar results in colorectal cancer cell lines and tissues. The induction of demethylation was recovered by treatment with 5-Aza-dC and the HOXD10 in colorectal cancer cell lines was re-expressed by transfection with a HOXD10 expression vector. The demethylation or overexpression of HOXD10 suppressed proliferation, migration, invasion and promoted apoptosis in colorectal cancer cells. HXOD10 suppressed the tumor growth and detected an opposite trend of protein RHOC. AKT and MAPK pathways were notably inactivated after the dephosphorylation due to the overexpression of HOXD10. CONCLUSIONS HOXD10 was suppressed in colon adenocarcinoma cells, which down-regulated RHOC/AKT/MAPK pathway to enhance colon cancer cells apoptosis and constrain the proliferation, migration and invasion.
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Affiliation(s)
- Yu-Hong Yuan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, Guangdong, China.,Department of Gastroenterology and Hepatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, Guangdong, China
| | - Han-Yu Wang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China.,Department of Radiation Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China
| | - Yu Lai
- Department of Gastroenterology and Hepatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, Guangdong, China
| | - Wa Zhong
- Department of Gastroenterology and Hepatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, Guangdong, China
| | - Wei-Ling Liang
- Department of Gastroenterology and Hepatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, Guangdong, China
| | - Fu-de Yan
- Department of Internal Medicine, Luopu Community Health Service Center of Panyu District, Guangzhou, 511431, Guangdong, China
| | - Zhong Yu
- Department of Gastroenterology and Hepatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, Guangdong, China
| | - Jun-Kai Chen
- Department of Gastroenterology and Hepatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, Guangdong, China
| | - Ying Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, Guangdong, China. .,Department of Gastroenterology and Hepatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, Guangdong, China.
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35
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Long non-coding RNA ABHD11-AS1 promotes colorectal cancer development through regulation of miR-133a/SOX4 axis. Biosci Rep 2018; 38:BSR20181386. [PMID: 30429229 PMCID: PMC6294614 DOI: 10.1042/bsr20181386] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Revised: 10/23/2018] [Accepted: 10/29/2018] [Indexed: 12/27/2022] Open
Abstract
Recently, lncRNA has been verified to regulate the development and progression of tumor. LncRNA ABHD11-AS1 has been proven to serve as an oncogene in several cancers. However, the role of ABHD11-AS1 in colorectal cancer remains totally unknown. In the present study, qRT-PCR assay revealed that ABHD11-AS1 expression was markedly higher in colorectal cancer tissues and cell lines. In addition, patients who displayed overexpression of ABHD11-AS1 showed a significantly poorer progression free survival (PFS) and overall survival (OS) by Kaplan–Meier analysis. Loss-of-function experiments suggested that silencing of ABHD11-AS1 expression could significantly reduce the proliferation, colony formation, migration and invasion of colorectal cancer cells, and increase cell apoptosis. Moreover, bioinformatics analysis, biotin pull-down assay, luciferase reporter assay, and RIP assay disclosed that ABHD11-AS1 straightly interacted with miR-133a. We also found that SOX4 was a downstream target of miR-133a and ABHD11-AS1 subsequently exerted its biological effects via modulating the expression of SOX4 in colorectal cancer cells. Collectively, these findings manifested that the ABHD11-AS1/miR-133a/SOX4 axis may be a cogitable and promising therapeutic target for colorectal cancer.
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Liu Y, Gao Y, Li D, He L, IW L, Hao B, Chen X, Cao Y. LASP1 promotes glioma cell proliferation and migration and is negatively regulated by miR-377-3p. Biomed Pharmacother 2018; 108:845-851. [DOI: 10.1016/j.biopha.2018.09.068] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 09/11/2018] [Accepted: 09/11/2018] [Indexed: 10/28/2022] Open
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Alhumaid A, AlYousef Z, Bakhsh HA, AlGhamdi S, Aziz MA. Emerging paradigms in the treatment of liver metastases in colorectal cancer. Crit Rev Oncol Hematol 2018; 132:39-50. [PMID: 30447926 DOI: 10.1016/j.critrevonc.2018.09.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 08/29/2018] [Accepted: 09/19/2018] [Indexed: 12/15/2022] Open
Abstract
Efforts to combat colorectal cancer have benefited from improved screening and surveillance, which facilitates early detection. The survival rate associated with diagnosis at stage I is approximately 90%. However, progress in improving survival in metastatic colorectal cancer (mCRC) has been minimal. This review focuses on mCRC with special emphasis on the molecular aspects of liver metastases, which is one of the most frequently involved organ site. Better molecular evidence is required to guide the decisions for surgical and other interventions used in the clinical management of mCRC. Results from different treatment modalities have exposed significant gaps in the existing paradigms of the mCRC management. Indeed there is a critical need to better understand molecular events and pathways that lead to colorectal cancer liver metastasis. Such a focused approach may help identify biomarkers and drug targets that can be useful in the clinical applications. With this focus, we provide an account of the molecular pathways involved in the spread of CRC to the liver. Specifically, the molecular changes at the DNA and RNA levels that are associated with liver metastases are discussed. Similarly, we describe relevant microRNAs that are identified as regulators of gene expression and can also serve as biomarkers. Conventionally applied biomarkers are not yet specific and sensitive enough to be relied in routine clinical decision making. Hence search for novel biomarkers is critically needed especially if these can be utilized using liquid biopsies. This review provides a comprehensive analysis of current molecular evidence along with potential future directions that could reshape the diagnostic and management paradigms and thus mitigate the devastating impact of colorectal cancer metastasis to the liver.
