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Hushmandi K, Alimohammadi M, Heiat M, Hashemi M, Nabavi N, Tabari T, Raei M, Aref AR, Farahani N, Daneshi S, Taheriazam A. Targeting Wnt signaling in cancer drug resistance: Insights from pre-clinical and clinical research. Pathol Res Pract 2025; 267:155837. [PMID: 39954370 DOI: 10.1016/j.prp.2025.155837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 12/22/2024] [Accepted: 02/10/2025] [Indexed: 02/17/2025]
Abstract
Cancer drug resistance, encompassing both acquired and intrinsic chemoresistance, remains a significant challenge in the clinical management of tumors. While advancements in drug discovery and the development of various small molecules and anti-cancer compounds have improved patient responses to chemotherapy, the frequent and prolonged use of these drugs continues to pose a high risk of developing chemoresistance. Therefore, understanding the primary mechanisms underlying drug resistance is crucial. Wnt proteins, as secreted signaling molecules, play a pivotal role in transmitting signals from the cell surface to the nucleus. Aberrant expression of Wnt proteins has been observed in a variety of solid and hematological tumors, where they contribute to key processes such as proliferation, metastasis, stemness, and immune evasion, often acting in an oncogenic manner. Notably, the role of the Wnt signaling pathway in modulating chemotherapy response in human cancers has garnered significant attention. This review focuses on the involvement of Wnt signaling and its related molecular pathways in drug resistance, highlighting their associations with cancer hallmarks, stemness, and tumorigenesis linked to chemoresistance. Additionally, the overexpression of Wnt proteins has been shown to accelerate cancer drug resistance, with regulation mediated by non-coding RNAs. Elevated Wnt activity reduces cell death in cancers, particularly by affecting mechanisms like apoptosis, autophagy, and ferroptosis. Furthermore, pharmacological compounds and small molecules have demonstrated the potential to modulate Wnt signaling in cancer therapy. Given its impact, Wnt expression can also serve as a prognostic marker and a factor influencing survival outcomes in human cancers.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Teimour Tabari
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mehdi Raei
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Dong F, Zhou J, Wu Y, Gao Z, Li W, Song Z. MicroRNAs in pancreatic cancer drug resistance: mechanisms and therapeutic potential. Front Cell Dev Biol 2025; 12:1499111. [PMID: 39882259 PMCID: PMC11774998 DOI: 10.3389/fcell.2024.1499111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 12/30/2024] [Indexed: 01/31/2025] Open
Abstract
Pancreatic cancer (PC) remains one of the most lethal malignancies, primarily due to its intrinsic resistance to conventional therapies. MicroRNAs (miRNAs), key regulators of gene expression, have been identified as crucial modulators of drug resistance mechanisms in this cancer type. This review synthesizes recent advancements in our understanding of how miRNAs influence treatment efficacy in PC. We have thoroughly summarized and discussed the complex role of miRNA in mediating drug resistance in PC treatment. By highlighting specific miRNAs that are implicated in drug resistance pathways, we provide insights into their functional mechanisms and interactions with key molecular targets. We also explore the potential of miRNA-based strategies as novel therapeutic approaches and diagnostic tools to overcome resistance and improve patient outcomes. Despite promising developments, challenges such as specificity, stability, and effective delivery of miRNA-based therapeutics remain. This review aims to offer a critical perspective on current research and propose future directions for leveraging miRNA-based interventions in the fight against PC.
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Affiliation(s)
- Fangying Dong
- Emergency Department, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Jing Zhou
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yijie Wu
- Department of general practice, Taozhuang Branch of the First People’s Hospital of Jiashan, Jiaxing, Zhejiang, China
| | - Zhaofeng Gao
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Weiwei Li
- Emergency Department, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Zhengwei Song
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
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Zhou S, Li H, Zhao C, Zhao W, Pan X, Jian W, Wang J. Single‑cell RNA sequencing reveals heterogeneity in ovarian cancer and constructs a prognostic signature for prognostic prediction and immunotherapy. Int Immunopharmacol 2024; 140:112855. [PMID: 39133955 DOI: 10.1016/j.intimp.2024.112855] [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: 06/21/2024] [Revised: 07/24/2024] [Accepted: 07/30/2024] [Indexed: 09/01/2024]
Abstract
BACKGROUND Ovarian cancer (OC) is one of the cancers with a high incidence at present, which poses a severe threat to women's health. This study focused on identifying the heterogeneity among malignant epithelial cell OC and constructing an effective prognostic signature to predict prognosis and immunotherapy according to a multidisciplinary study. METHODS The InterCNV algorithm was used to identify the heterogeneity of OC based on the scRNA-seq and bulk RNA-seq data. Six algorithms selected EMTscore. An effective prognostic signature was conducted using the COX and Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithms. The texting datasets were used to assess the accuracy of the prognostic signature. We evaluated different immune characteristics and immunotherapy response differences among other risk groups. RESULTS A prognostic signature including 14 genes was established. The patients in the high-risk group have poor survival outcomes. We also found that the patients in the low-risk group have higher immune cell infiltration, enrichment of immune checkpoints, and immunotherapy response, suggesting that the patients in the low-risk group may be more sensitive to immunotherapy. Finally, the laboratory test results showed that KREMEN2 was identified as a novel biomarker and therapeutic target for OC patients. CONCLUSIONS Our study established a GRG signature consisting of 16 genes based on the scRNA-seq and bulk RNA-seq data, which provides a new perspective on the prediction of prognosis and treatment strategy for OC.
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Affiliation(s)
- Shisi Zhou
- Department of Gynaecology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou, China
| | - Huiyan Li
- Department of Rheumatology and Immunology, The Fourth Affiliated Hospital, China Medical University, Shenyang 110000, China
| | - Chengzhi Zhao
- Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children, Chongqing, China
| | - Wancheng Zhao
- Department of Gynaecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xue Pan
- Department of Gynaecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Weilan Jian
- Department of Anesthesiology, Shanghai Tenth People's Hospital, Shanghai, China.
| | - Jieli Wang
- Department of Gynaecology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou, China.
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Samant C, Kale R, Pai KSR, Nandakumar K, Bhonde M. Role of Wnt/β-catenin pathway in cancer drug resistance: Insights into molecular aspects of major solid tumors. Biochem Biophys Res Commun 2024; 729:150348. [PMID: 38986260 DOI: 10.1016/j.bbrc.2024.150348] [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: 04/27/2024] [Revised: 06/23/2024] [Accepted: 07/03/2024] [Indexed: 07/12/2024]
Abstract
Adaptive resistance to conventional and targeted therapies remains one of the major obstacles in the effective management of cancer. Aberrant activation of key signaling mechanisms plays a pivotal role in modulating resistance to drugs. An evolutionarily conserved Wnt/β-catenin pathway is one of the signaling cascades which regulate resistance to drugs. Elevated Wnt signaling confers resistance to anticancer therapies, either through direct activation of its target genes or via indirect mechanisms and crosstalk over other signaling pathways. Involvement of the Wnt/β-catenin pathway in cancer hallmarks like inhibition of apoptosis, promotion of invasion and metastasis and cancer stem cell maintenance makes this pathway a potential target to exploit for addressing drug resistance. Accumulating evidences suggest a critical role of Wnt/β-catenin pathway in imparting resistance across multiple cancers including PDAC, NSCLC, TNBC, etc. Here we present a comprehensive assessment of how Wnt/β-catenin pathway mediates cancer drug resistance in majority of the solid tumors. We take a deep dive into the Wnt/β-catenin signaling-mediated modulation of cellular and downstream molecular mechanisms and their impact on cancer resistance.
