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Lee S, Lee B, Kwon SH, Park J, Kim SH. MCC in the spotlight: Its dual role in signal regulation and oncogenesis. Cell Signal 2025; 131:111756. [PMID: 40118128 DOI: 10.1016/j.cellsig.2025.111756] [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: 01/24/2025] [Revised: 03/13/2025] [Accepted: 03/18/2025] [Indexed: 03/23/2025]
Abstract
The mutated in colorectal cancer (MCC) gene is closely associated with the onset and progression of colorectal cancer. MCC plays a critical role in regulating the cell cycle and various signaling pathways and is recognized to inhibit cancer cell proliferation via the β-catenin signaling pathway. β-catenin is a key component of the WNT signaling pathway that influences cell growth, differentiation, survival, and migration, thereby positioning MCC as an important tumor suppressor. Notably, MCC has also been implicated in other cancer types, including lung, liver, and brain cancers. However, the precise mechanisms by which MCC functions in these malignancies remain inadequately understood. Comprehensive investigations into the interactions among MCC, various signaling pathways, and metabolic processes are essential for uncovering the molecular mechanisms of cancer and the pathological features characteristic of different cancer stages. This review presents the structural characteristics of MCC and its cell growth regulation mechanisms and functional roles within tissues, with the aims of enhancing our understanding of the role of MCC in cancer biology and highlighting potential therapeutic strategies targeting this gene.
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Affiliation(s)
- Soohyeon Lee
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon 35015, South Korea; Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon 35015, South Korea
| | - Beomwoo Lee
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon 35015, South Korea; Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon 35015, South Korea
| | - So Hee Kwon
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, South Korea.
| | - Jongsun Park
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon 35015, South Korea; Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon 35015, South Korea; Biomedical Research Institute, Chungnam National University Hospital, Daejeon 35015, Republic of Korea.
| | - Seon-Hwan Kim
- Biomedical Research Institute, Chungnam National University Hospital, Daejeon 35015, Republic of Korea; Department of Neurosurgery, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
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Asefi M, Rezvani N, Saidijam M, Soltanian AR, Khalilian AR, Mahdavinezhad A. Evaluation of epigenetic silencing of the miR-139-5p gene in the pathogenesis of colorectal cancer and its diagnostic biomarker capability in plasma samples. BMC Cancer 2025; 25:877. [PMID: 40375170 DOI: 10.1186/s12885-025-14290-x] [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: 11/26/2024] [Accepted: 05/08/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND The pathogenesis of CRC requires primary genetic and epigenetic mechanisms including, methylation of CpG islands of the genes. In the current study, micro RNA-139-5p (miR-139-5p) promoter methylated DNA was evaluated in tumor tissue and plasma samples from CRC affected patients. METHODS MiR-139-5p promoter methylation was investigated in 80 samples of tumoral tissue and healthy marginal tissue and the same number of plasma samples, using the MethyLight method. The miR-139-5p expression was assessed using the qPCR method. BT (Bioassay Technology) Elisa kit was applied to measure RAP-1b as a target gene of miR-139-5p. RESULTS Median PMR values of 12.4 (95% CI, 3.23-32.25) and 0.66 (95%CI, 0.51-1.0) were obtained from plasma samples of CRC patients and controls, sequentially. In plasma samples, the sensitivity and specificity of miR-139-5p promoter methylated marker were 75% and 92.5%, in the same order (AUC = 0.958). Lower expression of miR-139-5p in plasma and tumor tissue of patients (P < 0.001) was shown. Also, a significant rise of RAP-1b protein concentration was observed in both mentioned specimens. CONCLUSION Hyper-methylation of miR-139-5p could be suggested as high accuracy diagnostic biomarker for the detection of CRC in plasma samples, pending further validation with large prospective studies.
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Affiliation(s)
- Masoud Asefi
- Research Center for Molecular Medicine, Institute of Cancer, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Nayebali Rezvani
- Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Institute of Cancer, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Reza Soltanian
- Modeling of Noncommunicable Diseases Research Center, Institute of Health Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Reza Khalilian
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Mahdavinezhad
- Research Center for Molecular Medicine, Institute of Cancer, Hamadan University of Medical Sciences, Hamadan, Iran.
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Wang H, Gan X, Tang Y. Mechanisms of Heavy Metal Cadmium (Cd)-Induced Malignancy. Biol Trace Elem Res 2025; 203:608-623. [PMID: 38683269 DOI: 10.1007/s12011-024-04189-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 04/16/2024] [Indexed: 05/01/2024]
Abstract
The environmental pollution of cadmium is worsening, and its significant carcinogenic effects on humans have been confirmed. Cadmium can induce cancer through various signaling pathways, including the ERK/JNK/p38MAPK, PI3K/AKT/mTOR, NF-κB, and Wnt. It can also cause cancer by directly damaging DNA and inhibiting DNA repair systems, or through epigenetic mechanisms such as abnormal DNA methylation, LncRNA, and microRNA. However, the detailed mechanisms of Cd-induced cancer are still not fully understood and require further investigation.
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Affiliation(s)
- Hairong Wang
- School of Public Health, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, China
| | - Xuehui Gan
- School of Public Health, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, China
| | - Yan Tang
- School of Public Health, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, China.
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Ellakwa DES, Mushtaq N, Khan S, Jabbar A, Abdelmalek MA, Wadan AHS, Ellakwa TE, Raza A. Molecular functions of microRNAs in colorectal cancer: recent roles in proliferation, angiogenesis, apoptosis, and chemoresistance. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:5617-5630. [PMID: 38619588 DOI: 10.1007/s00210-024-03076-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 03/28/2024] [Indexed: 04/16/2024]
Abstract
MiRNAs (microRNAs) constitute a group of diminutive molecules of non-coding RNA intricately involved in regulating gene expression. This regulation is primarily accomplished through the binding of miRNAs to complementary sequences situated in the 3'-UTR of the messenger RNA (mRNA) target; as a result, they are degraded or repressed. The multifaceted biogenesis of miRNAs is characterized by a meticulously orchestrated sequence of events encompassing transcription, processing, transportation, and decay. Colorectal cancer stands as a pervasive and formidable ailment, afflicting millions across the globe. Colorectal cancer is not well diagnosed early, and metastasis rates are high, which results in low survival rates in advanced stages. The genesis and progression of colorectal cancer are subject to the influence of genetic and epigenetic factors, among which miRNAs play a pivotal role. When it comes to colorectal cancer, miRNAs have a dual character, depending on the genes they target, functioning as either tumor suppressors or oncogenes and the prevailing cellular milieu. Their impact extends to modulating critical facets of colorectal cancer pathogenesis, including proliferation, angiogenesis, apoptosis, chemoresistance, and radiotherapy response. The discernible potential of miRNAs which are used as biomarkers to diagnose colorectal cancer, prognosis, and treatment response has come to the forefront. Notably, miRNAs are easily found and detected readily in a variety of biological fluids, including saliva, blood, urine, and feces. This prominence is attributed to the inherent advantages of miRNAs over conventional biomarkers, including heightened stability, specificity, sensitivity, and accessibility. Various investigations have pinpointed miRNA signatures or panels capable of differentiating colorectal cancer patients from their healthy counterparts, predicting colorectal cancer stage and survival, and monitoring colorectal cancer recurrence and therapy response. Although there has been research on miRNAs in various diseases, there has been less research on miRNAs in cancer. Moreover, updated results of preclinical and clinical studies on miRNA biomarkers and drugs are required. Nevertheless, the integration of miRNAs as biomarkers for colorectal cancer is not devoid of challenges and limitations. These encompass the heterogeneity prevalent among colorectal cancer subtypes and stages, the variability in miRNA expression across different tissues and individuals, the absence of standardized methodologies for miRNA detection and quantification, and the imperative for validation through extensive clinical trials. Consequently, further research is imperative to conclusively establish the clinical utility and reliability of miRNAs as colorectal cancer biomarkers. MiR-21 demonstrates carcinogenic characteristics by targeting several tumor suppressor genes, which encourages cell division, invasion, and metastasis. On the other hand, by controlling the Wnt/β-catenin pathway, the tumor suppressor miRNA miR-34a prevents CRC cell proliferation, migration, and invasion. Furthermore, in colorectal cancer, the miR-200 family increases chemotherapy sensitivity while suppressing epithelial-mesenchymal transition (EMT). As an oncogene, the miR-17-92 cluster targets elements of the TGF-β signaling pathway to encourage the growth of CRC cells. Finally, miR-143/145, which is downregulated in CRC, influences apoptosis and the progression of the cell cycle. These miRNAs affect pathways like Wnt, TGF-β, PI3K-AKT, MAPK, and EMT, making them potential clinical biomarkers and therapeutic targets. This review summarizes recent research related to miRNAs, their role in tumor progression and metastasis, and their potential as biomarkers and therapeutic targets in colorectal cancer. In addition, we combined miRNAs' roles in tumorigenesis and development with the therapy of CRC patients, leading to novel perspectives on colorectal cancer diagnosis and treatment.
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Affiliation(s)
- Doha El-Sayed Ellakwa
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy for Girls, Al-Azhar University, Cairo, Egypt.
- Department of Biochemistry, Faculty of Pharmacy, Sinai University, Kantra Branch, Ismailia, Egypt.
| | - Nadia Mushtaq
- Department of Life Sciences, Lahore University of Management Sciences, Lahore, Pakistan
| | - Sahrish Khan
- Center for Applied Molecular Biology (CAMB), University of Punjab, Lahore, Pakistan
| | - Abdul Jabbar
- Department of Veterinary Medicine, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | | | | | - Takwa E Ellakwa
- Physical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Ali Raza
- Department of Veterinary Microbiology, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey
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Zhang HL, Doblin S, Zhang ZW, Song ZJ, Dinesh B, Tabana Y, Saad DS, Adam Ahmed Adam M, Wang Y, Wang W, Zhang HL, Wu S, Zhao R, Khaled B. Elucidating the molecular basis of ATP-induced cell death in breast cancer: Construction of a robust prognostic model. World J Clin Oncol 2024; 15:208-242. [PMID: 38455130 PMCID: PMC10915939 DOI: 10.5306/wjco.v15.i2.208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 12/10/2023] [Accepted: 01/12/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Breast cancer is a multifaceted and formidable disease with profound public health implications. Cell demise mechanisms play a pivotal role in breast cancer pathogenesis, with ATP-triggered cell death attracting mounting interest for its unique specificity and potential therapeutic pertinence. AIM To investigate the impact of ATP-induced cell death (AICD) on breast cancer, enhancing our understanding of its mechanism. METHODS The foundational genes orchestrating AICD mechanisms were extracted from the literature, underpinning the establishment of a prognostic model. Simultaneously, a microRNA (miRNA) prognostic model was constructed that mirrored the gene-based prognostic model. Distinctions between high- and low-risk cohorts within mRNA and miRNA characteristic models were scrutinized, with the aim of delineating common influence mechanisms, substantiated through enrichment analysis and immune infiltration assessment. RESULTS The mRNA prognostic model in this study encompassed four specific mRNAs: P2X purinoceptor 4, pannexin 1, caspase 7, and cyclin 2. The miRNA prognostic model integrated four pivotal miRNAs: hsa-miR-615-3p, hsa-miR-519b-3p, hsa-miR-342-3p, and hsa-miR-324-3p. B cells, CD4+ T cells, CD8+ T cells, endothelial cells, and macrophages exhibited inverse correlations with risk scores across all breast cancer subtypes. Furthermore, Kyoto Encyclopedia of Genes and Genomes analysis revealed that genes differentially expressed in response to mRNA risk scores significantly enriched 25 signaling pathways, while miRNA risk scores significantly enriched 29 signaling pathways, with 16 pathways being jointly enriched. CONCLUSION Of paramount significance, distinct mRNA and miRNA signature models were devised tailored to AICD, both potentially autonomous prognostic factors. This study's elucidation of the molecular underpinnings of AICD in breast cancer enhances the arsenal of potential therapeutic tools, offering an unparalleled window for innovative interventions. Essentially, this paper reveals the hitherto enigmatic link between AICD and breast cancer, potentially leading to revolutionary progress in personalized oncology.