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Affiliation(s)
- Abdulrahman Alhumaid
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, College of Medicine, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
| | - Zeyad AlYousef
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Department of Surgery, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
| | - Haafiz A Bakhsh
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Department of Hepatology, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
| | - Saleh AlGhamdi
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Department of Medical Genomics, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
| | - Mohammad Azhar Aziz
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Department of Medical Genomics, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia; King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Colorectal Cancer Research Program, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
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Butt E, Raman D. New Frontiers for the Cytoskeletal Protein LASP1. Front Oncol 2018; 8:391. [PMID: 30298118 PMCID: PMC6160563 DOI: 10.3389/fonc.2018.00391] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Accepted: 08/30/2018] [Indexed: 02/06/2023] Open
Abstract
In the recent two decades, LIM and SH3 protein 1 (LASP1) has been developed from a simple actin-binding structural protein to a tumor biomarker and subsequently to a complex, nuclear transcriptional regulator. Starting with a brief historical perspective, this review will mainly compare and contrast LASP1 and LASP2 from the angle of the newest data and importantly, examine their role in transcriptional regulation. We will summarize the current knowledge through pictorial models and tables including the roles of different microRNAs in the differential regulation of LASP1 levels and patient outcome rather than specify in detail all tumor entities. Finally, the novel functional roles of LASP1 in secretion of vesicles, expression of matrix metalloproteinases and transcriptional regulation as well as the activation of survival and proliferation pathways in different cancer types are described.
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Affiliation(s)
- Elke Butt
- Institute for Experimental Biomedicine II, University Clinic, Wuerzburg, Germany
| | - Dayanidhi Raman
- Department of Cancer Biology, University of Toledo Health Science Campus, Toledo, OH, United States
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Wang YB, Shi Q, Li G, Zheng JH, Lin J, Qiu W. MicroRNA-488 inhibits progression of colorectal cancer via inhibition of the mitogen-activated protein kinase pathway by targeting claudin-2. Am J Physiol Cell Physiol 2018; 316:C33-C47. [PMID: 30207785 DOI: 10.1152/ajpcell.00047.2018] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Colorectal cancer (CRC) affects people globally, and lymph node metastasis (LNM) is an important indicator of poor clinical outcome in CRC. The current study aims to evaluate the role of microRNA-448 (miR-488) and claudin-2 (CLDN2) in epithelial-mesenchymal transition (EMT) and LNM of CRC through the MAPK signaling pathway. First, microarray analysis indicated that miR-488 was poorly expressed in CRC, whereas CLDN2 was highly expressed. Additionally, the bioinformatics website MicroRNA.org and the dual luciferase reporter gene assay found that CLDN2 was a target gene of miR-488. Next, the results for the correlations between expression of miR-488 and clinicopathological characteristics of CRC indicated that the expression of miR-488 was closely associated with differentiation degree, LNM, and Dukes stages in CRC patients. Moreover, overexpression of miR-488 inhibited the activation of the MAPK signal transduction pathway. Notably, loss- and gain-of-function experiments demonstrated that upregulation of miR-488 suppressed SW480 cell viability, invasion, and migration and promoted apoptosis in SW480 cells. Finally, overexpression of miR-488 inhibited LNM, microlymphatic vessel density, and tumor growth in nude mice. We conclude that overexpression of miR-488 could suppress the cell proliferation, EMT, and LNM of CRC cells via inhibition of the CLDN2-mediated MAPK signaling pathway, which could be a new molecular therapy target for CRC.