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Affiliation(s)
- Charudatt Samant
- Department of Pharmacology, Novel Drug Discovery and Development (NDDD), Lupin Limited, Survey No. 46A/47A, Village Nande, Taluka Mulshi, Pune, 412115, Maharashtra, India.
| | - Ramesh Kale
- Department of Pharmacology, Novel Drug Discovery and Development (NDDD), Lupin Limited, Survey No. 46A/47A, Village Nande, Taluka Mulshi, Pune, 412115, Maharashtra, India
| | - K Sreedhara Ranganath Pai
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 576104, India
| | - Krishnadas Nandakumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 576104, India
| | - Mandar Bhonde
- Department of Pharmacology, Novel Drug Discovery and Development (NDDD), Lupin Limited, Survey No. 46A/47A, Village Nande, Taluka Mulshi, Pune, 412115, Maharashtra, India
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Przybyszewski O, Mik M, Nowicki M, Kusiński M, Mikołajczyk-Solińska M, Śliwińska A. Using microRNAs Networks to Understand Pancreatic Cancer-A Literature Review. Biomedicines 2024; 12:1713. [PMID: 39200178 PMCID: PMC11351910 DOI: 10.3390/biomedicines12081713] [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: 05/30/2024] [Revised: 07/26/2024] [Accepted: 07/28/2024] [Indexed: 09/02/2024] Open
Abstract
Pancreatic cancer is a severe disease, challenging to diagnose and treat, and thereby characterized by a poor prognosis and a high mortality rate. Pancreatic ductal adenocarcinoma (PDAC) represents approximately 90% of pancreatic cancer cases, while other cases include neuroendocrine carcinoma. Despite the growing knowledge of the pathophysiology of this cancer, the mortality rate caused by it has not been effectively reduced. Recently, microRNAs have aroused great interest among scientists and clinicians, as they are negative regulators of gene expression, which participate in many processes, including those related to the development of pancreatic cancer. The aim of this review is to show how microRNAs (miRNAs) affect key signaling pathways and related cellular processes in pancreatic cancer development, progression, diagnosis and treatment. We included the results of in vitro studies, animal model of pancreatic cancer and those performed on blood, saliva and tumor tissue isolated from patients suffering from PDAC. Our investigation identified numerous dysregulated miRNAs involved in KRAS, JAK/STAT, PI3/AKT, Wnt/β-catenin and TGF-β signaling pathways participating in cell cycle control, proliferation, differentiation, apoptosis and metastasis. Moreover, some miRNAs (miRNA-23a, miRNA-24, miRNA-29c, miRNA-216a) seem to be engaged in a crosstalk between signaling pathways. Evidence concerning the utility of microRNAs in the diagnosis and therapy of this cancer is poor. Therefore, despite growing knowledge of the involvement of miRNAs in several processes associated with pancreatic cancer, we are beginning to recognize and understand their role and usefulness in clinical practice.
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Affiliation(s)
- Oskar Przybyszewski
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland
| | - Michał Mik
- Department of General and Colorectal Surgery, Medical University of Lodz, 113 Stefana Żeromskiego St., 90-549 Lodz, Poland; (M.M.); (M.N.)
| | - Michał Nowicki
- Department of General and Colorectal Surgery, Medical University of Lodz, 113 Stefana Żeromskiego St., 90-549 Lodz, Poland; (M.M.); (M.N.)
| | - Michał Kusiński
- Department of Endocrinological, General and Oncological Surgery, Medical University of Lodz, 62 Pabianicka St., 93-513 Lodz, Poland;
| | - Melania Mikołajczyk-Solińska
- Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland;
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland
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Hou R, Wang Y, Cao S, Sun X, Jiang L. N 6-Methyladenosine-Modified KREMEN2 Promotes Tumorigenesis and Malignant Progression of High-Grade Serous Ovarian Cancer. J Transl Med 2024; 104:102059. [PMID: 38615731 DOI: 10.1016/j.labinv.2024.102059] [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: 11/23/2023] [Revised: 03/20/2024] [Accepted: 04/05/2024] [Indexed: 04/16/2024] Open
Abstract
High-grade serous ovarian cancer (HGSOC) remains the most lethal female cancer by far. Herein, clinical HGSOC samples had higher N6-methyladenosine (m6A) modification than normal ovarian tissue, and its dysregulation had been reported to drive aberrant transcription and translation programs. However, Kringle-containing transmembrane protein 2 (KREMEN2) and its m6A modification have not been fully elucidated in HGSOC. In this study, the data from the high-throughput messenger RNA (mRNA) sequencing of clinical samples were processed using the weighted correlation network analysis and functional enrichment analysis. Results revealed that KREMEN2 was a driver gene in the tumorigenesis of HGSOC and a potential target of m6A demethylase fat-mass and obesity-associated protein (FTO). KREMEN2 and FTO levels were upregulated and downregulated, respectively, and correlation analysis showed a significant negative correlation in HGSOC samples. Importantly, upregulated KREMEN2 was remarkably associated with lymph node metastasis, distant metastasis, peritoneal metastasis, and high International Federation of Gynecology and Obstetrics stage (Ⅲ/Ⅳ), independent of the age of patients. KREMEN2 promoted the growth of HGSOC in vitro and in vivo, which was dependent on FTO. The methylated RNA immunoprecipitation qPCR and RNA immunoprecipitation assays were performed to verify the m6A level and sites of KREMEN2. FTO overexpression significantly decreased m6A modification in the 3' and 5' untranslated regions of KREMEN2 mRNA and downregulated its expression. In addition, we found that FTO-mediated m6A modification of KREMEN2 mRNA was recognized and stabilized by the m6A reader IGF2BP1 rather than by IGF2BP2 or IGF2BP3. This study highlights the m6A modification of KREMEN2 and extends the importance of RNA epigenetics in HGSOC.
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Affiliation(s)
- Rui Hou
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yadong Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shiyao Cao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xinrui Sun
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Luo Jiang
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China.
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Stukas D, Jasukaitiene A, Bartkeviciene A, Matthews J, Maimets T, Teino I, Jaudzems K, Gulbinas A, Dambrauskas Z. Targeting AHR Increases Pancreatic Cancer Cell Sensitivity to Gemcitabine through the ELAVL1-DCK Pathway. Int J Mol Sci 2023; 24:13155. [PMID: 37685961 PMCID: PMC10487468 DOI: 10.3390/ijms241713155] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
The aryl hydrocarbon receptor (AHR) is a transcription factor that is commonly upregulated in pancreatic ductal adenocarcinoma (PDAC). AHR hinders the shuttling of human antigen R (ELAVL1) from the nucleus to the cytoplasm, where it stabilises its target messenger RNAs (mRNAs) and enhances protein expression. Among these target mRNAs are those induced by gemcitabine. Increased AHR expression leads to the sequestration of ELAVL1 in the nucleus, resulting in chemoresistance. This study aimed to investigate the interaction between AHR and ELAVL1 in the pathogenesis of PDAC in vitro. AHR and ELAVL1 genes were silenced by siRNA transfection. The RNA and protein were extracted for quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) analysis. Direct binding between the ELAVL1 protein and AHR mRNA was examined through immunoprecipitation (IP) assay. Cell viability, clonogenicity, and migration assays were performed. Our study revealed that both AHR and ELAVL1 inter-regulate each other, while also having a role in cell proliferation, migration, and chemoresistance in PDAC cell lines. Notably, both proteins function through distinct mechanisms. The silencing of ELAVL1 disrupts the stability of its target mRNAs, resulting in the decreased expression of numerous cytoprotective proteins. In contrast, the silencing of AHR diminishes cell migration and proliferation and enhances cell sensitivity to gemcitabine through the AHR-ELAVL1-deoxycytidine kinase (DCK) molecular pathway. In conclusion, AHR and ELAVL1 interaction can form a negative feedback loop. By inhibiting AHR expression, PDAC cells become more susceptible to gemcitabine through the ELAVL1-DCK pathway.
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Affiliation(s)
- Darius Stukas
- Surgical Gastroenterology Laboratory, Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (A.J.); (A.B.); (A.G.); (Z.D.)
| | - Aldona Jasukaitiene
- Surgical Gastroenterology Laboratory, Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (A.J.); (A.B.); (A.G.); (Z.D.)
| | - Arenida Bartkeviciene
- Surgical Gastroenterology Laboratory, Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (A.J.); (A.B.); (A.G.); (Z.D.)
| | - Jason Matthews
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 1046 Blindern, 0317 Oslo, Norway;
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Toivo Maimets
- Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010 Tartu, Estonia; (T.M.); (I.T.)
| | - Indrek Teino
- Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010 Tartu, Estonia; (T.M.); (I.T.)
| | - Kristaps Jaudzems
- Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia;
| | - Antanas Gulbinas
- Surgical Gastroenterology Laboratory, Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (A.J.); (A.B.); (A.G.); (Z.D.)
| | - Zilvinas Dambrauskas
- Surgical Gastroenterology Laboratory, Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (A.J.); (A.B.); (A.G.); (Z.D.)