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Affiliation(s)
- Hao-Ling Zhang
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Sandai Doblin
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Zhong-Wen Zhang
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Zhi-Jing Song
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Babu Dinesh
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Yasser Tabana
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Dahham Sabbar Saad
- Department of Science, University of Technology and Applied Sciences Rustaq, Rustaq 10 P.C. 329, Oman
| | - Mowaffaq Adam Ahmed Adam
- Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, United States
| | - Yong Wang
- Department of Pathology Center, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Wei Wang
- College of Acupuncture-moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hao-Long Zhang
- Universiti Sains Malaysia, Advanced Medical and Dental Institute, Penang 13200, Malaysia
| | - Sen Wu
- Department of Biomedical Science, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Rui Zhao
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Barakat Khaled
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
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Soltaninezhad P, Arab F, Mohtasham N, FakherBaheri M, Kavishahi NN, Aghaee-Bakhtiari SH, Zare-Mahmoodabadi R, Pakfetrat A, Taban KI, Mohajertehran F. Unveiling the Potential of Serum MiR-483-5p: A Promising Diagnostic and Prognostic Biomarker in OLP and OSCC Patients by In silico Analysis of Differential Gene Expression. Curr Pharm Des 2024; 30:310-322. [PMID: 38310566 DOI: 10.2174/0113816128276149240108163407] [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: 09/03/2023] [Revised: 12/09/2023] [Accepted: 12/15/2023] [Indexed: 02/06/2024]
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) and oral lichen planus (OLP) are two separate conditions affecting the mouth and result in varying clinical outcomes and levels of malignancy. Achieving early diagnosis and effective therapy planning requires the identification of reliable diagnostic biomarkers for these disorders. MicroRNAs (miRNAs) have recently received attention as powerful biomarkers for various illnesses, including cancer. In particular, miR-483-5p is a promising diagnostic and prognostic biomarker in various cancers. Therefore, this study aimed to investigate the role of serum miR-483-5p in the diagnosis and prognosis of OLP and OSCC patients by in silico analysis of differential gene expression. METHODS GSE23558 and GSE52130 data sets were selected, and differential gene expression analysis was performed using microarray data from GSE52130 and GSE23558. The analysis focused on comparing OLP and OSCC samples with normal samples. The genes intersected through the differential gene expression analysis were then extracted to determine the overlapping genes among the upregulated or downregulated DEGs. The downregulated genes among the DEGs were subsequently imported into the miRWalk database to search for potential target genes of miRNA 483-5p that lacked validation. To gain insight into the biological pathways associated with the DEGs, we conducted pathway analysis utilizing tools, such as Enrichr. Additionally, the cellular components associated with these DEGs were investigated by analyzing the String database. On the other hand, blood serum samples were collected from 35 OSCC patients, 34 OLP patients, and 34 healthy volunteers. The expression level of miR-483-5p was determined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The Kruskal-Wallis test was utilized to investigate the considerable correlation. Moreover, this study explored the prognostic value of miR-483-5p through its association with clinicopathological parameters in OSCC patients. RESULTS The results showed that serum expression of miR-483-5p was considerably higher in OSCC patients compared to OLP patients and healthy controls (p 0.0001) and that this difference was statistically significant. Furthermore, elevated miR-483-5p expression was associated with tumor size, lymph node metastasis, and stage of tumor nodal metastasis in OSCC patients (p 0.001, p 0.038, and p 0.0001, respectively). In silico analysis found 71 upregulated genes at the intersection of upregulated DEGs and 44 downregulated genes at the intersection of downregulated DEGs, offering insight into the potential underlying mechanisms of miR-483-5p's engagement in OSCC and OLP. The majority of these DEGs were found to be involved in autophagy pathways, but DEGs involved in the histidine metabolism pathway showed significant results. Most of these DEGs were located in the extracellular region. After screening for downregulated genes that were invalidated, miRNA 483-5p had 7 target genes. CONCLUSION This study demonstrates the potential of serum miR-483-5p as a promising diagnostic and prognostic biomarker in OSCC and OLP patients. Its upregulation in OSCC patients and its association with advanced tumor stage and potential metastasis suggest the involvement of miR-483-5p in critical signaling pathways involved in cell proliferation, apoptosis, and cell cycle regulation, making it a reliable indicator of disease progression. Nevertheless, additional experimental studies are essential to validate these findings and establish a foundation for the advancement of targeted therapies and personalized treatment approaches.
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MESH Headings
- Humans
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Carcinoma, Squamous Cell/diagnosis
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/blood
- Carcinoma, Squamous Cell/pathology
- Computer Simulation
- Gene Expression Regulation, Neoplastic
- Lichen Planus, Oral/genetics
- Lichen Planus, Oral/blood
- Lichen Planus, Oral/diagnosis
- MicroRNAs/blood
- MicroRNAs/genetics
- Mouth Neoplasms/genetics
- Mouth Neoplasms/blood
- Mouth Neoplasms/diagnosis
- Mouth Neoplasms/pathology
- Prognosis
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Affiliation(s)
| | - Fatemeh Arab
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nooshin Mohtasham
- Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammadhossein FakherBaheri
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Nima Nikbin Kavishahi
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Reza Zare-Mahmoodabadi
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Atessa Pakfetrat
- Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kiarash Izadi Taban
- Dental Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farnaz Mohajertehran
- Dental Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
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Moratalla-Navarro F, Díez-Villanueva A, Garcia-Serrano A, Closa A, Cordero D, Solé X, Guinó E, Sanz-Pamplona R, Sanjuan X, Santos C, Biondo S, Salazar R, Moreno V. Identification of a Twelve-microRNA Signature with Prognostic Value in Stage II Microsatellite Stable Colon Cancer. Cancers (Basel) 2023; 15:3301. [PMID: 37444411 DOI: 10.3390/cancers15133301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
We aimed to identify and validate a set of miRNAs that could serve as a prognostic signature useful to determine the recurrence risk for patients with COAD. Small RNAs from tumors of 100 stage II, untreated, MSS colon cancer patients were sequenced for the discovery step. For this purpose, we built an miRNA score using an elastic net Cox regression model based on the disease-free survival status. Patients were grouped into high or low recurrence risk categories based on the median value of the score. We then validated these results in an independent sample of stage II microsatellite stable tumor tissues, with a hazard ratio of 3.24, (CI95% = 1.05-10.0) and a 10-year area under the receiver operating characteristic curve of 0.67. Functional analysis of the miRNAs present in the signature identified key pathways in cancer progression. In conclusion, the proposed signature of 12 miRNAs can contribute to improving the prediction of disease relapse in patients with stage II MSS colorectal cancer, and might be useful in deciding which patients may benefit from adjuvant chemotherapy.
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Affiliation(s)
- Ferran Moratalla-Navarro
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), 08908 Barcelona, Spain
- Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona (UB), 08907 Barcelona, Spain
| | - Anna Díez-Villanueva
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), 08908 Barcelona, Spain
- Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain
| | - Ainhoa Garcia-Serrano
- Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, 14186 Stockholm, Sweden
| | - Adrià Closa
- Department of Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - David Cordero
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), 08908 Barcelona, Spain
- Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain
| | - Xavier Solé
- Molecular Biology CORE, Center for Biomedical Diagnostics, Hospital Clinic de Barcelona, 08036 Barcelona, Spain
- Translational Genomic and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
| | - Elisabet Guinó
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), 08908 Barcelona, Spain
- Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain
| | - Rebeca Sanz-Pamplona
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), 08908 Barcelona, Spain
- Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
- Lozano Blesa University Hospital, Aragon Health Research Institute (IISA), Aragon I+D Foundation (ARAID), Government of Aragon, 50009 Zaragoza, Spain
| | - Xavier Sanjuan
- Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain
- Department of Pathology, Bellvitge University Hospital, 08907 Barcelona, Spain
| | - Cristina Santos
- Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain
- Oncology Service, Catalan Institute of Oncology (ICO), 08908 Barcelona, Spain
- Consortium for Biomedical Research in Oncology (CIBERONC), 28029 Madrid, Spain
| | - Sebastiano Biondo
- Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona (UB), 08907 Barcelona, Spain
- Department of General and Digestive Surgery, Bellvitge University Hospital, 08907 Barcelona, Spain
| | - Ramón Salazar
- Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona (UB), 08907 Barcelona, Spain
- Oncology Service, Catalan Institute of Oncology (ICO), 08908 Barcelona, Spain
- Consortium for Biomedical Research in Oncology (CIBERONC), 28029 Madrid, Spain
| | - Victor Moreno
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), 08908 Barcelona, Spain
- Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona (UB), 08907 Barcelona, Spain
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8
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Li F, Zhou C, Li S, Wang J, Li M, Mu H. Bioinformatic analysis of differentially expressed profiles of lncRNAs and miRNAs with their related ceRNA network in endometrial cancer. Medicine (Baltimore) 2023; 102:e32573. [PMID: 36701720 PMCID: PMC9857477 DOI: 10.1097/md.0000000000032573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Increasing evidence suggests that long non-coding riboneucleic acids (lncRNAs), as competing endogenous RNA (ceRNA), play a key role in the initiation, invasion, and metastasis of cancer. As a new hypothesis, the lncRNA-micro RNA (miRNA)-messenger RNA (mRNA), ceRNA regulatory network has been successfully constructed in a variety of cancers. However, lncRNA, which plays a ceRNA function in endometrial cancer (EC), is still poorly understood. In this study, we downloaded EC expression profiling from The Cancer Genome Atlas database and used the R software "edgeR" package to analyze the differentially expressed genes between EC and normal endometrium samples. Then, differentially expressed (DE) lncRNAs, miRNAs and mRNAs were selected to construct a lncRNA-miRNA-mRNA prognosis-related regulatory network based on interaction information. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed on the genes in the network to predict the potential underlying mechanisms and functions of lncRNAs in EC. Kaplan-Meier method and the log-rank test were used for survival analysis. Based on the "ceRNA hypothesis," we constructed a co-expression network of mRNA and lncRNA genes mediated by miRNA in the process of tumor genesis. Furthermore, we successfully constructed a dysregulated lncRNA-associated ceRNA network containing 96 DElncRNAs, 27 DEmiRNAs, and 74 DEmRNAs. Through Kaplan-Meier curve analysis, we found that 9 lncRNAs, 3 miRNAs, and 12 mRNAs were significantly correlated with the overall survival rate of patients among all lncRNAs, miRNAs, and mRNAs involved in ceRNA (P < .05). Our research provides a new perspective for the interaction among lncRNAs, miRNAs, and mRNA and lays the foundation for further research on the mechanism of lncRNAs in the occurrence of EC.
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Affiliation(s)
- Fengfan Li
- The First Central Clinical College of Tianjin Medical University, Tianjin, China
| | - Chunlei Zhou
- Department of Clinical Laboratory, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Shuxuan Li
- Department of Clinical Laboratory, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Jingyu Wang
- Department of Clinical Laboratory, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Ming Li
- Department of Gynecology, Peking University Second Hospital, Beijing, China
| | - Hong Mu
- Department of Clinical Laboratory, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
- * Correspondence: Hong Mu, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin 300190, China (e-mail: )
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Schmitz U. Overview of Computational and Experimental Methods to Identify Tissue-Specific MicroRNA Targets. Methods Mol Biol 2023; 2630:155-177. [PMID: 36689183 DOI: 10.1007/978-1-0716-2982-6_12] [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] [Indexed: 01/24/2023]
Abstract
As ubiquitous posttranscriptional regulators of gene expression, microRNAs (miRNAs) play key roles in cell physiology and function across taxa. In the last two decades, we have gained a good understanding about miRNA biogenesis pathways, modes of action, and consequences of miRNA-mediated gene regulation. More recently, research has focused on exploring causes for miRNA dysregulation, miRNA-mediated crosstalk between genes and signaling pathways, and the role of miRNAs in disease.This chapter discusses methods for the identification of miRNA-target interactions and causes for tissue-specific miRNA-target regulation. Computational approaches for predicting miRNA target sites and assessing tissue-specific target regulation are discussed. Moreover, there is an emphasis on features that affect miRNA target recognition and how high-throughput sequencing protocols can help in assessing miRNA-mediated gene regulation on a genome-wide scale. In addition, this chapter introduces some experimental approaches for the validation of miRNA targets as well as web-based resources sharing predicted and validated miRNA-target interactions.
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Affiliation(s)
- Ulf Schmitz
- Department of Molecular & Cell Biology, College of Public Health, Medical & Vet Sciences, James Cook University, Douglas, Australia.
- Centre for Tropical Bioinformatics and Molecular Biology, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
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10
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He XX, Luo SS, Qin HQ, Mo XW. MicroRNA-766-3p-mediated downregulation of HNF4G inhibits proliferation in colorectal cancer cells through the PI3K/AKT pathway. Cancer Gene Ther 2022; 29:803-813. [PMID: 34158627 DOI: 10.1038/s41417-021-00362-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 05/06/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023]
Abstract
Nuclear receptors (NRs) are a class of transcription factors that play a pivotal role in carcinogenesis, but their function in colorectal cancer (CRC) remains unclear. Here, we investigate the role NRs play in CRC pathogenesis. We found that hepatocyte nuclear factor 4 gamma (HNF4G; NR2A2), hepatocyte nuclear factor 4α (HNF4A; NR2A1), and retinoid-related orphan receptor γ (RORC; NR1F3) were significantly upregulated in CRC tissues analyzed by GEPIA bioinformatics tool. The expression of HNF4G was examined in CRC samples and cell lines by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry. Increased expression of HNF4G was strongly associated with high tumor-node-metastasis stage and poor prognosis. Moreover, overexpression of HNF4G significantly promoted the proliferation of CRC cells in vitro. Next, we found that HNF4G promoted CRC proliferation via the PI3K/AKT pathway through targeting of GNG12 and PTK2. In addition, HNF4G was verified as a direct target of microRNA-766-3p (miR-766-3p). miR-766-3p inhibited the proliferation of CRC cells by targeting HNF4G in vitro and in vivo. Collectively, our study indicates that miR-766-3p reduces the proliferation of CRC cells by targeting HNF4G expression and thus inhibits the PI3K/AKT pathway. Therefore, development of therapies which target the miR-766-3p/HNF4G axis may aid in the treatment of CRC.