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Affiliation(s)
- Yong-Bing Wang
- Department of General Surgery, Shanghai University of Medicine and Health Sciences Affiliated Pudong New District People's Hospital , Shanghai , People's Republic of China
| | - Quan Shi
- Department of General Surgery, Shanghai University of Medicine and Health Sciences Affiliated Pudong New District People's Hospital , Shanghai , People's Republic of China
| | - Gang Li
- Department of General Surgery, Shanghai University of Medicine and Health Sciences Affiliated Pudong New District People's Hospital , Shanghai , People's Republic of China
| | - Jun-Hua Zheng
- Department of General Surgery, Shanghai University of Medicine and Health Sciences Affiliated Pudong New District People's Hospital , Shanghai , People's Republic of China
| | - Jie Lin
- Department of General Surgery, Shanghai University of Medicine and Health Sciences Affiliated Pudong New District People's Hospital , Shanghai , People's Republic of China
| | - Wei Qiu
- Department of General Surgery, Shanghai University of Medicine and Health Sciences Affiliated Pudong New District People's Hospital , Shanghai , People's Republic of China
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Chen XB, Li W, Chu AX. MicroRNA-133a inhibits gastric cancer cells growth, migration, and epithelial-mesenchymal transition process by targeting presenilin 1. J Cell Biochem 2018; 120:470-480. [PMID: 30161272 DOI: 10.1002/jcb.27403] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 07/10/2018] [Indexed: 12/15/2022]
Abstract
Gastric cancer (GC) is one of the most common malignancies and a leading cause of cancer-related death worldwide. Accumulating evidence reported that microRNA (miR)-133a was involved in GC. This study aimed to investigate the function and mechanism of miR-133a in the development and progression of GC. The expression of miR-133a and presenilin 1 (PSEN1) in two GC cell lines, SGC-7901 and BGC-823, were inhibited and overexpressed by transient transfections. Thereafter, cell viability, migration, and apoptosis were measured by trypan blue exclusion assay, transwell migration assay, and flow cytometry assay, respectively. Dual-luciferase reporter assay was conducted to verify whether PSEN1 was a direct target of miR-133a. Furthermore, quantitative real-time polymerase chain reaction and Western blot analysis were mainly performed to assess the expression changes of epithelial-mesenchymal transition (EMT)-associated proteins, apoptosis-related proteins, and Notch pathway proteins. MiR-133a inhibitor significantly increased cell viability and migration, while miR-133a mimic decreased cell viability, migration, and induced apoptosis. miR-133a suppression accelerated transforming growth factor-β1 (TGF-β1)-induce EMT, as evidenced by upregulation of E-cadherin, and downregulation of N-cadherin, vimentin, and Slug. Of contrast, miR-133a overexpression blocked TGF-β1-induce EMT by altering these factors. PSEN1 was a direct target of miR-133a, and suppression of PSEN1 abolished the promoting functions of miR-133 suppression on cell growth and metastasis. Moreover, PSEN1 inhibition decreased Notch 1, Notch 2, and Notch 3 protein expressions. This study demonstrates an antigrowth and antimetastasis role of miR-133a in GC cells. Additionally, miR-133a acts as a tumor suppressor may be via targeting PSEN1.
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Affiliation(s)
- Xin-Bo Chen
- Department of Gastroenterology, Shengli Oilfield Central Hospital, Dongying, China
| | - Wei Li
- Department of Gastroenterology, Shengli Oilfield Central Hospital, Dongying, China
| | - Ai-Xia Chu
- Department of Gastroenterology, Shengli Oilfield Central Hospital, Dongying, China
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Tang Y, Pan J, Huang S, Peng X, Zou X, Luo Y, Ren D, Zhang X, Li R, He P, Wa Q. Downregulation of miR-133a-3p promotes prostate cancer bone metastasis via activating PI3K/AKT signaling. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:160. [PMID: 30021600 PMCID: PMC6052526 DOI: 10.1186/s13046-018-0813-4] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 05/23/2018] [Indexed: 01/12/2023]
Abstract
BACKGROUND Bone metastasis is a leading cause of morbidity and mortality in advanced prostate cancer (PCa). Downexpression of miR-133a-3p has been found to contribute to the progression, recurrence and distant metastasis in PCa. However, clinical significance of miR-133a-3p in bone metastasis of PCa, and the biological role of miR-133a-3p and its molecular mechanisms underlying bone metastasis of PCa remain unclear. METHODS miR-133a-3p expression was evaluated in 245 clinical PCa tissues by real-time PCR. Statistical analysis was performed to evaluate the clinical correlation between miR-133a-3p expression and clinicopathological features, and overall and bone metastasis-free survival in PCa patients. The biological roles of miR-133a-3p in the bone metastasis of PCa were investigated both in vitro and in vivo. Bioinformatics analysis, real-time PCR, western blot and luciferase reporter analysis were applied to demonstrate the relationship between miR-133a-3p and its potential targets. Western blotting and luciferase assays were examined