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Wei L, Sun J, Wang X, Huang Y, Huang L, Han L, Zheng Y, Xu Y, Zhang N, Yang M. Noncoding RNAs: an emerging modulator of drug resistance in pancreatic cancer. Front Cell Dev Biol 2023; 11:1226639. [PMID: 37560164 PMCID: PMC10407809 DOI: 10.3389/fcell.2023.1226639] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/17/2023] [Indexed: 08/11/2023] Open
Abstract
Pancreatic cancer is the eighth leading cause of cancer-related deaths worldwide. Chemotherapy including gemcitabine, 5-fluorouracil, adriamycin and cisplatin, immunotherapy with immune checkpoint inhibitors and targeted therapy have been demonstrated to significantly improve prognosis of pancreatic cancer patients with advanced diseases. However, most patients developed drug resistance to these therapeutic agents, which leading to shortened patient survival. The detailed molecular mechanisms contributing to pancreatic cancer drug resistance remain largely unclear. The growing evidences have shown that noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are involved in pancreatic cancer pathogenesis and development of drug resistance. In the present review, we systematically summarized the new insight on of various miRNAs, lncRNAs and circRNAs on drug resistance of pancreatic cancer. These results demonstrated that targeting the tumor-specific ncRNA may provide novel options for pancreatic cancer treatments.
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Affiliation(s)
- Ling Wei
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jujie Sun
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xingwu Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yizhou Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linying Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linyu Han
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yanxiu Zheng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yuan Xu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
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Apurva, Abdul Sattar RS, Ali A, Nimisha, Kumar Sharma A, Kumar A, Santoshi S, Saluja SS. Molecular pathways in periampullary cancer: An overview. Cell Signal 2022; 100:110461. [PMID: 36096460 DOI: 10.1016/j.cellsig.2022.110461] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/19/2022] [Accepted: 08/29/2022] [Indexed: 11/22/2022]
Abstract
Molecular alterations in oncogenes and tumor suppressors in various signaling pathways are basis for personalized therapy in cancer. Periampullary carcinoma behaves differently from pancreatic carcinoma both in prognosis and outcome, therefore it needs special attention. Pancreatic cancer have higher incidence of nodal spread and perineural &lymphovascular invasion suggesting it biologically more aggressive tumor compared to periampullary cancer. Since PAC tumors consist of heterogenous tissue of origin, they might contain different mutations in tumor associated genes and other changes in tissue composition among different subgroups clubbed together. Significant progress has been made in understanding the molecular nature of PAC in the previous two decades, and a large number of mutations and other genetic changes have been identified as being responsible for the disease. This review article targets to collate and discuss the molecular evolution of PAC and their implication in its outcome. As per literature, mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and Wnt signaling are the most common pathways involved in PAC. Mutations in KRAS, TP53, CTNNB1, SMAD4 and APC genes were the most frequently reported. I-subtype resembles colorectal cancer while the morphology of PB-type shows close resemblance to pancreatic tumors. The frequency of driver gene mutations is higher in I-type compared to PB-type of PAC indicating I-type to be genetically more unstable. The genetic landscape of PAC obtained from WES data highlighted PI3/AKT pathway to be a primary target in I-type and RAS/RAF in PB-type.
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Affiliation(s)
- Apurva
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Amity University, Noida, India
| | - Real Sumayya Abdul Sattar
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Asgar Ali
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Nimisha
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Abhay Kumar Sharma
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Arun Kumar
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | | | - Sundeep Singh Saluja
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of GI Surgery, GovindBallabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India.
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10
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Nguyen TTP, Suman KH, Nguyen TB, Nguyen HT, Do DN. The Role of miR-29s in Human Cancers—An Update. Biomedicines 2022; 10:biomedicines10092121. [PMID: 36140219 PMCID: PMC9495592 DOI: 10.3390/biomedicines10092121] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 11/25/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that directly bind to the 3’ untranslated region (3’-UTR) of the target mRNAs to inhibit their expression. The miRNA-29s (miR-29s) are suggested to be either tumor suppressors or oncogenic miRNAs that are strongly dysregulated in various types of cancer. Their dysregulation alters the expression of their target genes, thereby exerting influence on different cellular pathways including cell proliferation, apoptosis, migration, and invasion, thereby contributing to carcinogenesis. In the present review, we aimed to provide an overview of the current knowledge on the miR-29s biological network and its functions in cancer, as well as its current and potential applications as a diagnostic and prognostic biomarker and/or a therapeutic target in major types of human cancer.
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Affiliation(s)
- Thuy T. P. Nguyen
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Kamrul Hassan Suman
- Department of Fisheries, Ministry of Fisheries and Livestock, Dhaka 1205, Bangladesh
| | - Thong Ba Nguyen
- Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, USA
| | - Ha Thi Nguyen
- Institute of Research and Development, Duy Tan University, Danang 550000, Vietnam
- Center for Molecular Biology, College of Medicine and Pharmacy, Duy Tan University, Danang 550000, Vietnam
- Correspondence: (H.T.N.); (D.N.D.)
| | - Duy Ngoc Do
- Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS B2N 5E3, Canada
- Correspondence: (H.T.N.); (D.N.D.)
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11
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Rahnama N, Jahangir M, Alesaeid S, Kahrizi MS, Adili A, Mohammed RN, Aslaminabad R, Akbari M, Özgönül AM. Association between microRNAs and chemoresistance in pancreatic cancer: Current knowledge, new insights, and forthcoming perspectives. Pathol Res Pract 2022; 236:153982. [PMID: 35779293 DOI: 10.1016/j.prp.2022.153982] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/27/2022] [Accepted: 06/11/2022] [Indexed: 11/25/2022]
Abstract
Pancreatic duct adenocarcinoma, commonly known as pancreatic cancer (PC), is a cancer-related cause of death due to delayed diagnosis, metastasis, and drug resistance. Patients with PC suffer from incorrect responses to chemotherapy due to inherent and acquired chemical resistance. Numerous studies have shown the mechanism of the effect of chemoresistance on PC, such as genetic and epigenetic changes or the elucidation of signaling pathways. In this regard, microRNAs (miRNAs) have been identified as essential modulators of gene expression in various cellular functions, including chemoresistance. Thus, identifying the underlying link between microRNAs and PC chemoresistance helps determine the exact pathogenesis of PC. This study aims to classify miRNAs and signaling pathways related to PC chemoresistance, suggesting new therapeutic approaches to overcome PC chemoresistance.
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Affiliation(s)
- Negin Rahnama
- Department of Internal Medicine and Health Services, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Samira Alesaeid
- Department of Internal Medicine and Rheumatology, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ali Adili
- Senior Adult Oncology Department, Moffitt Cancer Center, University of South Florida, FL, USA; Department of Oncology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rebar N Mohammed
- Medical Laboratory Analysis Department, College of Health Sciences, Cihan University of Sulaimaniya, Kurdistan Region, Iraq; College of Veterinary Medicine, University of Sulaimani, Sulaimaniyah, Iraq
| | - Ramin Aslaminabad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Ali Mert Özgönül
- Department of Biochemistry, Faculty of Medicine, Ege University, Bornova, Izmir, Turkey.
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12
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Abreu de Oliveira WA, El Laithy Y, Bruna A, Annibali D, Lluis F. Wnt Signaling in the Breast: From Development to Disease. Front Cell Dev Biol 2022; 10:884467. [PMID: 35663403 PMCID: PMC9157790 DOI: 10.3389/fcell.2022.884467] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/22/2022] [Indexed: 12/11/2022] Open
Abstract
The Wnt cascade is a primordial developmental signaling pathway that plays a myriad of essential functions throughout development and adult homeostasis in virtually all animal species. Aberrant Wnt activity is implicated in embryonic and tissue morphogenesis defects, and several diseases, most notably cancer. The role of Wnt signaling in mammary gland development and breast cancer initiation, maintenance, and progression is far from being completely understood and is rather shrouded in controversy. In this review, we dissect the fundamental role of Wnt signaling in mammary gland development and adult homeostasis and explore how defects in its tightly regulated and intricated molecular network are interlinked with cancer, with a focus on the breast.