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Affiliation(s)
- Xin-Xin He
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Colorectal Cancer Clinical Medical Research Center of Guangxi, Nanning, China
| | - Shan-Shan Luo
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Colorectal Cancer Clinical Medical Research Center of Guangxi, Nanning, China
| | - Hai-Quan Qin
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Colorectal Cancer Clinical Medical Research Center of Guangxi, Nanning, China
| | - Xian-Wei Mo
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Colorectal Cancer Clinical Medical Research Center of Guangxi, Nanning, China.
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11
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Nickel's Role in Pancreatic Ductal Adenocarcinoma: Potential Involvement of microRNAs. TOXICS 2022; 10:toxics10030148. [PMID: 35324773 PMCID: PMC8952337 DOI: 10.3390/toxics10030148] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 03/18/2022] [Accepted: 03/20/2022] [Indexed: 02/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types with a limited overall survival rate due to the asymptomatic progression of symptoms in metastatic stages of the malignancy and the lack of an early reliable diagnostic biomarker. MicroRNAs (miRs/miRNAs) are small (~18–24 nucleotides), endogenous, non-coding RNAs, which are closely linked to the development of numerous malignancies comprising PDAC. Recent studies have described the role of environmental pollutants such as nickel (Ni) in PDAC, but the mechanisms of Ni-mediated toxicity in cancer are still not completely understood. Specifically, Ni has been found to alter the expression and function of miRs in several malignancies, leading to changes in target gene expression. In this study, we found that levels of Ni were significantly higher in cancerous tissue, thus implicating Ni in pancreatic carcinogenesis. Hence, in vitro studies followed by using both normal and pancreatic tumor cell lines and increasing Ni concentration increased lethality. Comparing LC50 values, Ni-acetate groups demonstrated lower values needed than in NiCl2 groups, suggesting greater Ni-acetate. Panc-10.05 cell line appeared the most sensitive to Ni compounds. Exposure to Ni-acetate resulted in an increased phospho-AKT, and decreased FOXO1 expression in Panc-10.05 cells, while NiCl2 also increased PTEN expression in Panc-10.05 cells. Specifically, following NiCl2 exposure to PDAC cells, the expression levels of miR-221 and miR-155 were significantly upregulated, while the expression levels of miR-126 were significantly decreased. Hence, our study has suggested pilot insights to indicate that the environmental pollutant Ni plays an important role in the progression of PDAC by promoting an association between miRs and Ni exposure during PDAC pathogenesis.
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12
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Mortoglou M, Buha Djordjevic A, Djordjevic V, Collins H, York L, Mani K, Valle E, Wallace D, Uysal-Onganer P. Role of microRNAs in response to cadmium chloride in pancreatic ductal adenocarcinoma. Arch Toxicol 2022; 96:467-485. [PMID: 34905088 PMCID: PMC8837568 DOI: 10.1007/s00204-021-03196-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/10/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal and aggressive malignancies with a 5-year survival rate less than 9%. Early detection is particularly difficult due to the lack of symptoms even in advanced stages. microRNAs (miRs/miRNAs) are small (~ 18-24 nucleotides), endogenous, non-coding RNAs, which are involved in the pathogenesis of several malignancies including PDAC. Alterations of miR expressions can lead to apoptosis, angiogenesis, and metastasis. The role of environmental pollutants such as cadmium (Cd) in PDAC has been suggested but not fully understood. This study underlines the role of miRs (miR-221, miR-155, miR-126) in response to cadmium chloride (CdCl2) in vitro. Lethal concentration (LC50) values for CdCl2 resulted in a toxicity series of AsPC-1 > HPNE > BxPC-3 > Panc-1 = Panc-10.5. Following the treatment with CdCl2, miR-221 and miR-155 were significantly overexpressed, whereas miR-126 was downregulated. An increase in epithelial-mesenchymal transition (EMT) via the dysregulation of mesenchymal markers such as Wnt-11, E-cadherin, Snail, and Zeb1 was also observed. Hence, this study has provided evidence to suggest that the environmental pollutant Cd can have a significant role in the development of PDAC, suggesting a significant correlation between miRs and Cd exposure during PDAC progression. Further studies are needed to investigate the precise role of miRs in PDAC progression as well as the role of Cd and other environmental pollutants.
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Affiliation(s)
- Maria Mortoglou
- Cancer Research Group, School of Life Sciences, University of Westminster, London, W1W 6UW UK
| | | | | | - Hunter Collins
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - Lauren York
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - Katherine Mani
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - Elizabeth Valle
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - David Wallace
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - Pinar Uysal-Onganer
- Cancer Research Group, School of Life Sciences, University of Westminster, London, W1W 6UW UK
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Li B, Liu X, Wu G, Liu J, Cai S, Wang F, Yang C, Liu J. MicroRNA-934 facilitates cell proliferation, migration, invasion and angiogenesis in colorectal cancer by targeting B-cell translocation gene 2. Bioengineered 2021; 12:9507-9519. [PMID: 34699325 PMCID: PMC8809948 DOI: 10.1080/21655979.2021.1996505] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Colorectal cancer (CRC) is a global public health issue with increasing prevalence. MicroRNA-934 (miR-934) is a kind of non-coding RNA involved in the regulation of diverse cancers. Though previous researches have revealed part of association between miR-934 and CRC, the role of miR-934 in CRC pathogenesis has not been completely explored yet. In this study, we aim to investigate the effect of miR-934 on cell proliferation, migration, invasion and angiogenesis in CRC. Accordingly, miR-934 was found to be over-expressed in SW480 and HCT116 cells, two typical CRC cell lines. Meanwhile, miR-934 knockdown significantly inhibited cell proliferation and induced cell cycle arrest in SW480 and HCT116 cells. It was further validated that miR-934 knockdown displayed an inhibitory effect on cell migration and invasion in SW480 and HCT116 cells. Additionally, miR-934 deficiency markedly decreased VEGF expression in SW480 and HCT116 cells and suppressed capability of CRC cells to promote tube formation in vascular endothelial cells, which suggests the pro-angiogenesis role of miR-934 in vitro. Dual luciferase reporter assay further showed that miR-934 directly bound to B-cell translocation gene 2 (BTG2). BTG2 knockdown reversed the inhibitory effect of miR-934 silencing on cell proliferation, migration, invasion, and angiogenesis in SW480 and HCT116 cells. In summary, this study suggests that miR-934 facilitates CRC progression by targeting BTG2, and further highlights the role of miR-934 in pathogenesis of CRC.
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Affiliation(s)
- Bo Li
- Department of General Surgery, Ansteel Group General Hospital, Anshan, Liaoning, China
| | - Xianyi Liu
- Department of General Surgery, Ansteel Group General Hospital, Anshan, Liaoning, China
| | - Guogang Wu
- Department of General Surgery, Ansteel Group General Hospital, Anshan, Liaoning, China
| | - Jiawen Liu
- Department of General Surgery, Ansteel Group General Hospital, Anshan, Liaoning, China
| | - Shouliang Cai
- Department of General Surgery, Ansteel Group General Hospital, Anshan, Liaoning, China
| | - Fuxin Wang
- Department of General Surgery, Ansteel Group General Hospital, Anshan, Liaoning, China
| | - Chunyu Yang
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Jisheng Liu
- Department of General Surgery, Ansteel Group General Hospital, Anshan, Liaoning, China
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14
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Karimi MR, Karimi AH, Abolmaali S, Sadeghi M, Schmitz U. Prospects and challenges of cancer systems medicine: from genes to disease networks. Brief Bioinform 2021; 23:6361045. [PMID: 34471925 PMCID: PMC8769701 DOI: 10.1093/bib/bbab343] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/02/2021] [Accepted: 08/03/2021] [Indexed: 12/20/2022] Open
Abstract
It is becoming evident that holistic perspectives toward cancer are crucial in deciphering the overwhelming complexity of tumors. Single-layer analysis of genome-wide data has greatly contributed to our understanding of cellular systems and their perturbations. However, fundamental gaps in our knowledge persist and hamper the design of effective interventions. It is becoming more apparent than ever, that cancer should not only be viewed as a disease of the genome but as a disease of the cellular system. Integrative multilayer approaches are emerging as vigorous assets in our endeavors to achieve systemic views on cancer biology. Herein, we provide a comprehensive review of the approaches, methods and technologies that can serve to achieve systemic perspectives of cancer. We start with genome-wide single-layer approaches of omics analyses of cellular systems and move on to multilayer integrative approaches in which in-depth descriptions of proteogenomics and network-based data analysis are provided. Proteogenomics is a remarkable example of how the integration of multiple levels of information can reduce our blind spots and increase the accuracy and reliability of our interpretations and network-based data analysis is a major approach for data interpretation and a robust scaffold for data integration and modeling. Overall, this review aims to increase cross-field awareness of the approaches and challenges regarding the omics-based study of cancer and to facilitate the necessary shift toward holistic approaches.
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Affiliation(s)
| | | | | | - Mehdi Sadeghi
- Department of Cell & Molecular Biology, Semnan University, Semnan, Iran
| | - Ulf Schmitz
- Department of Molecular & Cell Biology, James Cook University, Townsville, QLD 4811, Australia
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15
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Luan XF, Wang L, Gai XF. The miR-28-5p-CAMTA2 axis regulates colon cancer progression via Wnt/β-catenin signaling. J Cell Biochem 2021; 122:945-957. [PMID: 31709644 DOI: 10.1002/jcb.29536] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 10/10/2019] [Indexed: 01/25/2023]
Abstract
BACKGROUND Colon cancer is the third most commonly diagnosed cancer with high morbidity and mortality. Calmodulin-binding transcription activator 2 (CAMTA2) belongs to the calmodulin-binding transcription activator protein family. The functional role of CAMTA2 in colon cancer development remains unclear. Our research found out that CAMTA2 was high-level expressed in colon cancer, and the upregulated CAMTA2 expression was markedly correlated with poor survival. Functional experiments showed that knockdown of CAMTA2 repressed colon cancer cell proliferation/migration in vitro and attenuated proliferation in vivo. In additional, CAMTA2 expression was controlled by miR-28-5p via posttranscriptional regulation and miR-28-5p expression was reversely correlated with CAMTA2 expression in colon cancer. Moreover, enforced miR-28-5p expression downregulated the expression of CAMTA2 significantly and the restoration of CAMTA2 expression abolished the inhibitory effect of miR-28-5p on colon cancer cell proliferation and metastasis. Mechanistically, overexpression of miR-28-5p suppressed Wnt/β-catenin signaling and the inhibitory could be partly abolished by overexpression of CAMTA2. In summary, our findings reveal that miR-28-5p/CAMTA2 axis plays a critical role in human colon cancer, which might be a promising diagnosis and therapeutic target for colon cancer treatment.
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Affiliation(s)
- Xiao-Feng Luan
- Department of General Surgery, Dalian Municipal Central Hospital, Dalian, China
| | - Lei Wang
- Department of General Surgery, Dalian Municipal Central Hospital, Dalian, China
| | - Xue-Feng Gai
- Department of General Surgery, Dalian Municipal Central Hospital, Dalian, China
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16
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Zhang ZB, Liu N. Long non-coding RNA KTN1-AS1 promotes progression in pancreatic cancer through regulating microRNA-23b-3p/high-mobility group box 2 axis. Aging (Albany NY) 2021; 13:20820-20835. [PMID: 34461605 PMCID: PMC8436926 DOI: 10.18632/aging.203481] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 07/30/2021] [Indexed: 12/11/2022]
Abstract
To explore the inhibitory effect of long non-coding RNA (LncRNA) antisense of KTN1 (KTN1-AS1) on the growth of pancreatic cancer (PC) cells by regulating the microRNA-23b-3p (miR-23b-3p)/high-mobility group box 2 (HMGB2) axis. The expression of KTN1-AS1 in tissues and cells was detected by qRT-PCR, and the relationship between KTN1-AS1 and clinicopathological data of patients with PC was analyzed. In addition, stable and transient overexpression and inhibition vectors were established and transfected into PC cells PANC-1, BxPC-3. CCK-8, transwell, and flow cytometry were responsible for the detection of proliferation, invasion, and apoptosis of transfected cells, respectively. The correlation of miR-23b-3p between KTN1-AS1 and HMGB2 was determined by dual luciferase reports, and the relationship between KTN1-AS1 and miR-23b-3p was further verified by RNA immunoprecipitation (RIP). The highly expressed KTN1-AS1 in PC patients was indicative of its high diagnostic value in this disease. Besides, it was found that KTN1-AS1 was linked with the pathological stage, differentiation degree and lymph node metastasis (LNM) of PC patients. Underexpressed KTN1-AS1 led to decreased proliferation and invasion ability of cells and increased apoptosis rate, while the effect of further overexpression of KTN1-AS1 on cells was the opposite. Dual luciferase reporter (DLR) assay confirmed that KTN1-AS1 could target miR-23b-3p, while miR-23b-3p could target HMGB2. Functional analysis showed that the overexpression of miR-23b-3p inhibited the expression of HMGB2 in PC cells and affected cell proliferation, invasion and apoptosis. Co-transfection of Sh-KTN1-AS1 and miR-23b-3p-mimics exhibited that up-regulation of KTN1-AS1 expression could reverse the effect of miR-23b-3p-mimics on PC cells.