to identify the underlying pathway involved in the anti-tumor role of miR-133a-3p. Clinical correlation of miR-133a-3p with its targets was verified in human PCa tissues. RESULTS miR-133a-3p expression is reduced in PCa tissues compared with the adjacent normal tissues and benign prostate lesion tissues, particularly in bone metastatic PCa tissues. Low expression of miR-133a-3p is significantly correlated with advanced clinicopathological characteristics and shorter bone metastasis-free survival in PCa patients by statistical analysis. Moreover, upregulating miR-133a-3p inhibits cancer stem cell-like phenotypes in vitro and in vivo, as well as attenuates anoikis resistance in vitro in PCa cells. Importantly, administration of agomir-133a-3p greatly suppresses the incidence of PCa bone metastasis in vivo. Our results further demonstrate that miR-133a-3p suppresses bone metastasis of PCa via inhibiting PI3K/AKT signaling by directly targeting multiple cytokine receptors, including EGFR, FGFR1, IGF1R and MET. The negative clinical correlation of miR-133a-3p with EGFR, FGFR1, IGF1R, MET and PI3K/AKT signaling activity is determined in clinical PCa tissues. CONCLUSION Our results unveil a novel mechanism by which miR-133a-3p inhibits bone metastasis of PCa, providing the evidence that miR-133a-3p may serve as a potential bone metastasis marker in PCa, and delivery of agomir-133a-3p may be an effective anti-bone metastasis therapeutic strategy in PCa.
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Affiliation(s)
- Yubo Tang
- Department of Pharmacy, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.,Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Jincheng Pan
- Department of Urology Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Shuai Huang
- Department of Orthopaedic Surgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.,Department of Orthopaedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, 510080, Guangdong Province, China
| | - Xinsheng Peng
- Department of Orthopaedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, 510080, Guangdong Province, China
| | - Xuenong Zou
- Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.,Department of Orthopaedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, 510080, Guangdong Province, China
| | - Yongxiang Luo
- Department of biomedical engineering, health science center, Shenzhen University, Shenzhen, 518060, China
| | - Dong Ren
- Department of Orthopaedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, 510080, Guangdong Province, China
| | - Xin Zhang
- Department of Pathology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China
| | - Ronggang Li
- Department of Pathology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China
| | - Peiheng He
- Department of Orthopaedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, 510080, Guangdong Province, China.
| | - Qingde Wa
- Department of Orthopaedic Surgery, the Affiliated Hospital of Zunyi Medical college, 149 Dalian Road, Zunyi, 563003, Guizhou Province, China.
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Zhong C, Chen Y, Tao B, Peng L, Peng T, Yang X, Xia X, Chen L. LIM and SH3 protein 1 regulates cell growth and chemosensitivity of human glioblastoma via the PI3K/AKT pathway. BMC Cancer 2018; 18:722. [PMID: 29980193 PMCID: PMC6035445 DOI: 10.1186/s12885-018-4649-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 06/29/2018] [Indexed: 11/29/2022] Open
Abstract
Background LIM and SH3 protein 1 (LASP1) is upregulated in several types of human cancer and implicated in cancer progression. However, the expression and intrinsic function of LASP1 in glioblastoma (GBM) remains unclear. Method Oncomine and The Cancer Genome Atlas (TCGA) database was analyzed for the expression and clinical significance of LASP1 in GBM. LASP1 mRNA and protein level were measured by qRT-PCR and western blotting. The effect of LASP1 on GBM proliferation was examined by MTT assay and colony formation assay, the effect of LASP1 on sensitivity of Temozolomide was measured by flow cytometry and subcutaneous tumor model. The association between LASP1 and PI3K/AKT signaling was assessed by western blotting. Results Oncomine GBM dataset analysis indicated LASP1 is significantly upregulated in GBM tissues compared to normal tissues. GBM dataset from The Cancer Genome Atlas (TCGA) revealed that high LASP1 expression is related to poor overall survival. LASP1 mRNA and protein in clinical specimens and tumor cell lines are frequently overexpressed. LASP1 knockdown dramatically suppressed U87 and U251 cell proliferation. Silencing LASP1 potentiated cell chemosensitivity to temozolomide in vitro, LASP1 knockdown inhibited tumor growth and enhanced the therapeutic effect of temozolomide in vivo. TCGA dataset analysis indicated LASP1 was correlated with PI3K/AKT signaling pathway, and LASP1 deletion inhibited this pathway. Combination treatment with PI3K/AKT pathway inhibitor LY294002 dramatically accelerated the suppression effect of temozolomide. Conclusion LASP1 may function as an oncogene in GBM and regulate cell proliferation and chemosensitivity in a PI3K/AKT-dependent mechanism. Thus, the LASP1/PI3K/AKT axis is a promising target and therapeutic strategy for GBM treatment.