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Affiliation(s)
- Willy Antoni Abreu de Oliveira
- Department of Development and Regeneration, Stem Cell Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
- *Correspondence: Willy Antoni Abreu de Oliveira, ; Frederic Lluis,
| | - Youssef El Laithy
- Department of Development and Regeneration, Stem Cell Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Alejandra Bruna
- Centre for Paediatric Oncology Experimental Medicine, Centre for Cancer Evolution, Molecular Pathology Division, London, United Kingdom
| | - Daniela Annibali
- Department of Oncology, Gynecological Oncology Laboratory, Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Frederic Lluis
- Department of Development and Regeneration, Stem Cell Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
- *Correspondence: Willy Antoni Abreu de Oliveira, ; Frederic Lluis,
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13
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Zhang WT, Zhang JJ, Shao Q, Wang YK, Jia JP, Qian B, Tian XW, Yan WJ. FGD5‑AS1 is an oncogenic lncRNA in pancreatic cancer and regulates the Wnt/β‑catenin signaling pathway via miR‑577. Oncol Rep 2021; 47:21. [PMID: 34821374 PMCID: PMC8630524 DOI: 10.3892/or.2021.8232] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 10/18/2021] [Indexed: 12/16/2022] Open
Abstract
The objective of the present study was to clarify the expression characteristics of long non-coding RNA (lncRNA) FGD5 antisense RNA 1 (FGD5-AS1) in pancreatic cancer, as well as its biological function and underlying mechanism. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was utilized for the detection of FGD5-AS1 and microRNA (miR)-577 expression levels in pancreatic cancer tissues. Transfection was performed to upregulate or downregulate FGD5-AS1 in pancreatic cancer cell lines. MTT and Transwell assays were then utilized to detect the proliferation, migration and invasion of cancer cells, respectively. Subsequently, dual-luciferase reporter gene assay, RNA immunoprecipitation assay, RNA pull-down assay, RT-qPCR, western blotting, and Pearson's correlation analysis were employed to confirm the regulatory relationships among FGD5-AS1, miR-577, low-density lipoprotein receptor-related protein 6 (LRP6) and β-catenin. Western blotting was employed to determine the expression levels of Axin2, cyclin D1 and c-Myc. The expression level of FGD5-AS1 was upregulated in pancreatic cancer tissues and cell lines. FGD5-AS1 knockdown inhibited pancreatic cancer cell proliferation, migration and invasion. By contrast, miR-577 was significantly inhibited in pancreatic cancer cells and tissues; its downregulation promoted pancreatic cancer cell proliferation, migration and invasion, and reversed the effects of FGD5-AS1 knockdown on pancreatic cancer cells. In addition, it was revealed that miR-577 was a target of FGD5-AS1, and FGD5-AS1 could modulate the expression levels of LRP6, β-catenin, Axin2, cyclin D1 and c-Myc via suppressing miR-577. In conclusion, in pancreatic cancer, highly expressed FGD5-AS1 activated the Wnt/β-catenin signaling and promoted cancer cell proliferation, migration and invasion via suppression of miR-577.
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Affiliation(s)
- Wei-Tao Zhang
- Cancer Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, P.R. China
| | - Ji-Jun Zhang
- Department of General Surgery, Sixth Hospital of Shanxi Medical University, Taiyuan, Shanxi 030008, P.R. China
| | - Quan Shao
- Department of General Surgery, Sixth Hospital of Shanxi Medical University, Taiyuan, Shanxi 030008, P.R. China
| | - Ying-Kai Wang
- Department of General Surgery, Sixth Hospital of Shanxi Medical University, Taiyuan, Shanxi 030008, P.R. China
| | - Jie-Peng Jia
- Department of General Surgery, Sixth Hospital of Shanxi Medical University, Taiyuan, Shanxi 030008, P.R. China
| | - Bo Qian
- Department of General Surgery, Sixth Hospital of Shanxi Medical University, Taiyuan, Shanxi 030008, P.R. China
| | - Xiao-Wen Tian
- Department of General Surgery, Sixth Hospital of Shanxi Medical University, Taiyuan, Shanxi 030008, P.R. China
| | - Wen-Ji Yan
- Department of Oncology, First Medical Center, Chinese PLA General Hospital, Beijing 100853, P.R. China
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14
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Sankarasubramanian S, Pfohl U, Regenbrecht CRA, Reinhard C, Wedeken L. Context Matters-Why We Need to Change From a One Size Fits all Approach to Made-to-Measure Therapies for Individual Patients With Pancreatic Cancer. Front Cell Dev Biol 2021; 9:760705. [PMID: 34805167 PMCID: PMC8599957 DOI: 10.3389/fcell.2021.760705] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is one of the deadliest cancers and remains a major unsolved health problem. While pancreatic ductal adenocarcinoma (PDAC) is associated with driver mutations in only four major genes (KRAS, TP53, SMAD4, and CDKN2A), every tumor differs in its molecular landscape, histology, and prognosis. It is crucial to understand and consider these differences to be able to tailor treatment regimens specific to the vulnerabilities of the individual tumor to enhance patient outcome. This review focuses on the heterogeneity of pancreatic tumor cells and how in addition to genetic alterations, the subsequent dysregulation of multiple signaling cascades at various levels, epigenetic and metabolic factors contribute to the oncogenesis of PDAC and compensate for each other in driving cancer progression if one is tackled by a therapeutic approach. This implicates that besides the need for new combinatorial therapies for PDAC, a personalized approach for treating this highly complex cancer is required. A strategy that combines both a target-based and phenotypic approach to identify an effective treatment, like Reverse Clinical Engineering® using patient-derived organoids, is discussed as a promising way forward in the field of personalized medicine to tackle this deadly disease.
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Affiliation(s)
| | - Ulrike Pfohl
- CELLphenomics GmbH, Berlin, Germany
- ASC Oncology GmbH, Berlin, Germany
- Institute for Molecular Bio Science, Goethe University Frankfurt Am Main, Frankfurt, Germany
| | - Christian R. A. Regenbrecht
- CELLphenomics GmbH, Berlin, Germany
- ASC Oncology GmbH, Berlin, Germany
- Institute for Pathology, Universitätsklinikum Göttingen, Göttingen, Germany
| | | | - Lena Wedeken
- CELLphenomics GmbH, Berlin, Germany
- ASC Oncology GmbH, Berlin, Germany
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15
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Ma Y, Xia P, Wang Z, Xu J, Zhang L, Jiang Y. PDIA6 promotes pancreatic cancer progression and immune escape through CSN5-mediated deubiquitination of β-catenin and PD-L1. Neoplasia 2021; 23:912-928. [PMID: 34325342 PMCID: PMC8329431 DOI: 10.1016/j.neo.2021.07.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 01/15/2023]
Abstract
Protein Disulfide Isomerase Family A Member 6 (PDIA6) is an endoplasmic reticulum protein that is capable of catalyzing protein folding and disulfide bond formation. Abnormally elevated expression of PDIA6 has been reported to predict poor outcomes in various cancers. Herein, gain-of- and loss-of-function experiments were performed to investigate how PDIA6 participated in the carcinogenesis of pancreatic cancer (PC). By analyzing the protein expression of PDIA6 in 28 paired PC and para carcinoma specimens, we first found that PDIA6 expression was higher in PC samples. Both the overall survival and disease-free survival rates of PC patients with higher PDIA6 expression were poorer than those with lower PDIA6 (n = 178). Furthermore, knockdown of PDIA6 impaired the malignancies of PC cells - suppressed cell proliferation, invasion, migration, cisplatin resistance, and xenografted tumor growth. PDIA6-silenced PC cells were more sensitive to cytotoxic natural killer (NK) cells. Overexpression of PDIA6 had opposite effects on PC cells. Interestingly, COP9 signalosome subunit 5 (CSN5), a regulator of E3 ubiquitin ligases known to promote deubiquitination of its downstream targets, was demonstrated to interact with PDIA6, and its expression was increased in PC cells overexpressing PDIA6. Additionally, PDIA6 overexpression promoted deubiquitination of β-catenin and PD-L1 and subsequently upregulated their expression in PC cells. These alterations were partly reversed by CSN5 shRNA. Collectively, the above results demonstrate that PDIA6 contributes to PC progression, which may be associated with CSN5-regulated deubiquitination of β-catenin and PD-L1. Our findings suggest PDIA6 as a potential target for the treatment of PC.