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Affiliation(s)
- Zhong-Bo Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Ning Liu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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17
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Zhang L, Zou L, Sun P. Relationship between miR-378c and YY1 expression in patients with gastric cancer and the clinicopathological features. Cell Mol Biol Lett 2021; 26:12. [PMID: 33794762 PMCID: PMC8017737 DOI: 10.1186/s11658-021-00256-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 03/18/2021] [Indexed: 12/24/2022] Open
Abstract
Background The purpose of this study was to explore the clinical value of miR-378c and its target gene YY1 in gastric cancer. Methods The TCGA database was employed to analyse miR-378c expression in gastric cancer. qRT-PCR was applied to identify miR-378c and YY1 in tissues and serum of patients suffering from gastric cancer. The association of miR-378c with the clinical data of patients with gastric cancer was analysed. Receiver operating characteristics (ROC) curve analysis was used to determine the diagnostic value of miR-378c and YY1 in gastric cancer, and analyse the relationship between miR-378c and YY1 and patients’ survival. Pearson’s test was applied to determine the association between miR-378c and YY1 in tissue and serum of patients. Dual-Luciferase Reporter assay was employed to examine the targeting association between miR-378c and YY1. Finally, independent prognostic factors was determined in patients with gastric cancer using Cox regression analysis. Results In the TCGA database, miR-378c was weakly expressed in gastric cancer. Overall, patients with low expression had a lower survival rate. The expression of miR-378c decreased and the expression of YY1 increased in cancer tissues and serum of tumour patients. In patients with low expression of miR-378c the tumour size was ≥ 5 cm. Low differentiation, high TNM staging and lymph node invasion rate increased significantly, but the 5-year survival rate decreased in the patients. miR-378c and YY1 had better diagnostic value in gastric cancer. TargetScan, miRDB, starBase and miRTarBase predicted that YY1 was a potential gene of miR-378c, and the Dual-Luciferase Reporter assay revealed that there was a targeting relationship between the two, which was proved by correlation analysis. Multivariate Cox analysis revealed that differentiation, TNM staging and miR-378c were independent prognostic factors for patients. Conclusions MiR-378c is weakly expressed in gastric cancer patients and may be considered as a promising diagnostic and prognostic indicator for gastric cancer.
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Affiliation(s)
- Lei Zhang
- Department of Gastroenterology, Zibo Central Hospital, No. 54 Gongqingtuan West Road, Zhangdian District, Zibo, 255000, Shandong, China
| | - Lei Zou
- Department of Gastroenterology, Zibo Central Hospital, No. 54 Gongqingtuan West Road, Zhangdian District, Zibo, 255000, Shandong, China
| | - Peng Sun
- Department of Gastroenterology, Zibo Central Hospital, No. 54 Gongqingtuan West Road, Zhangdian District, Zibo, 255000, Shandong, China.
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18
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Grady WM. Epigenetic alterations in the gastrointestinal tract: Current and emerging use for biomarkers of cancer. Adv Cancer Res 2021; 151:425-468. [PMID: 34148620 DOI: 10.1016/bs.acr.2021.02.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is a leading cause of cancer related deaths worldwide. One of the hallmarks of cancer and a fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological process of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the initiation and progression of cancers, including colorectal cancer. Epigenetic alterations, which include changes affecting DNA methylation, histone modifications, chromatin structure, and noncoding RNA expression, have emerged as a major class of molecular alteration in colon polyps and colorectal cancer. The classes of epigenetic alterations, their status in colorectal polyps and cancer, their effects on neoplasm biology, and their application to clinical care will be discussed.
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Affiliation(s)
- William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA, United States.
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.
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20
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The Outer Retinal Membrane Protein 1 Could Inhibit Lung Cancer Progression as a Tumor Suppressor. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2021; 2021:6651764. [PMID: 33680068 PMCID: PMC7904357 DOI: 10.1155/2021/6651764] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/29/2021] [Accepted: 02/06/2021] [Indexed: 12/25/2022]
Abstract
Some related reports indicate that the outer retinal membrane protein 1 (ROM1) functions importantly in the regulation of the biological process of tumor. Nevertheless, studies towards the role of ROM1 in lung cancer are few. Here, our data demonstrated that ROM1 displayed a relation with lung cancer tumorigenesis and development. In the Tumor Genome Atlas (TCGA) cohort, reduced ROM1 level was observed in lung cancer tissues, instead of normal tissues. After bioinformatics analysis, the data revealed that ROM1 level was associated with the tumor stage. Additional results indicated that highly expressed ROM1 exhibited a positive correlation with the overall survival rate, and ROM1 was probably a promising prognostic biomarker of lung cancer. Additionally, our results indicated that knocking out ROM1 could promote cell proliferation, migration, and invasion. Our data conclusively demonstrated that ROM1 modulated lung cancer tumorigenesis and development, as a prognosis and treatment biomarker.
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21
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Ge JN, Yan D, Ge CL, Wei MJ. LncRNA C9orf139 can regulate the growth of pancreatic cancer by mediating the miR-663a/Sox12 axis. World J Gastrointest Oncol 2020; 12:1272-1287. [PMID: 33250960 PMCID: PMC7667452 DOI: 10.4251/wjgo.v12.i11.1272] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 09/24/2020] [Accepted: 10/12/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Recent studies have proved the important role of many oncogenic long non-coding RNAs (lncRNAs) in the progression of pancreatic cancer, but little is known about the mechanisms of tumor suppression in pancreatic cancer. AIM To evaluate the function of tumor suppressor lncRNA C9orf139 in pancreatic cancer progression and to study the underlying mechanism. METHODS We assigned 54 patients with pancreatic ductal adenocarcinoma treated at our hospital to the patient group and 30 normal subjects undergoing physical examination to the control group. RT-qPCR was used to measure the relative expression of C9orf139 in the tissue and serum of patients, in an attempt to investigate the prognostic value of C9orf139 in pancreatic cancer patients. The luciferase reporter gene assay was performed to determine the interaction between C9orf139 and miR-663a. The biological function of C9orf139 was assessed by in vitro assays and in vivo subcutaneous tumor formation tests in animal models. To figure out the molecular mechanism of C9orf139 to act on miR-663a/Sox12, RNA pull-down, Western blot assay, RNA immunoprecipitation assay, and co-immunoprecipitation assay were performed. RESULTS C9orf139 level significantly increased in the tissue and serum of patients, which had clinical diagnostic value for pancreatic cancer. Patients with high C9orf139 expression had a higher risk of progressing to stage III + IV, lymph node metastasis, and poor differentiation. Cox regression analysis suggested that C9orf139, tumor-node-metastasis stage, and lymph node metastasis were independent prognostic factors in patients. The underlying mechanism of C9orf139 was that it promoted the growth of pancreatic cancer cells by modulating the miR-663a/Sox12 axis. CONCLUSION C9orf139 is highly expressed in pancreatic cancer, qualified to be used as a potential diagnostic and prognostic marker for pancreatic cancer. Its promotion of pancreatic cancer cell growth is achieved by mediating the miR-663a/Sox12 axis.
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Affiliation(s)
- Jin-Nian Ge
- Department of General Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Di Yan
- Intensive Care Unit, The Central Affiliated Hospital of Shenyang Medical College, Shenyang 110024, Liaoning Province, China
| | - Chun-Lin Ge
- Department of General Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Min-Jie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, Liaoning Province, China
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22
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Sur D, Burz C, Sabarimurugan S, Irimie A. Diagnostic and Prognostic Significance of MiR-150 in Colorectal Cancer: A Systematic Review and Meta-Analysis. J Pers Med 2020; 10:99. [PMID: 32847098 PMCID: PMC7563128 DOI: 10.3390/jpm10030099] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/21/2020] [Accepted: 08/22/2020] [Indexed: 12/11/2022] Open
Abstract
Although treatment options have improved, the survival and quality of life of colorectal cancer (CRC) patients remain dismal. Therefore, significant biomarker prediction may help to improve colorectal cancer patient's prognosis profile. MiRNAs have come as an option because of their essential role in cancer initiation and progression by regulating several molecular processes. MiR-150 has different roles in cancer, but its function in CRC is still ambiguous. We undertook a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) research criteria by interrogating several databases in order to assess the diagnostic accuracy and prognostic value of miR-150. Additionally, clinicalgov.org was scanned for possible trials. The literature was screened from inception to February 2020. A total of 12 out of 70 full-text articles were included in the meta-analysis. Among these, nine studies were included for diagnostic accuracy, and the remaining three were considered for prognostic significance of miR-150. With our results, miR-150 is an appropriate diagnostic biomarker, especially in serum and plasma, while the prognostic value of miR-150 was not statistically significant. The present study findings suggest that miR-150 has high specificity and sensitivity values as a potential diagnostic biomarker in colorectal cancer patients.
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Affiliation(s)
- Daniel Sur
- 11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania;
| | - Claudia Burz
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania;
- Department of Immunology and Allergology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400162 Cluj-Napoca, Romania
| | - Shanthi Sabarimurugan
- School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Nedlands, WA 6009, Australia;
| | - Alexandru Irimie
- 11th Department of Oncological Surgery and Gynecological Oncology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania;
- Department of Surgery, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania
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Xue Y, Zhong Y, Wu T, Sheng Y, Dai Y, Xu L, Bao C. Anti-Proliferative and Apoptosis-Promoting Effect of microRNA-125b on Pancreatic Cancer by Targeting NEDD9 via PI3K/AKT Signaling. Cancer Manag Res 2020; 12:7363-7373. [PMID: 32903925 PMCID: PMC7445537 DOI: 10.2147/cmar.s227315] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 01/28/2020] [Indexed: 12/22/2022] Open
Abstract
PURPOSE The expression of microRNA-125b (miR-125b) is low in a variety of cancers, including gastric, lung, bladder, thyroid, and esophageal cancers. However, its specific mechanism in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study is aimed to explore the role of miR-125b in PDAC. METHODS PDAC tissues and adjacent tissues were collected for miR-125b analysis by qRT-PCR. Different PDAC cell lines were cultured for miR-125b detection by qRT-PCR, and CAPAN1 cells were selected for the downstream experiments. Cell proliferation was characterized by methyl thiazolyl tetrazolium (MTT) and 5-bromo-2-deoxyUridine (BrdU) staining. Flow cytometry was utilized for apoptosis and cell cycle changes. Cell invasion was determined by the Transwell assay and the dual-luciferase assay was utilized for validating the target gene. Western blotting was used to detect apoptosis related and PI3K/AKT signaling proteins. RESULTS miR-125b was significantly down-regulated in human PDAC tissues and cell lines (P < 0.05). miR-125b inhibited the growth and invasion of CAPAN1 cells, facilitated apoptosis, and blocked the cell cycle at the G0/G1 phase. Furthermore, miR-125 directly targeted NEDD9. The high expression of NEDD9 impaired the anti-proliferative and anti-apoptotic activity of miR-125b. miR-125b also inhibited apoptosis-related proteins and PI3K/AKT signaling pathways via NEDD9. CONCLUSION miR-125b decreased cell growth and invasion, and facilitated apoptosis in CAPAN1 cells through PI3K/AKT inhibition via targeting NEDD9.