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Affiliation(s)
- Chuanhong Zhong
- Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yitian Chen
- Department of Clinical Medicine, Medical College of Soochow University, Suzhou, China
| | - Bei Tao
- Rheumatism Department, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lilei Peng
- Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Tangming Peng
- Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Xiaobo Yang
- Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Xiangguo Xia
- Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Ligang Chen
- Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
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Yu PY, Lopez G, Braggio D, Koller D, Bill KLJ, Prudner BC, Zewdu A, Chen JL, Iwenofu OH, Lev D, Strohecker AM, Fenger JM, Pollock RE, Guttridge DC. miR-133a function in the pathogenesis of dedifferentiated liposarcoma. Cancer Cell Int 2018; 18:89. [PMID: 29983640 PMCID: PMC6019219 DOI: 10.1186/s12935-018-0583-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 06/12/2018] [Indexed: 01/01/2023] Open
Abstract
Background Sarcomas are malignant heterogeneous tumors of mesenchymal derivation. Dedifferentiated liposarcoma (DDLPS) is aggressive with recurrence in 80% and metastasis in 20% of patients. We previously found that miR-133a was significantly underexpressed in liposarcoma tissues. As this miRNA has recently been shown to be a tumor suppressor in many cancers, the objective of this study was to characterize the biological and molecular consequences of miR-133a underexpression in DDLPS. Methods Real-time PCR was used to evaluate expression levels of miR-133a in human DDLPS tissue, normal fat tissue, and human DDLPS cell lines. DDLPS cells were stably transduced with miR-133a vector to assess the effects in vitro on proliferation, cell cycle, cell death, migration, and metabolism. A Seahorse Bioanalyzer system was also used to assess metabolism in vivo by measuring glycolysis and oxidative phosphorylation (OXPHOS) in subcutaneous xenograft tumors from immunocompromised mice. Results miR-133a expression was significantly decreased in human DDLPS tissue and cell lines. Enforced expression of miR-133a decreased cell proliferation, impacted cell cycle progression kinetics, decreased glycolysis, and increased OXPHOS. There was no significant effect on cell death or migration. Using an in vivo xenograft mouse study, we showed that tumors with increased miR-133a expression had no difference in tumor growth compared to control, but did exhibit an increase in OXPHOS metabolic respiration. Conclusions Based on our collective findings, we propose that in DDPLS, loss of miR-133a induces a metabolic shift due to a reduction in oxidative metabolism favoring a Warburg effect in DDLPS tumors, but this regulation on metabolism was not sufficient to affect DDPLS. Electronic supplementary material The online version of this article (10.1186/s12935-018-0583-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Peter Y Yu
- 1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.,2College of Medicine, The Ohio State University, Columbus, OH USA
| | - Gonzalo Lopez
- 1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.,3Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH USA
| | - Danielle Braggio
- 1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.,3Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH USA
| | - David Koller
- 1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.,3Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH USA
| | - Kate Lynn J Bill
- 1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.,3Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH USA
| | - Bethany C Prudner
- 4Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH USA
| | - Abbie Zewdu
- 1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.,3Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH USA
| | - James L Chen
- 1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.,5Biomedical Informatics, Internal Medicine in the Division of Medical Oncology, The Ohio State University, Columbus, OH USA
| | - O Hans Iwenofu
- 1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.,6Department of Pathology & Laboratory Services, The Ohio State University, Columbus, OH USA
| | - Dina Lev
- 7Department of Surgery, Sheba Medical Center, Tel Aviv, Israel
| | - Anne M Strohecker
- 1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.,3Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH USA.,8Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH USA
| | - Joelle M Fenger
- 9Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH USA
| | - Raphael E Pollock
- 1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.,3Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH USA
| | - Denis C Guttridge