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Affiliation(s)
- Yihui Ma
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Peiyi Xia
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhengyang Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingjing Xu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lan Zhang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanan Jiang
- Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
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16
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Mollaei M, Hassan ZM, Khorshidi F, Langroudi L. Chemotherapeutic drugs: Cell death- and resistance-related signaling pathways. Are they really as smart as the tumor cells? Transl Oncol 2021; 14:101056. [PMID: 33684837 PMCID: PMC7938256 DOI: 10.1016/j.tranon.2021.101056] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/05/2021] [Accepted: 02/22/2021] [Indexed: 02/07/2023] Open
Abstract
Chemotherapeutic drugs kill cancer cells or control their progression all over the patient's body, while radiation- and surgery-based treatments perform in a particular site. Based on their mechanisms of action, they are classified into different groups, including alkylating substrates, antimetabolite agents, anti-tumor antibiotics, inhibitors of topoisomerase I and II, mitotic inhibitors, and finally, corticosteroids. Although chemotherapeutic drugs have brought about more life expectancy, two major and severe complications during chemotherapy are chemoresistance and tumor relapse. Therefore, we aimed to review the underlying intracellular signaling pathways involved in cell death and resistance in different chemotherapeutic drug families to clarify the shortcomings in the conventional single chemotherapy applications. Moreover, we have summarized the current combination chemotherapy applications, including numerous combined-, and encapsulated-combined-chemotherapeutic drugs. We further discussed the possibilities and applications of precision medicine, machine learning, next-generation sequencing (NGS), and whole-exome sequencing (WES) in promoting cancer immunotherapies. Finally, some of the recent clinical trials concerning the application of immunotherapies and combination chemotherapies were included as well, in order to provide a practical perspective toward the future of therapies in cancer cases.
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Affiliation(s)
- Mojtaba Mollaei
- Department of Immunology, School of Medicine, Tarbiat Modares University, Tehran, Iran.
| | | | - Fatemeh Khorshidi
- Department of Immunology, School of Medicine, Tarbiat Modares University, Tehran, Iran; Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
| | - Ladan Langroudi
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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17
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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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18
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Crosstalk between miRNAs and signaling pathways involved in pancreatic cancer and pancreatic ductal adenocarcinoma. Eur J Pharmacol 2021; 901:174006. [PMID: 33711308 DOI: 10.1016/j.ejphar.2021.174006] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 01/19/2021] [Accepted: 03/02/2021] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide with 5-year survival rates below 8%. Most patients with PC and pancreatic ductal adenocarcinoma (PDAC) die after relapse and cancer progression as well as resistance to treatment. Pancreatic tumors contain a high desmoplastic stroma that forms a rigid mass and has a potential role in tumor growth and metastasis. PC initiates from intraepithelial neoplasia lesions leading to invasive cancer through various pathways. These lesions harbor particular changes in signaling pathways involved in the tumorigenesis process. These events affect both the epithelial cells, including the tumor and the surrounding stroma, and eventually lead to the formation of complex signaling networks. Genetic studies of PC have revealed common molecular features such as the presence of mutations in KRAS gene in more than 90% of patients, as well as the inactivation or deletion mutations of some tumor suppressor genes including TP53, CDKN2A, and SMAD4. In recent years, studies have also identified different roles of microRNAs in PC pathogenesis as well as their importance in PC diagnosis and treatment, and their involvement in various signaling pathways. In this study, we discussed the most common pathways involved in PC and PDAC as well as their role in tumorigenesis and progression. Furthermore, the miRNAs participating in the regulation of these signaling pathways in PC progression are summarized in this study. Therefore, understanding more about pathways involved in PC can help with the development of new and effective therapies in the future.
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19
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Noncoding RNAs Associated with Therapeutic Resistance in Pancreatic Cancer. Biomedicines 2021; 9:biomedicines9030263. [PMID: 33799952 PMCID: PMC7998345 DOI: 10.3390/biomedicines9030263] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Therapeutic resistance is an inevitable impediment towards effective cancer therapies. Evidence accumulated has shown that the signaling pathways and related factors are fundamentally responsible for therapeutic resistance via regulating diverse cellular events, such as epithelial-to-mesenchymal transition (EMT), stemness, cell survival/apoptosis, autophagy, etcetera. Noncoding RNAs (ncRNAs) have been identified as essential cellular components in gene regulation. The expression of ncRNAs is altered in cancer, and dysregulated ncRNAs participate in gene regulatory networks in pathological contexts. An in-depth understanding of molecular mechanisms underlying the modulation of therapeutic resistance is required to refine therapeutic benefits. This review presents an overview of the recent evidence concerning the role of human ncRNAs in therapeutic resistance, together with the feasibility of ncRNAs as therapeutic targets in pancreatic cancer.
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20
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Chen B, Wang SQ, Huang J, Xu W, Lv H, Nie C, Wang J, Zhao H, Liu Y, Li J, Lu C, Zhang J, Chen XB. Knockdown of Kremen2 Inhibits Tumor Growth and Migration in Gastric Cancer. Front Oncol 2021; 10:534095. [PMID: 33489867 PMCID: PMC7817645 DOI: 10.3389/fonc.2020.534095] [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: 03/10/2020] [Accepted: 11/11/2020] [Indexed: 12/19/2022] Open
Abstract
Kremen2 (Krm2) plays an important role in embryonic development, bone formation, and tumorigenesis as a crucial regulator of classical Wnt/β-catenin signaling pathway. However, the role of Krm2 in gastric cancer is not clear. The aim of this study was to explore the regulatory role of Krm2 in the tumorigenesis and metastasis of gastric cancer. It was demonstrated that, compared to para-cancerous tissues, Krm2 was significantly up-regulated in gastric cancer tissues and was positively correlated with the pathological grade of gastric cancer patients. Given that Krm2 is abundantly expressed in most tested gastric cancer cell lines, Krm2 knockdown cell models were established and further used to construct mice xenograft model. After knocking down Krm2, both the cell survival in vitro and tumorigenesis in vivo of gastric cancer cells were inhibited. At the same time, knockdown of Krm2 induced apoptosis, cell cycle arrest at G2/M phase and repression of migration in gastric cancer cells in vitro. Mechanistically, we found that knockdown of Krm2 suppressed PI3K/Akt pathway. Therefore, we revealed the novel role and the molecular mechanism of Krm2 in promoting the tumorigenesis and metastasis in gastric cancer. Krm2 can be a potent candidate for designing of targeted therapy.
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Affiliation(s)
- Beibei Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, China
| | - Sai-Qi Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, China
| | - Jinxi Huang
- Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Weifeng Xu
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huifang Lv
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Caiyun Nie
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jianzheng Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huichen Zhao
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yingjun Liu
- Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jitian Li
- Department of Biological Sciences, University of Texas, El Paso, TX, United States
| | - Canrong Lu
- Department of General surgery, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Jianying Zhang
- Department of Biological Sciences, University of Texas, El Paso, TX, United States
| | - Xiao-Bing Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, China
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21
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Tavano F, Fontana A, Mazza T, Gioffreda D, Biagini T, Palumbo O, Carella M, Andriulli A. Early-Onset Diabetes as Risk Factor for Pancreatic Cancer: miRNA Expression Profiling in Plasma Uncovers a Role for miR-20b-5p, miR-29a, and miR-18a-5p in Diabetes of Recent Diagnosis. Front Oncol 2020; 10:1567. [PMID: 33072549 PMCID: PMC7533599 DOI: 10.3389/fonc.2020.01567] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022] Open
Abstract
The high prevalence of early-diabetes in patients with pancreatic cancer (PanC) implies that its recognition could help identify people at high risk of developing PanC. Candidate microRNAs (miRNAs) associated with recent diabetes were screened from our previous miRNA expression profiling on 10 pools of plasma from PanC patients and non-PanC controls, both including also subjects with early- and late-diabetes. The droplet digital PCR (ddPCR) was used to re-test candidate miRNAs in a new independent cohort of 69 subjects (40 PanC, 29 non-PanC) with early- (17 PanC, 13 non-PanC) or late-diabetes (23 PanC, 16 non-PanC), and in 100 non-diabetic healthy subjects (HS). miRNA levels were evaluated for differences between subjects enrolled into the study and for their diagnostic performance, also compared to the CA 19-9 determinations. MiR-20b-5p, miR-29a, and miR-18a-5p were selected from the previous miRNA expression profiling. The ddPCR confirmed the increase of miR-20b-5p and miR-29a levels in PanC with early- compared to those with late-diabetes. Conversely, miR-20b-5p, miR-29a, and miR-18a-5p were over-expressed in both PanC and non-PanC with recent diabetes compared to HS, and each miRNA achieved a similar diagnostic performance in distinguishing either PanC or non-PanC with early-diabetes from HS (miR-20b-5p: AUC = 0.877 vs. AUC = 0.873; miR-29a: AUC = 0.838 vs. AUC = 0.810; miR-18a-5p: AUC = 0.824 vs. AUC = 0.875). Despite miR-20b-5p and miR-29a expressions were also higher both in PanC and non-PanC with late-diabetes with respect to HS, the diagnostic accuracy in PanC with late-diabetes vs. HS reached by each miRNA (miR-20b-5p: AUC = 0.760; miR-29a: AUC = 0.630) was lower than the ones achieved in PanC with early-diabetes vs. HS. Furthermore, miR-20b-5p achieved a higher diagnostic accuracy to discriminate non-PanC with early-diabetes from HS (AUC = 0.868; SP = 81%; PPV = 32.1%) compared to the CA 19-9 (AUC = 0.700; SP = 40.0%; PPV = 15.5%), and the joint (miR-20b-5p and CA 19-9) discrimination ability was higher than the one achieved by the CA 19-9 tested alone (AUC = 0.900, p = 0.003). Our data highlighted the association between miR-18a-5p and early-diabetes, and suggested for miR-20b-5p and miR-29 a role in identifying early diabetes in PanC, albeit not as an early manifestation of cancer. MiR-20b-5p as more informative marker than CA 19-9 in distinguishing non-PanC with recent diabetes from HS was also uncovered.