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Affiliation(s)
- Yuzheng Xue
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi214041, Jiangsu, People’s Republic of China
| | - Yao Zhong
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi214041, Jiangsu, People’s Republic of China
| | - Tielong Wu
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi214041, Jiangsu, People’s Republic of China
| | - Yingyue Sheng
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi214041, Jiangsu, People’s Republic of China
| | - Yuanyuan Dai
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi214041, Jiangsu, People’s Republic of China
| | - Lingling Xu
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi214041, Jiangsu, People’s Republic of China
| | - Chuanqing Bao
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi214041, Jiangsu, People’s Republic of China
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Zong S, Zhao J, Liu L. miR-30d Induced Apoptosis by Targeting Sox4 to Inhibit the Proliferation, Invasion and Migration of Nephroblastoma. Onco Targets Ther 2020; 13:7177-7188. [PMID: 32821117 PMCID: PMC7419636 DOI: 10.2147/ott.s251714] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 05/15/2020] [Indexed: 01/10/2023] Open
Abstract
Background Wilms tumor (WT) is an embryonic malignant tumor, and its related mechanism is still unclear. microRNA (miR), as a short-chain non-coding RNA, has low expression in various tumors. In this study, WT differential miR was screened by multi-chip in GEO database and its mechanism was explored to provide potential therapeutic targets and ideas for clinic. Methods We logged into GEO database and downloaded GSE57370 and GSE48137 chip matrix files to analyze potential differences in miR. TargetScan, miRDB, miRTarBase and starBase were applied to predict the target genes of miR with significant differences. qRT-PCR was applied to determine the expression of miR-30d and Sox4 in WT tissue and cell line (G401). The interaction of miR-30d with Sox4 was confirmed by qRT-PCR, Western blot and luciferase assay, respectively. CCK-8, Transwell and flow cytometry were applied to determine the proliferation, invasion, migration and apoptosis of cells. Results We found that miR-30d was low expressed in two chips. qRT-PCR showed that miR-30d was down-regulated and SOX4 was up-regulated in WT tissues and cells. The online target gene prediction software showed there was a targeted binding site between Sox4 and miR-30d. Sox4 was negatively controlled by miR-30d. Subsequent studies found that over-expression of miR-30d inhibited the proliferation, invasion, migration and induced apoptosis of C64 and WiT49 cells. In addition, Sox4 could reverse the proliferation, invasion and migration of C64 and WiT49 induced by miR-30d and induce apoptosis. Conclusion miR-30d is poorly expressed in WT and can induce apoptosis and inhibit proliferation, invasion and migration by mediating Sox4.
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Affiliation(s)
- Shi Zong
- Department of Urology Surgery, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, People's Republic of China
| | - Jia Zhao
- Department of Anesthesia, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, People's Republic of China
| | - Ling Liu
- Department of Pediatrics, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, People's Republic of China
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Wang X, Liu S, Shao Z, Zhang P. Bioinformatic analysis of the potential molecular mechanism of PAK7 expression in glioblastoma. Mol Med Rep 2020; 22:1362-1372. [PMID: 32626960 PMCID: PMC7339666 DOI: 10.3892/mmr.2020.11206] [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: 08/21/2018] [Accepted: 11/08/2019] [Indexed: 01/01/2023] Open
Abstract
The present study aimed to determine the potential molecular mechanisms underlying p21 (RAC1)-activated kinase 7 (PAK7) expression in glioblastoma (GBM) and evaluate candidate prognosis biomarkers for GBM. Gene expression data from patients with GBM, including 144 tumor samples and 5 normal brain samples, were downloaded. Long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) were explored via re-annotation. The differentially expressed genes (DEGs), including differentially expressed mRNAs and differentially expressed lncRNAs, were investigated and subjected to pathway analysis via gene set enrichment analysis. The miRNA-lncRNA-mRNA interaction [competing endogenous RNA (ceRNA)] network was investigated and survival analysis, including of overall survival (OS), was performed on lncRNAs/mRNAs to reveal prognostic markers for GBM. A total of 954 upregulated and 1,234 downregulated DEGs were investigated between GBM samples and control samples. These DEGs, including PAK7, were mainly enriched in pathways such as axon guidance. ceRNA network analysis revealed several outstanding ceRNA relationships, including miR-185-5p-LINC00599-PAK7. Moreover, paraneoplastic antigen Ma family member 5 (PNMA5) and somatostatin receptor 1 (SSTR1) were the two outstanding prognostic genes associated with OS. PAK7 may participate in the tumorigenesis of GBM by regulating axon guidance, and miR-185-5p may play an important role in GBM progression by sponging LINC00599 to prevent interactions with PAK7. PNMA5 and SSTR1 may serve as novel prognostic markers for GBM.
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Affiliation(s)
- Xuefeng Wang
- Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Shuang Liu
- Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Zhengkai Shao
- Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Penghai Zhang
- Department of Neurosurgery, Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150030, P.R. China
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Chen C, Huang Z, Mo X, Song Y, Li X, Li X, Zhang M. The circular RNA 001971/miR-29c-3p axis modulates colorectal cancer growth, metastasis, and angiogenesis through VEGFA. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:91. [PMID: 32430042 PMCID: PMC7236474 DOI: 10.1186/s13046-020-01594-y] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 05/08/2020] [Indexed: 02/06/2023]
Abstract
Background Colorectal cancer (CRC) is one of the most common malignant tumors globally. Angiogenesis is a key event maintaining tumor cell survival and aggressiveness. The expression of vascular endothelial growth factor A (VEGFA), one of the most significant tumor cell-secreted proangiogenic factors, is frequently upregulated in CRC. Methods The MTT assay was used to detect the viability of CRC cells. Transwell assays were performed to detect the invasion capacity of target cells. Relative protein levels were determined by immunoblotting. Pathological characteristics of tissues were detected by H&E staining and immunohistochemical (IHC) staining. A RIP assay was conducted to validate the predicted binding between genes. Results We observed that circ-001971 expression was dramatically increased in CRC tissue samples and cells. Circ-001971 knockdown suppressed the capacity of CRC cells to proliferate and invade and HUVEC tube formation in vitro, as well as tumor growth in mice bearing SW620 cell-derived tumors in vivo. The expression of circ-001971 and VEGFA was dramatically increased whereas the expression of miR-29c-3p was reduced in tumor tissue samples. Circ-001971 relieved miR-29c-3p-induced inhibition of VEGFA by acting as a ceRNA, thereby aggravating the proliferation, invasion and angiogenesis of CRC. Consistent with the above findings, the expression of VEGFA was increased, whereas the expression of miR-29c-3p was decreased in tumor tissue samples. miR-29c-3p had a negative correlation with both circ-001971 and VEGFA, while circ-001971 was positively correlated with VEGFA. Conclusions In conclusion, the circ-001971/miR-29c-3p axis modulated CRC cell proliferation, invasion, and angiogenesis by targeting VEGFA.
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Affiliation(s)
- Chen Chen
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Zhiguo Huang
- Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Xiaoye Mo
- Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Yanmin Song
- Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Xiangmin Li
- Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Xiaogang Li
- Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Mu Zhang
- Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
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Luan C, Li Y, Liu Z, Zhao C. Long Noncoding RNA MALAT1 Promotes the Development of Colon Cancer by Regulating miR-101-3p/STC1 Axis. Onco Targets Ther 2020; 13:3653-3665. [PMID: 32431516 PMCID: PMC7200234 DOI: 10.2147/ott.s242300] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 04/08/2020] [Indexed: 12/24/2022] Open
Abstract
Purpose Colon cancer (CC) is a leading cause of cancer-related deaths worldwide. This study aimed to clarify the effect of long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on CC progression and the potential mechanism. Methods CC cell lines HCT116 and HT29 were selected for functional analysis. The expression of MALAT1, microRNA (miR)-101-3p, and stanniocalcin 1 (STC1) in CC tissues and cells were measured by quantitative reverse transcription PCR (qRT-PCR). Cell proliferation, apoptosis, migration and invasion were measured by Cell Counting Kit-8 (CCK-8), flow cytometry, wound scratch and transwell assay, respectively. The target relationships (MALAT1 and miR-101-3p, miR-101-3p and STC1) were validated by dual-luciferase reporter and RNA pull-down assay. Results The expression of MALAT1 was elevated in CC tissues compared with adjacent normal tissues and was associated with lymph node metastasis, depth of invasion and tumor-node-metastasis (TNM) stage. Up-regulation of MALAT1 promoted the proliferation, migration, and invasion and inhibited the apoptosis of CC cells; while MALAT1 knockdown exhibited opposite results. MiR-101-3p was a target of MALAT1, which was negatively regulated by MALAT1. Silencing of miR-101-3p reverses the anti-tumor effect of MALAT1 knockdown on CC cells. STC1 was a target of miR-101-3p, which was negatively regulated by miR-101-3p. Silencing of STC1 reverses the tumor promoting effects of MALAT1 up-regulation and miR-101-3p down-regulation on CC cells. Conclusion MALAT1 may function as an oncogene in CC progression by affecting the miR-101-3p/STC1 axis, providing a hopeful therapeutic option for CC.
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Affiliation(s)
- Chunyan Luan
- Department of Gastroenterology, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, People's Republic of China
| | - Yongzhu Li
- Department of Gastroenterology, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, People's Republic of China
| | - Zhigang Liu
- Department of Cardiology, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, People's Republic of China
| | - Cunxin Zhao
- Department of Gastroenterology, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, People's Republic of China
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Li P, Cai JX, Han F, Wang J, Zhou JJ, Shen KW, Wang LH. Expression and significance of miR-654-5p and miR-376b-3p in patients with colon cancer. World J Gastrointest Oncol 2020; 12:492-502. [PMID: 32368326 PMCID: PMC7191333 DOI: 10.4251/wjgo.v12.i4.492] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 02/05/2020] [Accepted: 03/12/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The relationship between microRNAs, such as miR-654-5p and miR-376b-3p, and the prognosis of colon cancer has not been studied until now.
AIM To evaluate the expression levels of miR-654-5p and miR-376b-3p and their clinical significance in colon cancer.
METHODS RT-qPCR was performed to evaluate miR-654-5p and miR-376b-3p expression in 34 pairs of colon cancer and adjacent noncancerous tissues. Subsequently, the association of miR-654-5p and miR-376b-3p expression with clinical factors or the survival of patients suffering from colon cancer was determined by using The Cancer Genome Atlas.
RESULTS miR-654-5p was upregulated and miR-376b-3p was downregulated in colon cancer tissues compared with adjacent noncancerous tissues (P < 0.001). Increased miR-654-5p and decreased miR-376b-3p expression levels were significantly associated with metastasis and clinical stage. Moreover, a univariate analysis demonstrated that colon cancer patients with high miR-654-5p or low miR-376b-3p expression (P = 0.044 and 0.007, respectively) had a poor overall survival rate. A multivariate analysis identified high miR-654-5p expression and low miR-376b-3p expression as independent predictors of poor survival in colon cancer patients.
CONCLUSION Upregulated miR-654-5p and downregulated miR-376b-3p may be associated with tumour progression in colon cancer, and these microRNAs may serve as independent prognostic markers for colon cancer.
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Affiliation(s)
- Ping Li
- Department of Central Laboratory, Huaian Tumor Hospital & Huaian Hospital of Huaian City, Huaian 223200, Jiangsu Province, China
- Department of General Surgery, Huaian Tumor Hospital & Huaian Hospital of Huaian City, Huaian 223200, Jiangsu Province, China
| | - Jia-Xun Cai
- Department of Anorectal, Clinical Medical College of Yangzhou University and Northern Jiangsu People’s Hospital, Yangzhou 225001, Jiangsu Province, China
| | - Fei Han
- Clinical Medical College, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
| | - Jie Wang
- Clinical Medical College, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
| | - Jia-Jie Zhou
- Clinical Medical College, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
| | - Kai-Wen Shen
- Clinical Medical College, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
| | - Liu-Hua Wang
- Department of General Surgery, General Surgery Institute of Yangzhou, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225001, Jiangsu Province, China
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Dai R, Zhou Y, Chen Z, Zou Z, Liu P, Gao X. The analysis of a ceRNA network and the correlation between lncRNA, miRNA, and mRNA in bladder cancer. Transl Cancer Res 2020; 9:869-881. [PMID: 35117432 PMCID: PMC8797384 DOI: 10.21037/tcr.2019.12.27] [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: 07/08/2019] [Accepted: 11/29/2019] [Indexed: 01/08/2023]
Abstract
Background To explore the correlation between the lncRNA-miRNA-mRNA and ceRNA network through the differential expression analysis of lncRNAs, miRNAs and mRNAs in bladder cancer based on The Cancer Genome Atlas (TCGA) database combined with Gene Ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) enrichment analysis. Methods Firstly, the expression profile data and corresponding clinical data of RNAs in bladder cancer were searched and downloaded from TCGA database, and aberrantly expressed long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) were screened and found by using TCGA database. The relationship between lncRNA-miRNA-mRNA was established by comparing these lncRNAs, miRNAs, and mRNAs, while the ceRNA network was constructed. Combined with the analysis of the GO annotation and KEGG pathway, the effects of lncRNA-miRNA-mRNA interaction on the development of bladder cancer were explored. Results A total of 1,742 differentially expressed lncRNA, 511 differentially expressed miRNAs, and 4,373 differentially expressed mRNAs were identified, and 328 lncRNAs, 73 miRNAs, and 677 mRNAs were screened by survival analysis. With the lncRNA-miRNA-mRNA correlation analysis, a ceRNA network consisting of 45 lncRNAs, 14 miRNAs, and 29 mRNAs was successfully constructed. The GO annotation and functional enrichment of target gene mRNAs in the network are mainly concentrated in the signal pathways and include fatty acid biosynthesis, gap junction, insulin signaling pathway, and the MAPK signaling pathway biological processes such as positive regulation of cellular process and system development. Conclusions We successfully identified the target gene correlating lncRNA, miRNA, and mRNA, and constructed a ceRNA network. Our findings can provide a potential target for the study of the occurrence, development, diagnosis, treatment, and prognosis of bladder cancer.