- 1Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.,8Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH USA
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Zhao H, Liu B, Li J. LIM and SH3 protein 1 knockdown suppresses proliferation and metastasis of colorectal carcinoma cells via inhibition of the mitogen-activated protein kinase signaling pathway. Oncol Lett 2018; 15:6839-6844. [PMID: 29731863 PMCID: PMC5920965 DOI: 10.3892/ol.2018.8222] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 10/13/2017] [Indexed: 12/15/2022] Open
Abstract
LIM and SH3 protein 1 (Lasp-1), a focal adhesion protein, serves a critical role in the regulation of cell proliferation and migration. The role of Lasp-1, as well as the intracellular signaling pathways involved in metastasis and progression of colorectal carcinoma, remains unclear. In the present study, the regulatory effect of Lasp-1 and the underlying molecular mechanism involved in migration and invasion of colorectal carcinoma were investigated. RNA interference and overexpression in SW480 cells were performed to elucidate the role of Lasp-1. Reverse transcription-quantitative polymerase chain reaction, western blotting and immunofluorescence were conducted to determine the mRNA and protein levels of Lasp-1 and extracellular-signal-regulated kinase 1/2 (ERK1/2) in SW480 cells as well as tumor and adjacent normal tissues obtained from 20 patients with colorectal carcinoma. Furthermore, a cell proliferation assay, flow cytometric analysis, and cell migration and invasion assays were performed to examine the effect of Lasp-1 on cell growth. The results of the present study demonstrated that Lasp-1 and ERK1/2 were upregulated in tumor tissue compared with adjacent normal colorectal mucosa. Cell-based in vitro assays demonstrated that Lasp-1 knockdown suppressed the expression and activation of ERK1/2, whereas Lasp-1 overexpression resulted in ERK1/2 upregulation. Additionally, Lasp-1 knockdown inhibited cell proliferation, migration, and invasion and induced cellular apoptosis and G0/G1 cell-cycle arrest. The results of the present study indicate that Lasp-1 serves a critical role in the progression of colorectal carcinoma regulating the activation of the mitogen-activated protein kinase signaling pathway.
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Affiliation(s)
- Hongpeng Zhao
- Department of Gastrointestinal Surgery, Shandong Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Bo Liu
- Department of Gastrointestinal Surgery, Shandong Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Jie Li
- Department of Hepatobiliary Surgery, Shandong Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
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Zhou R, Shao Z, Liu J, Zhan W, Gao Q, Pan Z, Wu L, Xu L, Ding Y, Zhao L. COPS5 and LASP1 synergistically interact to downregulate 14-3-3σ expression and promote colorectal cancer progression via activating PI3K/AKT pathway. Int J Cancer 2017; 142:1853-1864. [PMID: 29226323 DOI: 10.1002/ijc.31206] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 10/25/2017] [Accepted: 11/30/2017] [Indexed: 02/01/2023]
Abstract
Overexpression of LIM and SH3 protein 1 (LASP1) is required for colorectal cancer (CRC) development and progression. Here, C-Jun activation domain-binding protein-1 (Jab1), also known as COP9 signalosome subunit 5 (COPS5), was verified as a new LASP1-interacting protein through yeast two-hybrid assay. The role of COPS5 in LASP1-mediated CRC progression remains unknown. GST pull-down assay indicated that the SH3 domain of LASP1 could directly bind to MPN domain of COPS5. In vitro gain- and loss-of-function analyses revealed the stimulatory role of COPS5 on CRC cell proliferation, migration and invasion. Endogenous overexpression of COPS5 could also enhance the homing capacity of CRC cells in vivo. Further analysis showed that COPS5 and LASP1 synergistically interact to stimulate the ubiquitination and degradation of 14-3-3σ and promote colorectal cancer progression via PI3K/Akt dependent signaling pathway. Clinically, the expression of COPS5 was studied in CRC tissues and it is associated with CRC differentiation, metastasis and poor prognosis. The colocalization of LASP1 and COPS5 was demonstrated in both nonmetastatic and metastatic CRC tissues. A positive correlation was found between the expression of LASP1 and COPS5 while a negative correlation existed between 14-3-3σ and COPS5/LASP1 in most CRC samples. A combination of COPS5 and LASP1 tends to be an independent prognostic indicator for CRC patients, and this is also suitable for CRC without lymph node metastasis. The current research has further advanced our understanding on the complicated molecular mechanism underlying LASP1-mediated CRC progression, which hopefully will contribute to the development of novel diagnostic and therapeutic strategies in CRC.