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Affiliation(s)
- Francesca Tavano
- Division of Gastroenterology and Research Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Andrea Fontana
- Unit of Biostatistics, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Tommaso Mazza
- Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Domenica Gioffreda
- Division of Gastroenterology and Research Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Tommaso Biagini
- Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Orazio Palumbo
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Massimo Carella
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Angelo Andriulli
- Division of Gastroenterology and Research Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
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22
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Chiang S, Huang MLH, Richardson DR. Treatment of dilated cardiomyopathy in a mouse model of Friedreich's ataxia using N-acetylcysteine and identification of alterations in microRNA expression that could be involved in its pathogenesis. Pharmacol Res 2020; 159:104994. [PMID: 32534099 DOI: 10.1016/j.phrs.2020.104994] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/01/2020] [Accepted: 06/01/2020] [Indexed: 01/01/2023]
Abstract
Deficient expression of the mitochondrial protein, frataxin, leads to a deadly cardiomyopathy. Our laboratory reported the master regulator of oxidative stress, nuclear factor erythroid 2-related factor-2 (Nrf2), demonstrates marked down-regulation after frataxin deletion in the heart. This was due, in part, to a pronounced increase in Keap1. To assess if this can be therapeutically targeted, cells were incubated with N-acetylcysteine (NAC), or buthionine sulfoximine (BSO), which increases or decreases glutathione (GSH), respectively, or the NRF2-inducer, sulforaphane (SFN). While SFN significantly (p < 0.05) induced NRF2, KEAP1 and BACH1, NAC attenuated SFN-induced NRF2, KEAP1 and BACH1. The down-regulation of KEAP1 by NAC was of interest, as Keap1 is markedly increased in the MCK conditional frataxin knockout (MCK KO) mouse model and this could lead to the decreased Nrf2 levels. Considering this, MCK KO mice were treated with i.p. NAC (500- or 1500-mg/kg, 5 days/week for 5-weeks) and demonstrated slightly less (p > 0.05) body weight loss versus the vehicle-treated KO. However, NAC did not rescue the cardiomyopathy. To additionally examine the dys-regulation of Nrf2 upon frataxin deletion, studies assessed the role of microRNA (miRNA) in this process. In MCK KO mice, miR-144 was up-regulated, which down-regulates Nrf2. Furthermore, miRNA screening in MCK KO mice demonstrated 23 miRNAs from 756 screened were significantly (p < 0.05) altered in KOs versus WT littermates. Of these, miR-21*, miR-34c*, and miR-200c, demonstrated marked alterations, with functional clustering analysis showing they regulate genes linked to cardiac hypertrophy, cardiomyopathy, and oxidative stress, respectively.
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MESH Headings
- Acetylcysteine/pharmacology
- Animals
- Basic-Leucine Zipper Transcription Factors/metabolism
- Cardiomyopathy, Dilated/drug therapy
- Cardiomyopathy, Dilated/etiology
- Cardiomyopathy, Dilated/genetics
- Cardiomyopathy, Dilated/metabolism
- Cell Line, Tumor
- Disease Models, Animal
- Friedreich Ataxia/complications
- Friedreich Ataxia/genetics
- Gene Expression Regulation
- Humans
- Iron-Binding Proteins/genetics
- Iron-Binding Proteins/metabolism
- Isothiocyanates/pharmacology
- Kelch-Like ECH-Associated Protein 1/metabolism
- Mice, Knockout
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- NF-E2-Related Factor 2/genetics
- NF-E2-Related Factor 2/metabolism
- Sulfoxides/pharmacology
- Frataxin
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Affiliation(s)
- S Chiang
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006 Australia
| | - M L H Huang
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006 Australia
| | - D R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006 Australia; Centre for Cancer Cell Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia.
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23
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Zhu N, Lin E, Zhang H, Liu Y, Cao G, Fu C, Chen L, Zeng Y, Cai B, Yuan Y, Xia B, Huang K, Lin C. LncRNA H19 Overexpression Activates Wnt Signaling to Maintain the Hair Follicle Regeneration Potential of Dermal Papilla Cells. Front Genet 2020; 11:694. [PMID: 32849769 PMCID: PMC7417632 DOI: 10.3389/fgene.2020.00694] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 06/05/2020] [Indexed: 02/05/2023] Open
Abstract
Androgenetic alopecia (AGA) is a common hair loss disorder resulting in seriously abnormal social interaction and psychological disorders. Transplantation with autologous dermal papilla cells represents a prospective therapy. However, the ability of dermal papilla cells to induce hair follicle development is lost upon cell culturing. Long non-coding RNAs (lncRNAs) are an important class of genes involved in various biological functions, are aberrantly expressed in disease and may play roles in the regulation of Wnt signaling, a critical pathway in maintaining the hair follicle-inducing capability of dermal papilla cells. Examination of dermal papilla cells by lncRNA microarray revealed that H19 was highly expressed in early passage dermal papilla cells compared with late-passage dermal papilla cells. In this study, we constructed H19-overexpressing dermal papilla cells to examine the role of H19 on hair follicle inductivity. Dermal papilla cells infected with lentivirus encoding H19 maintained their cell shape, and continued to display both multiple-layer aggregation and hair follicle-inducing ability upon prolonged culture. H19 exerted these effects through inducing miR-29a to activate Wnt signaling by directly downregulating the expression of Wnt suppressors, including DKK1, Kremen2, and sFRP2, thereby forming a novel regulatory feedback loop between H19 and miR-29a to maintain hair follicle- inducing potential. These results suggest that lncRNA H19 maintains the hair follicle-inducing ability of dermal papilla cells through activation of the Wnt pathway and could be a target for treatment of androgenetic alopecia.
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Affiliation(s)
- Ningxia Zhu
- Department of Pathophysiology, Guilin Medical University, Guilin, China
| | - En Lin
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China.,Department of Reproductive Center, First Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Huan Zhang
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Yang Liu
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Guiyuan Cao
- Department of Pathophysiology, Guilin Medical University, Guilin, China
| | - Congcong Fu
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Le Chen
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Yang Zeng
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Bozhi Cai
- Tissue Engineering Laboratory, First Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Yanping Yuan
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Bin Xia
- Department of Pathophysiology, Guilin Medical University, Guilin, China
| | - Keng Huang
- Department of Emergency, Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Changmin Lin
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
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24
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Zhong Z, Virshup DM. Wnt Signaling and Drug Resistance in Cancer. Mol Pharmacol 2020; 97:72-89. [PMID: 31787618 DOI: 10.1124/mol.119.117978] [Citation(s) in RCA: 154] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 11/21/2019] [Indexed: 12/22/2022] Open
Abstract
Wnts are secreted proteins that bind to cell surface receptors to activate downstream signaling cascades. Normal Wnt signaling plays key roles in embryonic development and adult tissue homeostasis. The secretion of Wnt ligands, the turnover of Wnt receptors, and the signaling transduction are tightly regulated and fine-tuned to keep the signaling output "just right." Hyperactivated Wnt signaling due to recurrent genetic alterations drives several human cancers. Elevated Wnt signaling also confers resistance to multiple conventional and targeted cancer therapies through diverse mechanisms including maintaining the cancer stem cell population, enhancing DNA damage repair, facilitating transcriptional plasticity, and promoting immune evasion. Different classes of Wnt signaling inhibitors targeting key nodes of the pathway have been developed and show efficacy in treating Wnt-driven cancers and subverting Wnt-mediated therapy resistance in preclinical studies. Several of these inhibitors have advanced to clinical trials, both singly and in combination with other existing US Food and Drug Administration-approved anti-cancer modalities. In the near future, pharmacological inhibition of Wnt signaling may be a real choice for patients with cancer. SIGNIFICANCE STATEMENT: The latest insights in Wnt signaling, ranging from basic biology to therapeutic implications in cancer, are reviewed. Recent studies extend understanding of this ancient signaling pathway and describe the development and improvement of anti-Wnt therapeutic modalities for cancer.