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Affiliation(s)
- Ranran Dai
- Department of Urology Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - You Zhou
- Department of Urology Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Zhishan Chen
- Department of Urology Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Zihao Zou
- Department of Urology Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Ping Liu
- Department of Urology Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Xingcheng Gao
- Department of Urology Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
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Yuan L, Bing Z, Yan P, Li R, Wang C, Sun X, Yang J, Shi X, Zhang Y, Yang K. Integrative data mining and meta-analysis to investigate the prognostic role of microRNA-200 family in various human malignant neoplasms: A consideration on heterogeneity. Gene 2019; 716:144025. [DOI: 10.1016/j.gene.2019.144025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 07/26/2019] [Accepted: 07/29/2019] [Indexed: 12/15/2022]
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Amirkhah R, Naderi-Meshkin H, Shah JS, Dunne PD, Schmitz U. The Intricate Interplay between Epigenetic Events, Alternative Splicing and Noncoding RNA Deregulation in Colorectal Cancer. Cells 2019; 8:cells8080929. [PMID: 31430887 PMCID: PMC6721676 DOI: 10.3390/cells8080929] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 08/16/2019] [Accepted: 08/16/2019] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) results from a transformation of colonic epithelial cells into adenocarcinoma cells due to genetic and epigenetic instabilities, alongside remodelling of the surrounding stromal tumour microenvironment. Epithelial-specific epigenetic variations escorting this process include chromatin remodelling, histone modifications and aberrant DNA methylation, which influence gene expression, alternative splicing and function of non-coding RNA. In this review, we first highlight epigenetic modulators, modifiers and mediators in CRC, then we elaborate on causes and consequences of epigenetic alterations in CRC pathogenesis alongside an appraisal of the complex feedback mechanisms realized through alternative splicing and non-coding RNA regulation. An emphasis in our review is put on how this intricate network of epigenetic and post-transcriptional gene regulation evolves during the initiation, progression and metastasis formation in CRC.
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Affiliation(s)
- Raheleh Amirkhah
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7AE, UK
- Nastaran Center for Cancer Prevention (NCCP), Mashhad 9185765476, Iran
| | - Hojjat Naderi-Meshkin
- Nastaran Center for Cancer Prevention (NCCP), Mashhad 9185765476, Iran
- Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture Research (ACECR), Khorasan Razavi Branch, Mashhad 9177949367, Iran
| | - Jaynish S Shah
- Gene & Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia
- Sydney Medical School, The University of Sydney, Camperdown, NSW 2050, Australia
| | - Philip D Dunne
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7AE, UK
| | - Ulf Schmitz
- Gene & Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia.
- Sydney Medical School, The University of Sydney, Camperdown, NSW 2050, Australia.
- Computational BioMedicine Laboratory Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia.
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Meng L, Yang H, Jin C, Quan S. miR‑28‑5p suppresses cell proliferation and weakens the progression of polycystic ovary syndrome by targeting prokineticin‑1. Mol Med Rep 2019; 20:2468-2475. [PMID: 31322191 DOI: 10.3892/mmr.2019.10446] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Accepted: 04/30/2019] [Indexed: 11/05/2022] Open
Abstract
Prokineticin‑1 (PROK1) serves important roles in the pathogenesis of polycystic ovary syndrome (PCOS); however, the association between microRNA (miR)‑28‑5p and PROK1 remains unclear. In the present study, the roles of miR‑28‑5p and PROK1, and their interaction in PCOS were investigated. Rat ovary granule cells were transfected with miR‑28‑5p mimics, and PROK1 expression levels were measured by reverse transcription‑quantitative PCR and western blotting. A dual‑luciferase reporter assay was performed to determine the association between miR‑28‑5p and PROK1. Additionally, pcDNA‑PROK1 was co‑transfected into rat ovary granule cells with miR‑28‑5p mimics. Cell proliferation, apoptosis, cell cycle and the expression of signaling proteins were investigated using Cell Counting Kit‑8 assays, 5‑ethynyl‑2'‑deoxyuridine staining, flow cytometry and western blotting, respectively. PROK1 expression was suppressed in rat ovary granule cells by miR‑28‑5p mimics, but upregulated following transfection with miR‑28‑5p inhibitors. The dual‑luciferase reporter assay revealed that miR‑28‑5p binds to the 3'‑untranslated region of PROK1. Proliferation activity was increased in PROK1‑overexpressing cells; this effect was eliminated by co‑transfection with miR‑28‑5p mimics. PROK1‑overexpressing rat ovary granule cells exhibited significantly suppressed cell apoptosis and a decreased number of cells in G1; miR‑28‑5p mimics reversed these effects. Western blotting revealed that the PI3K/AKT/mTOR signaling pathway was activated by PROK1. The present results suggested that miR‑28‑5p attenuated the progression of PCOS by targeting PROK1, which may promote the pathogenesis of PCOS via the PI3K/AKT/mTOR pathway, indicating that the miR‑28‑5p/PROK1 axis may be a potential therapeutic target for patients with PCOS.
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Affiliation(s)
- Lyuhe Meng
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, P.R. China
| | - Haiyan Yang
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Congcong Jin
- Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Song Quan
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, P.R. China
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Wang H, Ma Y, Lin Y, Liu J, Chen R, Xu B, Liang Y. An Isoxazole Derivative SHU00238 Suppresses Colorectal Cancer Growth through miRNAs Regulation. Molecules 2019; 24:molecules24122335. [PMID: 31242597 PMCID: PMC6630644 DOI: 10.3390/molecules24122335] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 06/22/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Isoxazoline and isoxazole derivatives represent an important class of five-membered heterocycles, which play a pivotal role in drug discovery. In our previous study, we developed a series of isoxazole derivatives with an efficient method. In this study, we evaluated their effects on tumor cell growth. HCT116 cells were treated with isoxazole derivatives; an cholecystokinin octapeptide (CCK-8) assay was used to calculate the IC50 (half maximal inhibitory concentration) of each derivative. Compound SHU00238, which was obtained by the copper nitrate-mediated [2+2+1] cycloaddition reaction of olefinic azlactone with naphthalene-1,4-dione, has a lower IC50; we analyzed its inhibitory activity in further assays. Cell apoptosis was estimated by flow cytometry analysis in vitro. SHU00238 injection was used to treat tumor-bearing mice. We found that SHU00238 suppressed cell viability and promoted cell apoptosis in vitro. SHU00238 treatment significantly inhibited colonic tumor growth in vivo. Furthermore, we compared the miRNAs expression changes in HCT116 cells before and after SHU00238 treatment. MiRNA profiling revealed that SHU00238 treatment affected cell fate by regulating a set of miRNAs. In conclusion, SHU00238 impedes CRC tumor cell proliferation and promotes cell apoptosis by miRNAs regulation.
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Affiliation(s)
- Haoyu Wang
- Department of Chemistry, Qianweichang College, Shanghai University, Shanghai 200444, China.
- School of Life Science, Shanghai University, Shanghai 200444, China.
| | - Yurui Ma
- School of Life Science, Shanghai University, Shanghai 200444, China.
| | - Yifan Lin
- Department of Chemistry, Qianweichang College, Shanghai University, Shanghai 200444, China.
| | - Jiajie Liu
- Department of Chemistry, Qianweichang College, Shanghai University, Shanghai 200444, China.
| | - Rui Chen
- School of Life Science, Shanghai University, Shanghai 200444, China.
| | - Bin Xu
- Department of Chemistry, Qianweichang College, Shanghai University, Shanghai 200444, China.
- Innovative Drug Research Center, Shanghai University, Shanghai 200444, China.
| | - Yajun Liang
- School of Life Science, Shanghai University, Shanghai 200444, China.
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Liang F, Fu X, Wang L. miR-5590-3p-YY1 feedback loop promotes the proliferation and migration of triple-negative breast cancer cells. J Cell Biochem 2019; 120:18415-18424. [PMID: 31190375 DOI: 10.1002/jcb.29158] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 05/17/2019] [Accepted: 05/23/2019] [Indexed: 01/13/2023]
Abstract
Lacking of diagnostic and prognostic biomarkers is a significant reason for the poor prognosis of patients with triple-negative breast cancer (TNBC). MicroRNAs (miRNAs) have been discovered to engage in the tumorigenesis and development of TNBC. miR-5590-3p has been found to be involved in the development of gastric cancer, but its role and underlying mechanism in TNBC remain obscure. In this study, it was discovered that miR-5590-3p was downregulated in TNBC tissues and cells. Function assays confirmed that miR-5590-3p overexpression inhibited cell proliferation, migration, and epithelial-mesenchymal transition (EMT) process as well as promoted cell apoptosis in TNBC. Moreover, YY1 could bind with the promoter of miR-5590-3p and overexpression of YY1 inhibited the transcription of miR-5590-3p. It was found that YY1 acted as a downstream target gene to bind with miR-5590-3p and was negatively regulated by miR-5590-3p. Finally, it was discovered that overexpression of YY1 could partially rescue the miR-5590-3p overexpression-mediated inhibitive effect on TNBC progression. Taken together these results, it can be concluded that miR-5590-3p-YY1 feedback loop promoted the proliferation and migration of TNBC.
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Affiliation(s)
- Feng Liang
- Department of Anaesthesia, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
| | - Xin Fu
- Department of Anaesthesia, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
| | - Linlin Wang
- Department of Ultrasonography, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
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35
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Long S, Li G. Comprehensive analysis of a long non-coding RNA-mediated competitive endogenous RNA network in glioblastoma multiforme. Exp Ther Med 2019; 18:1081-1090. [PMID: 31316603 PMCID: PMC6601370 DOI: 10.3892/etm.2019.7647] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 05/02/2019] [Indexed: 12/29/2022] Open
Abstract
The present bioinformatics study focused on glioblastoma multiforme (GBM; grade IV glioma), a common and aggressive type of primary malignant brain tumor in adults. Long non-coding RNAs (lncRNAs) function as competing endogenous RNAs (ceRNA) to regulate gene expression by interacting with microRNAs (miRNAs) in cancer. These mechanisms and phenomenon are always present but they may be deregulated or activated in cancer. In the present study, a computational method was applied to construct lncRNA-mediated ceRNA networks by integrating lncRNA and mRNA expression profiles and miRNA-mediated interactions, and functional Gene Ontology (GO) and pathway analyses were performed. From the ceRNA network, a total of 7 miRNAs, 159 lncRNAs and 31 mRNAs were obtained that were differentially expressed between GBM and adjacent tissue groups. Through survival analysis based on these RNAs from the ceRNA network, 2 mRNAs and 14 lncRNAs that had a significant impact on the survival of GBM patients were identified. Subsequently, GO and pathway analyses revealed that certain functions of the differentially expressed mRNAs were associated with processes important for the pathogenesis of GBM. The biological functions of several miRNA-mediated ceRNAs in GBM were predicted. The present study provides novel insight that may enhance the understanding of the functions of ceRNAs in GBM, as well as biomarkers for the development of therapies for GBM.
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Affiliation(s)
- Shengrong Long
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Guangyu Li
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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36
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Song Y, Pan Y, Liu J. Functional analysis of lncRNAs based on competitive endogenous RNA in tongue squamous cell carcinoma. PeerJ 2019; 7:e6991. [PMID: 31179185 PMCID: PMC6544013 DOI: 10.7717/peerj.6991] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/21/2019] [Indexed: 02/05/2023] Open
Abstract
BACKROUND Tongue squamous cell carcinoma (TSCC) is the most common malignant tumor in the oral cavity. An increasing number of studies have suggested that long noncoding RNA (lncRNA) plays an important role in the biological process of disease and is closely related to the occurrence and development of disease, including TSCC. Although many lncRNAs have been discovered, there remains a lack of research on the function and mechanism of lncRNAs. To better understand the clinical role and biological function of lncRNAs in TSCC, we conducted this study. METHODS In this study, 162 tongue samples, including 147 TSCC samples and 15 normal control samples, were investigated and downloaded from The Cancer Genome Atlas (TCGA). We constructed a competitive endogenous RNA (ceRNA) regulatory network. Then, we investigated two lncRNAs as key lncRNAs using Kaplan-Meier curve analysis and constructed a key lncRNA-miRNA-mRNA subnetwork. Furthermore, gene set enrichment analysis (GSEA) was carried out on mRNAs in the subnetwork after multivariate survival analysis of the Cox proportional hazards regression model. RESULTS The ceRNA regulatory network consists of six differentially expressed miRNAs (DEmiRNAs), 29 differentially expressed lncRNAs (DElncRNAs) and six differentially expressed mRNAs (DEmRNAs). Kaplan-Meier curve analysis of lncRNAs in the TSCC ceRNA regulatory network showed that only two lncRNAs, including LINC00261 and PART1, are correlated with the total survival time of TSCC patients. After we constructed the key lncRNA-miRNA -RNA sub network, the GSEA results showed that key lncRNA are mainly related to cytokines and the immune system. High expression levels of LINC00261 indicate a poor prognosis, while a high expression level of PART1 indicates a better prognosis.