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Affiliation(s)
- Rui Zhou
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Ziyun Shao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.,Department of Nephrology, Wuhan General Hospital of Guangzhou Military Command, Wuhan, China
| | - Jian Liu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Wanqi Zhan
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Qingzu Gao
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhihua Pan
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Ling Wu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Lijun Xu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yanqing Ding
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
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MicroRNA-105 is involved in TNF-α-related tumor microenvironment enhanced colorectal cancer progression. Cell Death Dis 2017; 8:3213. [PMID: 29238068 PMCID: PMC5870598 DOI: 10.1038/s41419-017-0048-x] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 10/10/2017] [Indexed: 12/15/2022]
Abstract
TNF-α is a central proinflammatory cytokine contributing to malignant tumor progression in tumor microenvironment. In this study, we found the upregulation of miR-105 in colorectal cancer was associated with aggressive phenotype, and the enhanced expression of miR-105 was required for TNF-α-induced epithelial–mesenchymal transition (EMT). The expression of miR-105 was remarkably stimulated by TNF-α in a time-dependent manner using real-time qPCR analysis. Inhibition of miR-105 remarkably weakened the aggressive effects of TNF-α through preventing the activation of NF-κB signaling and the initiation of EMT. Furthermore, miR-105 was demonstrated directly targeted on the 3′-UTRs of RAP2C, a Rap2 subfamily of small GTP-binding protein. Consistently, suppression of RAP2C stimulated the role of miR-105, which dramatically promoted the invasion and metastasis of CRC cells. Thalidomide, a TNF-α and NF-κB inhibitor, significantly weakened the metastasis and homing capacity of miR-105-overexpressed CRC cells in nude mice. Our investigation initiatively illustrated the modulatory role of miR-105 in TNF-α-induced EMT and further CRC metastasis. We also offer a better understanding of TNFα-induced metastasis and suggest an effective therapeutic strategy against CRC metastasis.
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Sui Y, Zhang X, Yang H, Wei W, Wang M. MicroRNA-133a acts as a tumour suppressor in breast cancer through targeting LASP1. Oncol Rep 2017; 39:473-482. [PMID: 29207145 PMCID: PMC5783615 DOI: 10.3892/or.2017.6114] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 10/27/2017] [Indexed: 12/12/2022] Open
Abstract
Many microRNAs (miRs) have been demonstrated to play promoting or tumor suppressive roles in human cancers including breast cancer. However, the molecular mechanism of miR-133a underlying the malignant progression of breast cancer still remains obscure. In the present study we observed that the expression of miR-133a was significantly downregulated in breast cancer tissues and cell lines, when compared with adjacent non-tumor tissues and normal breast cell line, respectively. Reduced miR-133a levels were significantly associated with advanced clinical stage, lymph node metastasis, as well as shorter survival time of patients with breast cancer. Restoration of miR-133a expression led to significant decrease in the proliferation, migration, and invasion of SK-BR-3 and MDA-MB-231 cells in vitro, as well as in tumor xenograft growth in nude mice. Luciferase reporter gene assay data identified LASP1 as a target gene of miR-133a, and the expression of LASP1 was negatively regulated by miR-133a in breast cancer cells. LASP1 was significantly upregulated in breast cancer tissues and cell lines, and its upregulation was significantly associated with disease progression. siRNA-induced LASP1 downregulation caused a significant reduction in breast cancer cell proliferation, migration and invasion. Furthermore, overexpression of LASP1 impaired the suppressive effects of miR-133a upregulation on the proliferation, migration and invasion of SK-BR-3 and MDA-MB-231 cells. In summary, the present study demonstrates that miR-133a acts as a tumor suppressor in breast cancer partly at least via targeting LASP1, and thus suggests that the miR-133a/LASP1 axis may become a potential therapeutic target for breast cancer.
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Affiliation(s)
- Yanmin Sui
- Department of Oncology, Dongying People's Hospital, Dongying, Shandong 257091, P.R. China
| | - Xiaolei Zhang
- Department of Oncology, Dongying People's Hospital, Dongying, Shandong 257091, P.R. China
| | - Honglan Yang
- Department of Oncology, Dongying People's Hospital, Dongying, Shandong 257091, P.R. China
| | - Wei Wei
- Department of Oncology, Dongying People's Hospital, Dongying, Shandong 257091, P.R. China
| | - Minglin Wang
- Department of Oncology, Dongying People's Hospital, Dongying, Shandong 257091, P.R. China
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Zhao F, Ge YZ, Zhou LH, Xu LW, Xu Z, Ping WW, Wang M, Zhou CC, Wu R, Jia RP. Identification of hub miRNA biomarkers for bladder cancer by weighted gene coexpression network analysis. Onco Targets Ther 2017; 10:5551-5559. [PMID: 29200870 PMCID: PMC5702163 DOI: 10.2147/ott.s146479] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Bladder cancer (BC) is a common urinary system tumor with high aggressiveness, and it results in relatively high mortality due to a lack of precise and suitable biomarkers. In this study, we applied the weighted gene coexpression network analysis method to miRNA expression data from BC patients, and screened for network modules associated with BC progression. Hub miRNAs were selected, followed by functional enrichment analyses of their target genes for the most closely related module. These hub miRNAs were found to be involved in several functional pathways including pathway in cancer, regulation of actin cytoskeleton, PI3K-Akt signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, Wnt signaling pathway, proteoglycans in cancer, focal adhesion and p53 signaling pathway via regulating target genes. Finally, their prognostic significance was tested using analyses of overall survival. A few novel prognostic miRNAs were identified based on expression profiles and related survival data. In conclusion, several miRNAs that were critical in BC initiation and progression have been identified in this study. These miRNAs, which may contribute to a comprehensive understanding of the pathogenesis of BC, could serve as potential biomarkers for BC prognosis or as new therapeutic targets.