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Affiliation(s)
- Zheng Zhong
- Department of Physiology, National University of Singapore, Singapore, Singapore (Z.Z.); Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore (Z.Z., D.M.V.); and Department of Pediatrics, Duke University, Durham, North Carolina (D.M.V.)
| | - David M Virshup
- Department of Physiology, National University of Singapore, Singapore, Singapore (Z.Z.); Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore (Z.Z., D.M.V.); and Department of Pediatrics, Duke University, Durham, North Carolina (D.M.V.)
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25
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Tesfaye AA, Azmi AS, Philip PA. miRNA and Gene Expression in Pancreatic Ductal Adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:58-70. [PMID: 30558723 DOI: 10.1016/j.ajpath.2018.10.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/20/2018] [Accepted: 10/04/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease that is mostly diagnosed late in the course of the illness. Unlike other cancers in which measurable successes have been achieved with traditional chemotherapy, targeted therapy, and, recently, immunotherapy, PDAC has proved to be poorly responsive to these treatments, with only marginal to modest incremental benefits using conventional cytotoxic therapy. There is, therefore, a great unmet need to develop better therapies based on improved understanding of biology and identification of predictive and prognostic biomarkers that would guide therapy. miRNAs are small noncoding RNAs that regulate the expression of some key genes by targeting their 3'-untranslated mRNA region. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. A series of miRNAs have been identified as potential tools for early diagnosis, prediction of treatment response, and prognosis of patients with PDAC. In this review, we present a summary of the miRNAs that have been studied in PDAC in the context of disease biology.
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Affiliation(s)
- Anteneh A Tesfaye
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
| | - Asfar S Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan
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26
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Gao Z, Jiang W, Zhang S, Li P. The State of the Art on Blood MicroRNAs in Pancreatic Ductal Adenocarcinoma. Anal Cell Pathol (Amst) 2019; 2019:9419072. [PMID: 31583198 PMCID: PMC6754866 DOI: 10.1155/2019/9419072] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 09/03/2019] [Indexed: 02/07/2023] Open
Abstract
Despite enormous advances being made in diagnosis and therapeutic interventions, pancreatic ductal adenocarcinoma (PDAC) is still recognized as one of the most lethal malignancies. Early diagnosis and timely curative surgery can markedly improve the prognosis; hence, there is an unmet necessity to explore efficient biomarkers for patients' benefit. Recently, blood miRNAs (miRNAs) have been reported to be a novel biomarker in human cancers. Part of it is selectively packaged by plasma exosomes released from cells via exocytosis and is highly sensitive to changes in the tumor microenvironment. Furthermore, due to less invasiveness and technical availability, miRNA-based liquid biopsy holds promise for further wide usage. Therefore, this review is aimed at presenting an update on the association between blood miRNAs and the biology of PDAC, then discussing its clinical utilization further.
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Affiliation(s)
- Zhuqing Gao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Wei Jiang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
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27
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Ram Makena M, Gatla H, Verlekar D, Sukhavasi S, K Pandey M, C Pramanik K. Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance. Int J Mol Sci 2019; 20:E4242. [PMID: 31480221 PMCID: PMC6747343 DOI: 10.3390/ijms20174242] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 08/22/2019] [Accepted: 08/27/2019] [Indexed: 12/24/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/β-catenin pathway controls the maintenance of somatic stem cells in many tissues and organs and is implicated in pancreatic carcinogenesis by regulating cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, tumor immune microenvironment, etc. Further, dysregulated Wnt has been shown to cause drug resistance in pancreatic cancer. Although different Wnt antagonists are effective in pancreatic patients, limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy. In this review, we have summarized the role of Wnt signaling in pancreatic cancer and suggested future directions to enhance the survival of pancreatic cancer patients.
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Affiliation(s)
- Monish Ram Makena
- Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Himavanth Gatla
- Department of Pediatric Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
| | - Dattesh Verlekar
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Sahithi Sukhavasi
- Center for Distance Learning, GITAM University, Visakhapatnam 530045, India
| | - Manoj K Pandey
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
| | - Kartick C Pramanik
- Department of Basic Sciences, Kentucky College of Osteopathic Medicine, University of Pikeville, Pikeville, KY 41501, USA.
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28
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Huang C, Wang L, Song H, Wu C. MiR-29a inhibits the progression of oral squamous cell carcinoma by targeting Wnt/β-catenin signalling pathway. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:3037-3042. [PMID: 31342798 DOI: 10.1080/21691401.2019.1576712] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Chao Huang
- Department of Stomatology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Lili Wang
- Department of Prosthodontics, Tianjin Stomatological Hospital, Tianjin, China
| | - Hongguang Song
- Department of Stomatology, Beijing DCN Orthopaedic Hospital, Beijing, China
| | - Cungang Wu
- Department of Ultrasonography, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
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29
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Chen SY, Du Y, Song J. MicroRNA-340 Inhibits Epithelial-Mesenchymal Transition by Impairing ROCK-1-Dependent Wnt/β-Catenin Signaling Pathway in Epithelial Cells from Human Benign Prostatic Hyperplasia. Chin Med J (Engl) 2019; 131:2008-2012. [PMID: 30082536 PMCID: PMC6085864 DOI: 10.4103/0366-6999.238145] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Si-Yang Chen
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Yuan Du
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Jian Song
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
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30
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miRNA Predictors of Pancreatic Cancer Chemotherapeutic Response: A Systematic Review and Meta-Analysis. Cancers (Basel) 2019; 11:cancers11070900. [PMID: 31252688 PMCID: PMC6678460 DOI: 10.3390/cancers11070900] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/13/2019] [Accepted: 06/21/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND pancreatic cancer (PC) has increasing incidence and mortality in developing countries, and drug resistance is a significant hindrance to the efficacy of successful treatment. The objective of this systematic review and meta-analysis was to evaluate the association between miRNAs and response to chemotherapy in pancreatic cancer patients. METHODS the systematic review and meta-analysis was based on articles collected from a thorough search of PubMed and Science Direct databases for publications spanning from January 2008 to December 2018. The articles were screened via a set of inclusion and exclusion criteria based on the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. Data was extracted, collated and tabulated in MS Excel for further synthesis. Hazard ratio (HR) was selected as the effect size metric to be pooled across studies for the meta-analysis, with the random effects model being applied. Subgroup analysis was also conducted, and the presence of publication bias in the selected studies was assessed. Publication bias of the included studies was quantified. FINDINGS of the 169 articles screened, 43 studies were included in our systematic review and 13 articles were included in the meta-analysis. Gemcitabine was observed to be the principal drug used in a majority of the studies. A total of 48 miRNAs have been studied, and 18 were observed to have possible contributions to chemoresistance, while 15 were observed to have possible contributions to chemosensitivity. 41 drug-related genetic pathways have been identified, through which the highlighted miRNA may be affecting chemosensitivity/resistance. The pooled HR value for overall survival was 1.603; (95% Confidence Interval (CI) 1.2-2.143; p-value: 0.01), with the subgroup analysis for miR-21 showing HR for resistance of 2.061; 95% CI 1.195-3.556; p-value: 0.09. INTERPRETATION our results highlight multiple miRNAs that have possible associations with modulation of chemotherapy response in pancreatic cancer patients. Further studies are needed to discover the molecular mechanisms underlying these associations before they can be suggested for use as biomarkers of response to chemotherapeutic interventions in pancreatic cancer.