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Affiliation(s)
- Yidan Song
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yihua Pan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jun Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Zhao Q, Chen S, Zhu Z, Yu L, Ren Y, Jiang M, Weng J, Li B. miR-21 promotes EGF-induced pancreatic cancer cell proliferation by targeting Spry2. Cell Death Dis 2018; 9:1157. [PMID: 30464258 PMCID: PMC6249286 DOI: 10.1038/s41419-018-1182-9] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 10/07/2018] [Accepted: 10/19/2018] [Indexed: 12/25/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer that lacks effective targets for therapy. Alteration of epidermal growth factor (EGF) expression has been recognized as an essential molecular event in pancreatic carcinogenesis. Accumulating studies have demonstrated that miRNAs play critical roles in EGF signaling regulation, tumor initiation, cell proliferation and apoptosis. Here, we demonstrated that miR-21 expression was induced by EGF in pancreatic cancer cells. miR-21 promoted EGF-induced proliferation, inhibited cell apoptosis and accelerated cell cycle progression. In vivo experiments confirmed the influence of miR-21 on tumor growth. Mechanistic studies revealed that miR-21 targeted MAPK/ERK and PI3K/AKT signaling pathways to modulate cell proliferation. In addition, Spry2 was proven to be a target of miR-21. Furthermore, miR-21 and Spry2 were significantly related to clinical features and may be valuable predictors of PDAC patient prognosis.
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Affiliation(s)
- Qiuyan Zhao
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China
| | - Sumin Chen
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China
| | - Zhonglin Zhu
- Department of General Surgery, Henan Provincial People's Hospital, Henan, 450003, China.,Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China
| | - Lanting Yu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China
| | - Yingchun Ren
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China
| | - Mingjie Jiang
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China
| | - Junyong Weng
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China
| | - Baiwen Li
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China. .,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, China.
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38
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Wang W, Wang Z, Chen S, Zang X, Miao J. Interleukin-1β/nuclear factor-κB signaling promotes osteosarcoma cell growth through the microRNA-181b/phosphatase and tensin homolog axis. J Cell Biochem 2018; 120:1763-1772. [PMID: 30977354 DOI: 10.1002/jcb.27477] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 07/19/2018] [Indexed: 02/06/2023]
Abstract
So far, microRNA has attracted plenty of interest due to its role in tumorigenesis. Reportedly, miR-181b may be involved in the tumorigenesis of osteosarcoma (OS). In the current study, we attempted to investigate the detailed function and mechanism of miR-181b in OS carcinogenesis. Herein, miR-181a, miR-181b, miR-181c, and miR-181d expressions in OS tissues were higher than that in nontumor tissue samples as examined real-time polymerase chain reaction. Via direct targeting, miR-181b negatively regulated the expression of phosphatase and tensin homolog (PTEN), a well-known tumor suppressor. Furthermore, a small interfering RNA strategy was used to find that interleukin (IL)-1B and nuclear factor-κB (NF-κB) regulate miR-181b and PTEN expression. Consequently, the repression of PTEN by miR-181b promotes OS cell proliferation. In summary, our data support a critical role for NF-κB-dependent upregulation of miR-181b, which further inhibited PTEN expression and promoted the cell proliferation of OS cell lines. The above findings represent a new pathway for the repression of PTEN and the promotion of cell proliferation upon IL-1β induction.
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Affiliation(s)
- Weiguo Wang
- Department of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Zhengguang Wang
- Department of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Shijie Chen
- Department of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Xiaofang Zang
- Department of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jinglei Miao
- Department of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, China
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39
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Fang XN, Yin M, Li H, Liang C, Xu C, Yang GW, Zhang HX. Comprehensive analysis of competitive endogenous RNAs network associated with head and neck squamous cell carcinoma. Sci Rep 2018; 8:10544. [PMID: 30002503 PMCID: PMC6043529 DOI: 10.1038/s41598-018-28957-y] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 07/02/2018] [Indexed: 02/07/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) can regulate gene expression directly or indirectly through interacting with microRNAs (miRNAs). However, the role of differentially expressed mRNAs, lncRNAs and miRNAs, and especially their related competitive endogenous RNAs (ceRNA) network in head and neck squamous cell carcinoma (HNSCC), is not fully comprehended. In this paper, the lncRNA, miRNA, and mRNA expression profiles of 546 HNSCC patients, including 502 tumor and 44 adjacent non-tumor tissues, from The Cancer Genome Atlas (TCGA) were analyzed. 82 miRNAs, 1197 mRNAs and 1041 lncRNAs were found to be differentially expressed in HNSCC samples (fold change ≥ 2; P < 0.01). Further bioinformatics analysis was performed to construct a lncRNA-miRNA-mRNA ceRNA network of HNSCC, which includes 8 miRNAs, 71 lncRNAs and 16 mRNAs. Through survival analysis based on the expression profiles of RNAs in the ceRNA network, we detected 1 mRNA, 1 miRNA and 13 lncRNA to have a significant impact on the overall survival of HNSCC patients (P < 0.05). Finally, some lncRNAs, which are more important for survival, were also predicted. Our research provides data to further understand the molecular mechanisms implicated in HNSCC.
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Affiliation(s)
- Xiao-Nan Fang
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China
- Key Laboratory of TCM Data Cloud Service in Universities of Shandong, School of Information Engineering, Shandong Management University, Jinan, 250357, China
| | - Miao Yin
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China
| | - Hua Li
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China
| | - Cheng Liang
- School of Information Science & Engineering, Shandong Normal University, Jinan, 250358, China
| | - Cong Xu
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China
- College of Pharmacy, Binzhou Medical University, Yantai, 264003, China
| | - Gui-Wen Yang
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China.
| | - Hua-Xiang Zhang
- School of Information Science & Engineering, Shandong Normal University, Jinan, 250358, China.
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40
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Steviol, a natural product inhibits proliferation of the gastrointestinal cancer cells intensively. Oncotarget 2018; 9:26299-26308. [PMID: 29899860 PMCID: PMC5995179 DOI: 10.18632/oncotarget.25233] [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: 09/13/2017] [Accepted: 03/24/2018] [Indexed: 12/19/2022] Open
Abstract
New anticancer agents with lower toxicity have been always urged because of drug resistance associated with overused chemotherapy agents. In this study, steviol, a colonic metabolite of natural sweetener and also a component in leaves of stevia rebaudiana bertoni, was found to possess intensive anticancer activity on the human gastrointestinal cancer cells. Steviol inhibited six human gastrointestinal cancer cells intensively as 5-fluorouracil did at 100 μg/mL. The inhibition mechanism follows mitochondrial apoptotic pathway that was evidenced by increase of Bax/Bcl-2 ratio, activation of p21 and p53; and caspase 3-independent mechanism was also involved. These results are consistent with the miRNA expression analysis. The most regulated miRNAs in the steviol treated gastrointestinal cancer cells were miR-203a-3p (log2 =1.32) and miR-6088 (log2 =-2.54) in HCT-116, miR-1268b (log2 =19.85) and miR-23c (log2 =-2.05) in MKN-45. In view of the metabolic characteristics of steviol and its cytotoxicity on the cancer cells, steviol could be a chemotherapy agent potentially for cancer treatment.
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41
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Ruhl R, Rana S, Kelley K, Espinosa-Diez C, Hudson C, Lanciault C, Thomas CR, Liana Tsikitis V, Anand S. microRNA-451a regulates colorectal cancer proliferation in response to radiation. BMC Cancer 2018; 18:517. [PMID: 29720118 PMCID: PMC5932766 DOI: 10.1186/s12885-018-4370-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 04/15/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis. Therefore, we hypothesized that specific miRs modulate CRC response to chemoradiation. METHODS In this study, we used miR expression profiling and discovered a set of microRNAs upregulated rapidly in response to either a single 2 Gy dose fraction or a 10 Gy dose of γ-radiation in mouse colorectal carcinoma models. We used gain and loss-of-function studies in 2D and 3Dcell proliferation assays and colony formation assays to understand the role of the top miR candidate from our profiling. We used Student's T-tests for simple comparisons and two-factor ANOVA for evaluating significance. RESULTS The most upregulated candidate at early time points in our signature, miR-451a inhibited tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation, and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes, CAB39, EMSY, MEX3C, and EREG, as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was high and CAB39, EMSY levels were low in a small subset of rectal cancer patients who had a partial response to chemoradiation when compared to patients that had no response. Finally, analysis of a TCGA colorectal cancer dataset revealed that CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients. Higher levels of CAB39 and EMSY correlated with poorer overall survival. CONCLUSIONS Taken together, our data indicates miR-451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways.
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Affiliation(s)
- Rebecca Ruhl
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA
| | - Shushan Rana
- Department of Radiation Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA
| | - Katherine Kelley
- Department of Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA
| | - Cristina Espinosa-Diez
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA
| | - Clayton Hudson
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA
| | - Christian Lanciault
- Department of Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA
| | - Charles R Thomas
- Department of Radiation Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA
| | - V Liana Tsikitis
- Department of Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
| | - Sudarshan Anand
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. .,Department of Radiation Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
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Li C, Du X, Xia S, Chen L. MicroRNA-150 inhibits the proliferation and metastasis potential of colorectal cancer cells by targeting iASPP. Oncol Rep 2018; 40:252-260. [PMID: 29750311 PMCID: PMC6059748 DOI: 10.3892/or.2018.6406] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 04/19/2018] [Indexed: 01/06/2023] Open
Abstract
In the present study, the function of miR-150 and its downstream target iASPP in the growth and metastasis of colorectal cancer (CRC) cells was investigated. The expression of miR-150 and iASPP was first investigated in clinical CRC samples. Subsequently, the effects of miR-150 overexpression and iASPP inhibition on cell viability, cell cycle distribution, apoptosis, migration and invasion were detected with CCK-8, flow cytometry, scratch and Transwell assays. The interaction between miR-150 and iASPP was confirmed using a dual-luciferase assay. Subsequently, the key role of iASPP in the anti-CRC function of miR-150 was assessed by inducing the expression of the gene in miR-150 overexpressed SW480 cells. In clinical samples, the level of miR-150 was downregulated, while iASPP was induced. Enforced expression of miR-150 decreased the viability, induced G1 cell cycle arrest and apoptosis, and inhibited the migration and invasion of SW480 cells. Knockdown of iASPP exerted a similar effect on SW480 cells to that of the overexpression of miR-150. Dual-luciferase assay demonstrated that miR-150 directly bound to iASPP and inhibited its transcription. The function of miR-150 depended on the inhibition of iASPP; induced expression of iASPP in miR-150-knockdown SW480 and HCT116 cells restored cell viability, migration and invasion while inhibiting G1 cell cycle arrest and apoptosis. Increased expression of miR-150 suppressed viability, proliferation, migration and invasion of SW480 cells. Furthermore, iASPP was a direct target of miR-150 and played a key role in its anti-CRC function. miR-150 may be a promising predictor of prognosis in CRC patients.
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Affiliation(s)
- Chen Li
- Department of Surgery, Clinical Division, The Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
| | - Xiaohui Du
- Department of Surgery, Clinical Division, The Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
| | - Shaoyou Xia
- Department of Surgery, Clinical Division, The Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
| | - Lin Chen
- Department of Surgery, Clinical Division, The Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
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43
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Li C, Shen Z, Zhou Y, Yu W. Independent prognostic genes and mechanism investigation for colon cancer. Biol Res 2018; 51:10. [PMID: 29653552 PMCID: PMC5897983 DOI: 10.1186/s40659-018-0158-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 03/29/2018] [Indexed: 12/14/2022] Open
Abstract
PROPOSE We aimed to explore the potential molecular mechanism and independent prognostic genes for colon cancer (CC). METHODS Microarray datasets GSE17536 and GSE39582 were downloaded from Gene Expression Omnibus. Meanwhile, the whole CC-related dataset were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNA (DEMs) were identified between cancer tissue samples and para-carcinoma tissue samples in TCGA dataset, followed by the KEGG pathway and GO function analyses. Furthermore, the clinical prognostic analysis including overall survival (OS) and disease-free survival (DFS) were performed in all three datasets. RESULTS A total of 633 up- and 321 down-regulated mRNAs were revealed in TCGA dataset. The up-regulated mRNAs were mainly assembled in functions including extracellular matrix and pathways including Wnt signaling. The down-regulated mRNAs were mainly assembled in functions like Digestion and pathways like Drug metabolism. Furthermore, up-regulation of UL16-binding protein 2 (ULBP2) was associated with OS in CC patients. A total of 12 DEMs including Surfactant Associated 2 (SFTA2) were potential DFS prognostic genes in CC patients. Meanwhile, the GRP and Transmembrane Protein 37 (TMEM37) were two outstanding independent DFS prognostic genes in CC. CONCLUSIONS ULBP2 might be a potential novel OS prognostic biomarker in CC, while GRP and TMEM37 could be served as the independent DFS prognostic genes in CC. Furthermore, functions including extracellular matrix and digestion, as well as pathways including Wnt signaling and drug metabolism might play important roles in the process of CC.