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Affiliation(s)
- Feng Zhao
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yu-Zheng Ge
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Liu-Hua Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Lu-Wei Xu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Zheng Xu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Wen-Wen Ping
- Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Wang
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Chang-Cheng Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Ran Wu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Rui-Peng Jia
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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Law IKM, Padua DM, Iliopoulos D, Pothoulakis C. Role of G protein-coupled receptors-microRNA interactions in gastrointestinal pathophysiology. Am J Physiol Gastrointest Liver Physiol 2017; 313:G361-G372. [PMID: 28774868 PMCID: PMC5792214 DOI: 10.1152/ajpgi.00144.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 07/13/2017] [Accepted: 07/24/2017] [Indexed: 01/31/2023]
Abstract
G protein-coupled receptors (GPCRs) make up the largest transmembrane receptor superfamily in the human genome and are expressed in nearly all gastrointestinal cell types. Coupling of GPCRs and their respective ligands activates various phosphotransferases in the cytoplasm, and, thus, activation of GPCR signaling in intestine regulates many cellular and physiological processes. Studies in microRNAs (miRNAs) demonstrate that they represent critical epigenetic regulators of different pathophysiological responses in different organs and cell types in humans and animals. Here, we reviewed recent research on GPCR-miRNA interactions related to gastrointestinal pathophysiology, such as inflammatory bowel diseases, irritable bowel syndrome, and gastrointestinal cancers. Given that the presence of different types of cells in the gastrointestinal tract suggests the importance of cell-cell interactions in maintaining gastrointestinal homeostasis, we also discuss how GPCR-miRNA interactions regulate gene expression at the cellular level and subsequently modulate gastrointestinal pathophysiology through molecular regulatory circuits and cell-cell interactions. These studies helped identify novel molecular pathways leading to the discovery of potential biomarkers for gastrointestinal diseases.
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Affiliation(s)
- Ivy Ka Man Law
- 1Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and
| | - David Miguel Padua
- 1Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and
| | - Dimitrios Iliopoulos
- 1Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and ,2Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Charalabos Pothoulakis
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and
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MiR-143 inhibits endometrial cancer cell proliferation and metastasis by targeting MAPK1. Oncotarget 2017; 8:84384-84395. [PMID: 29137432 PMCID: PMC5663604 DOI: 10.18632/oncotarget.21037] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 08/04/2017] [Indexed: 12/31/2022] Open
Abstract
Endometrial cancer (EC) is one of the most commonly diagnosed gynecologic malignancies in the world, with the morbidity rate of over 7%. The mechanism of the pathogenesis has not been specifically elucidated to date, which is imperative for EC treatment. The aim of our study was to investigate the target relationship between miR-143 and mitogen-activated protein kinase 1 (MAPK1) and explore the effect of miR-143 on the endometrial cancers (EC) cells through targeting MAPK1. We collected EC tissues and adjacent tissues, and transfected miR-143 mimics and MAPK1 siRNA into EC cells with lipofectamine. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to examine the expression of miR-143 and MAPK1 mRNA and the protein expression of MAPK1. Cell counting kit-8, wound healing assay, flow cytometry and transwell assay were applied to examining the alteration of the proliferation, migration, cell cycle and invasion ability of EC cells. We predicted the targeting gene of miR-143 through bioinformatics analysis. MiR-143 was found under-expressed in EC tissues and cells. Overexpression of miR-143 or knockdown of MAPK1 in human EC cell line HEC-1B inhibited the EC cell proliferation, migration and invasion and induced apoptosis. MAPK1 was verified to be a target gene of miR-143. MiR-143 overexpression could effectively inhibit mRNA and protein expression of MAPK1 in HEC-1B cells. Collectively, miR-143 might inhibit the proliferation, migration and invasion of EC cells, and promote the apoptosis of EC cells by suppressing MAPK1. These findings provided a view for new and potential therapeutic method for the clinical treatment of EC.
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