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Affiliation(s)
- Chunsheng Li
- Gastrointestinal Colorectal and Anal surgery, China-Japan Union Hospital of Jilin University, No. 126 Xiantai Street, Changchun, Jilin 130033 China
| | - Zhen Shen
- Gastrointestinal Colorectal and Anal surgery, China-Japan Union Hospital of Jilin University, No. 126 Xiantai Street, Changchun, Jilin 130033 China
| | - Yangyang Zhou
- Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin 130021 China
| | - Wei Yu
- Gastrointestinal Colorectal and Anal surgery, China-Japan Union Hospital of Jilin University, No. 126 Xiantai Street, Changchun, Jilin 130033 China
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Wang H, Niu L, Jiang S, Zhai J, Wang P, Kong F, Jin X. Comprehensive analysis of aberrantly expressed profiles of lncRNAs and miRNAs with associated ceRNA network in muscle-invasive bladder cancer. Oncotarget 2018; 7:86174-86185. [PMID: 27863388 PMCID: PMC5349905 DOI: 10.18632/oncotarget.13363] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 11/07/2016] [Indexed: 12/14/2022] Open
Abstract
Although initially thought to be transcriptional noise, long noncoding RNAs (lncRNAs) are gaining increased attention in human cancers as its diversity function. At present, lncRNAs are regarded as the main part of competing endogenous RNA (ceRNA) network due to its regulation on protein-coding gene expression by acting as miRNA sponges. However, functional roles of lncRNA-mediated ceRNAs in muscle-invasive bladder cancer remain unclear. To clarify relevant potential mechanisms, here we comprehensively compared the expression profiles of mRNAs, lncRNAs and miRNAs between 322 muscle-invasive bladder cancer tissues and 19 non-tumor bladder tissues, based on the Cancer Genome Atlas (TCGA). A total of 22 lncRNAs were identified as aberrantly expressed and had correlations with tumorigenesis and/or progression of muscle-invasive bladder cancer (|log2FoldChange| > 1.5, corrected P value < 0.01). 6 out of the 22 dysregulated lncRNAs functioned as prognostic biomarkers for patients with muscle-invasive bladder cancer according to the overall survival analysis (P value < 0.05). Finally, a dysregulated lncRNA-associated ceRNA network was successfully constructed, which inculdes five muscle-invasive bladder cancer-specific lncRNAs, nine miRNAs and 32 mRNAs. In summary, our study identified novel lncRNAs as candidate prognostic biomarkers and potential therapeutic targets for muscle-invasive bladder cancer, based on large-scale sample size. More importantly, the newly identified ceRNA network will be beneficial for improving the understanding of lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of muscle-invasive bladder cancer.
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Affiliation(s)
- Hanbo Wang
- Minimally Invasive Urology Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Leilei Niu
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Sha Tin, New Territories, Hong Kong SAR, China
| | - Shaobo Jiang
- Minimally Invasive Urology Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Jing Zhai
- Department of Biochemistry, School of Basic Medical Sciences, Taishan Medical University, Taian, China
| | - Ping Wang
- Department of Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Feng Kong
- Central Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Xunbo Jin
- Minimally Invasive Urology Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
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Wu QB, Sheng X, Zhang N, Yang MW, Wang F. Role of microRNAs in the resistance of colorectal cancer to chemoradiotherapy. Mol Clin Oncol 2018; 8:523-527. [PMID: 29556386 DOI: 10.3892/mco.2018.1578] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 02/12/2018] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is among the main tumor-related causes of death worldwide. The fact that the majority of the patients develop resistance to chemoradiotherapy (CRT) is a major obstacle for the treatment of CRC. In order to develop more effective treatment strategies, it is crucial to elucidate the mechanisms underlying the development of resistance to CRT. Several studies have recently indicated the regulatory effects of microRNAs (miRNAs) in response to antitumor agents. For example, miR-34a attenuates the chemoresistance of colon cancer to 5-FU by inhibiting E2F3 and SIRT1. The miR-34a mimic MRX34 is the first synthetic miRNA to have been entered into clinical trials. miR-21 prevents tumor cell stemness, invasion and drug resistance, which are required for the development of CRC. These findings suggest that miRNAs represent a focus in the research of novel cancer treatments aimed at sensitizing cancer cells to chemotherapeutic drugs. The aim of the present study was to review the functions of miRNAs and investigate the roles of miRNAs in CRC radioresistance or chemoresistance. Furthermore, the potential of including miRNAs in therapeutic strategies and using them as molecular biomarkers for predicting radiosensitivity and chemosensitivity was discussed.
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Affiliation(s)
- Qi-Bing Wu
- Department of Radiotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xin Sheng
- Department of Radiotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Ning Zhang
- Department of Radiotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Ming-Wei Yang
- Department of Radiotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Fan Wang
- Department of Radiotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
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Site-specific associations between miRNA expression and survival in colorectal cancer cases. Oncotarget 2018; 7:60193-60205. [PMID: 27517623 PMCID: PMC5312378 DOI: 10.18632/oncotarget.11173] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 07/23/2016] [Indexed: 12/15/2022] Open
Abstract
Background MicroRNAs (miRNA) are small non-coding RNA involved in cellular processes, including cell proliferation and angiogenesis. Thus, miRNA expression may alter survival after diagnosis with colorectal cancer (CRC). Results Individuals diagnosed with stage 1 or stage 2 rectal cancer had worse survival than colon cancer cases diagnosed at stage 1 or stage 2. After adjustment for multiple comparisons, no miRNAs were significantly associated with disease stage. Two miRNAs infrequently expressed in the population and not previously reported were associated with survival after diagnosis with colon cancer (miR-1 HR 2.17 95% CI 1.41, 3.36; and miR-101-3p HR 3.51 95% CI 1.72, 7.15). Among those diagnosed with rectal cancer, 201 miRNAs were associated with survival when the FDR q value was < 0.05. Assessment of 105 previously reported miRNAs associated with prognosis showed that four miRNAs influenced colon cancer survival and 17 influenced survival after a diagnosis with rectal cancer when raw p values were considered. Patients and Methods This study includes data from population-based studies of CRC conducted in Utah and the Kaiser Permanente Medical Care Program. A total of 1893 carcinoma and normal paired colorectal mucosa tissue samples were run using the Agilent Human miRNA Microarray V19.0. We assessed miRNA differential expression between paired carcinoma and normal colonic mucosa tissue with CRC- specific survival evaluating stage and site-specific associations after adjusting for age, sex, microsatellite instability tumor status, and AJCC stage. Conclusions MiRNAs dysregulated for both colon and rectal cancer had a greater impact on survival after a diagnosis with rectal cancer.
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Gong H, Fang L, Li Y, Du J, Zhou B, Wang X, Zhou H, Gao L, Wang K, Zhang J. miR‑873 inhibits colorectal cancer cell proliferation by targeting TRAF5 and TAB1. Oncol Rep 2018; 39:1090-1098. [PMID: 29328486 PMCID: PMC5802030 DOI: 10.3892/or.2018.6199] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 12/20/2017] [Indexed: 12/17/2022] Open
Abstract
MicroRNA-873 (miR-873) has been reported to be dysregulated in a variety of malignancies, however, the biological function and underlying molecular mechanism of miR-873 in colorectal cancer (CRC) remain unclear. In the present study we found that the expression levels of miR-873 were markedly decreased in CRC cell lines and tissues from patients. Statistical analysis revealed that miR-873 expression was inversely correlated with the disease stage of CRC. Kaplan-Meier survival analysis revealed that patients with CRC with lower miR-873 expression had shorter overall survival rates. Additionally, downregulation of miR-873 enhanced the proliferation of CRC cells, while upregulation of miR-873 reduced this proliferation. Furthermore, we found that tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) and TGF-β activated kinase 1 (MAP3K7) binding protein 1 (TAB1) were direct targets of miR-873 in CRC cells. A luciferase assay revealed that ectopic expression of miR-873 significantly reduced nuclear factor κB (NF-κB) luciferase activity, while ectopic expression of miR-873 inhibitor enhanced luciferase activity, suggesting that downregulation of miR-873 can activate NF-κB signaling. Therefore, our findings established a tumor-suppressive role for miR-873 in the inhibition of CRC progression, which may be employed as a novel prognostic marker and as an effective therapeutic target for CRC.
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Affiliation(s)
- Hui Gong
- Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Lishan Fang
- Central Laboratory, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518033, P.R. China
| | - Yifan Li
- Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Jihui Du
- Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Bei Zhou
- Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Xiu Wang
- Clinical Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Hekai Zhou
- Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Lingli Gao
- Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Kaixin Wang
- Department of Pathology, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Juan Zhang
- Department of Pathology, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
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Li F, Huang C, Li Q, Wu X. Construction and Comprehensive Analysis for Dysregulated Long Non-Coding RNA (lncRNA)-Associated Competing Endogenous RNA (ceRNA) Network in Gastric Cancer. Med Sci Monit 2018; 24:37-49. [PMID: 29295970 PMCID: PMC5761711 DOI: 10.12659/msm.905410] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Accepted: 06/26/2017] [Indexed: 12/15/2022] Open
Abstract
Long non-coding RNA (lncRNA) is a kind of non-coding RNA with transcripts more than 200 bp in length. LncRNA can interact with the miRNA as a competing endogenous RNA (ceRNA) to regulate the expression of target genes, which play a significant role in the initiation and progression of tumors. In this study, we explored the functional roles and regulatory mechanisms of lncRNAs as ceRNAs in gastric cancer, and their potential implications for prognosis. The lncRNAs, miRNAs, and mRNAs expression profiles of 375 gastric cancer tissues and 32 non-tumor gastric tissues were downloaded from The Cancer Genome Atlas (TCGA) database. Differential expression of RNAs was identified using the DESeq package. Survival analysis was estimated based on Kaplan-Meier curve analysis. KEGG pathway analysis was performed using KOBAS 3.0. The dysregulated lncRNA-associated ceRNA network was constructed in gastric cancer based on bioinformatics generated from miRcode and miRTarBase. A total of 237 differentially expressed lncRNAs and 198 miRNAs between gastric cancer and matched normal tissues were screened in our study with thresholds of |log2FC| >2 and adjusted P value <0.01. Eleven discriminatively expressed lncRNAs may be correlated with tumorigenesis of gastric cancer. Seven out of 11 dysregulated lncRNA were found to be significantly associated with overall survival in gastric cancer (P value <0.05). The newly identified ceRNA network includes 11 gastric cancer-specific lncRNAs, 9 miRNAs, and 41 mRNAs. Collectively, our study will contribute to improving the understanding of the lncRNA-associated ceRNA network regulatory mechanisms in the pathogenesis of gastric cancer and provide and identify novel lncRNAs as candidate prognostic biomarkers or potential therapeutic targets.
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Affiliation(s)
- Fengxi Li
- Department of Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang, P.R. China
| | - Chuiguo Huang
- Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henanm, P.R. China
| | - Qian Li
- Department of Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang, P.R. China
| | - Xianghua Wu
- Department of Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang, P.R. China
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Zhou W, Yang W, Ma J, Zhang H, Li Z, Zhang L, Liu J, Han Z, Wang H, Hong L. Role of miR-483 in digestive tract cancers: from basic research to clinical value. J Cancer 2018; 9:407-414. [PMID: 29344287 PMCID: PMC5771348 DOI: 10.7150/jca.21394] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 12/01/2017] [Indexed: 12/17/2022] Open
Abstract
Digestive tract cancers (DTCs) is the most common malignant tumors in the world. Despite surgery and medical technology have witnessed the increasing development and sharp advancement in the past decade, DTCs remain a critical concern with high morbidity and mortality. Since a class of small noncoding RNAs termed miRNAs were identified several years ago, increasing studies have attempted to illustrate the relationship between the specific miRNAs dysregulated expression levels and the diseases phenotypic changes. For example, microRNA-483 (miR-483) aberrant expression plays a pivotal part in tumor biology in a variety of human cancer, including DTCs. In this review, we focus on the present key findings from recent profiling studies, discuss the use of miR-483 as a novel biomarker for DTCs. At the same time, we emphasize the significant diversities and technical difficulties must be overcome before clinically relevant signatures arose. It is believed that this might provide researchers an insight into the molecular targeting cancer treatment.
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Affiliation(s)
- Wei Zhou
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Wanli Yang
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Jiaojiao Ma
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Hongwei Zhang
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Zeng Li
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Lei Zhang
- Department of General Surgery, NO.406 Hospital, Dalian 116041, Liaoning Province, China
| | - Jinqiang Liu
- Xinyang Cadres Sanatorium of Wuhan Military Logistics Base, Xinyang 464000, Henan Province, China
| | - Zhenyu Han
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Hu Wang
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Liu Hong
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
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50
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Lott SC, Wolfien M, Riege K, Bagnacani A, Wolkenhauer O, Hoffmann S, Hess WR. Customized workflow development and data modularization concepts for RNA-Sequencing and metatranscriptome experiments. J Biotechnol 2017; 261:85-96. [DOI: 10.1016/j.jbiotec.2017.06.1203] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 06/22/2017] [Accepted: 06/26/2017] [Indexed: 12/14/2022]
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