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31
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Chen X, Wei R, Jin T, Du H. RETRACTED ARTICLE: Notoginsenoside R1 alleviates TNF-α-induced pancreatic β-cell Min6 apoptosis and dysfunction through up-regulation of miR-29a. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:2379-2388. [PMID: 31184222 DOI: 10.1080/21691401.2019.1624368] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Xiabo Chen
- Department of Endocrinology, Ningbo Municipal Hospital of Traditional Chinese Medicine, Ningbo, China
| | - Renxiong Wei
- Department of Clinical Laboratory, Ningbo Municipal Hospital of Traditional Chinese Medicine, Ningbo China
| | - Tinglong Jin
- Department of Endocrinology, Ningbo Municipal Hospital of Traditional Chinese Medicine, Ningbo, China
| | - Hanguang Du
- Department of Endocrinology, Ningbo Municipal Hospital of Traditional Chinese Medicine, Ningbo, China
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32
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Feng W, Su Z, Yin Q, Zong W, Shen X, Ju S. ncRNAs associated with drug resistance and the therapy of digestive system neoplasms. J Cell Physiol 2019; 234:19143-19157. [PMID: 30941775 DOI: 10.1002/jcp.28551] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/25/2019] [Accepted: 03/05/2019] [Indexed: 12/19/2022]
Abstract
Digestive system cancer remains a common cancer and the main cause of cancer-related death worldwide. Drug resistance is a major challenge in the therapy of digestive system cancer, and represents a primary obstacle in the treatment of cancer by restricting the efficiency of both traditional chemotherapy and biological therapies. Existing studies indicate that noncoding RNAs play an important role in the evolution and progression of drug resistance in digestive system cancer, mainly by modulating drug transporter-related proteins, DNA damage repair, cell-cycle-related proteins, cell apoptosis-related proteins, drug target-related proteins, and the tumor microenvironment. In this review, we address the potential mechanisms of ncRNAs underlying drug resistance in digestive system tumors and discuss the possible application of ncRNAs against drug resistance in digestive system tumors.
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Affiliation(s)
- Wei Feng
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Zhangyao Su
- School of Medicine, Nantong University, Nantong, China
| | - Qingqing Yin
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Wei Zong
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Xianjuan Shen
- Clinical Medical Research Center, Affiliated Hospital of Nantong University, Nantong, China
| | - Shaoqing Ju
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
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33
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Funamizu N, Lacy CR, Kamada M, Yanaga K, Manome Y. MicroRNA-200b and -301 are associated with gemcitabine response as biomarkers in pancreatic carcinoma cells. Int J Oncol 2019; 54:991-1000. [PMID: 30628651 DOI: 10.3892/ijo.2019.4676] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 11/13/2018] [Indexed: 11/05/2022] Open
Abstract
Chemotherapy resistance (congenital or acquired) is one of the principal challenges for the treatment of pancreatic carcinoma. Recent evidence has demonstrated that epithelial to mesenchymal transition (EMT) is associated with chemoresistance in pancreatic carcinoma cells. However, the molecular mechanism underlying the development of chemoresistance remains unknown, and limited therapeutic options are available. Therefore, to anticipate individual chemosensitivity or acquired chemoresistance for patients with pancreatic carcinoma, predictive biomarkers are urgently required. Extensive evidence suggests that microRNAs (miRNAs) serve a crucial role in regulating EMT. The aim of this study was to examine the potential role of miRNA (miR)‑200b and miR‑301 in predicting the chemo‑responses to treatment for pancreatic carcinoma. The present results demonstrate that miR‑200b expression predicted chemo‑sensitivity and may have potential as a biomarker. In six different pancreatic carcinoma cell lines (Capan‑1, Capan‑2, Panc‑1, MIAPaCa‑2, BxPC‑3 and PL45 cells), the expression of miR‑200b correlated positively with chemosensitivity. Moreover, the enhanced expression of miR‑200b increased chemosensitivity and induced mesenchymal to epithelial transition. Conversely, miR‑301 modulated gemcitabine resistance and induced EMT through the downregulation of cadherin 1 expression. In addition, gemcitabine‑resistant cells (Capan‑2 and Panc‑1) exhibited upregulated miR‑301 expression and downregulated gemcitabine‑induced apoptosis. In summary, these two miRNAs may serve roles as biomarkers in pancreatic carcinoma, miR‑200b expression may predict chemosensitivity, and elevated miR‑301 expression may have potential applications in the prediction of acquired gemcitabine resistance.
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Affiliation(s)
- Naotake Funamizu
- Department of Surgery, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Curtis Ray Lacy
- Howard University School of Medicine, Washington DC 20059, USA
| | - Minori Kamada
- Department of Molecular Cell Biology, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Katsuhiko Yanaga
- Department of Surgery, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Yoshinobu Manome
- Department of Molecular Cell Biology, The Jikei University School of Medicine, Tokyo 105-8461, Japan
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34
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Yin X, Liu Z, Zhu P, Wang Y, Ren Q, Chen H, Xu J. CXCL12/CXCR4 promotes proliferation, migration, and invasion of adamantinomatous craniopharyngiomas via PI3K/AKT signal pathway. J Cell Biochem 2018; 120:9724-9736. [PMID: 30582214 DOI: 10.1002/jcb.28253] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 10/22/2018] [Indexed: 02/05/2023]
Abstract
OBJECTIVES Adamantinomatous craniopharyngiomas (adaCP) accounts for 5.6% to 15% of intracranial tumors. High expression of chemokine (C-X-C motif) ligand 12 (CXCL12, also known as stromal cell-derived factor 1 [SDF1]) and its receptor CXC receptor type 4 (CXCR4) are widespread in various malignancy via multiple signal transduction pathways. This study aims to investigate the mechanism of CXCL12/CXCR4 promoting proliferation, migration, and invasion of adaCP. METHODS Quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry were used to evaluate the expression of CXCL12/CXCR4 mRNA and protein in 10 human adaCP tissues. Three successfully primary cell lines were obtained from native mainly solid tumor specimens, and confirmed by the means of inverted contrast microscope directly and following hematoxylin and eosin staining. Immunofluorescence was used to detect protein expression in vivo for the verification of primary cell line. Proliferation, migration, and invasion assays were performed to assess the biological functional role of CXCL12/CXCR4 in adaCP. The signal pathways involved in the action of CXCL12/CXCR4 in adaCP were also evaluated. RESULTS CXCL12 and CXCR4 were highly expressed in human adaCP samples. Primary adaCP cells were isolated and detected by the means of immunofluorescence for the detection of pan cytokeratin (pan-CK) and vimentin (VIM). Overexpression of CXCL12/CXCR4 significantly promoted the proliferation, migration, and invasion of primary adaCP cells. Moreover, cancer-promoting activity of CXCL12/CXCR4 is partially through its facilitation of PI3K/AKT signal pathway. CONCLUSIONS Our data showed that CXCL12/CXCR4 promotes adaCP proliferation, migration, and invasion through PI3K/AKT signal pathway. These findings suggested that therapeutic strategies regulating CXCL12/CXCR4 expression may provide an effective treatment of adaCP.
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Affiliation(s)
- Xiaohong Yin
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.,Department of Neurosurgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Zhiyong Liu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Pan Zhu
- Department of Clinical Laboratory, Taihe Hospital (Affiliated Hubei University of Medicine), Shiyan, Hubei, People's Republic of China
| | - Yuelong Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Qingqing Ren
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Hongxu Chen
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
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35
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You Y, Que K, Zhou Y, Zhang Z, Zhao X, Gong J, Liu Z. MicroRNA-766-3p Inhibits Tumour Progression by Targeting Wnt3a in Hepatocellular Carcinoma. Mol Cells 2018; 41:830-841. [PMID: 30145863 PMCID: PMC6182221 DOI: 10.14348/molcells.2018.0181] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 06/09/2018] [Accepted: 07/12/2018] [Indexed: 12/20/2022] Open
Abstract
Recent studies have indicated that microRNAs (miRNAs) play an important role in hepatocellular carcinoma (HCC) progression. In this study, we showed that miR-766-3p was decreased in approximately 72% of HCC tissues and cell lines, and its low expression level was significantly correlated with tumour size, TNM stage, metastasis, and poor prognosis in HCC. Ectopic miR-766-3p expression inhibited HCC cell proliferation, colony formation, migration and invasion. In addition, we showed that miR-766-3p repressed Wnt3a expression. A luciferase reporter assay revealed that Wnt3a was a direct target of miR-766-3p, and an inverse correlation between miR-766-3p and Wnt3a expression was observed. Moreover, Wnt3a up-regulation reversed the effects of miR-766-3p on HCC progression. In addition, our study showed that miR-766-3p up-regulation decreased the nuclear β-catenin level and expression of Wnt targets (TCF1 and Survivin) and reduced the level of MAP protein regulator of cytokinesis 1 (PRC1). However, these effects of miR-766-3p were reversed by Wnt3a up-regulation. In addition, PRC1 up-regulation increased the nuclear β-catenin level and protein expression of TCF1 and Survivin. iCRT3, which disrupts the β-catenin-TCF4 interaction, repressed the TCF1, Survivin and PRC1 protein levels. Taken together, our results suggest that miR-766-3p down-regulation promotes HCC cell progression, probably by targeting the Wnt3a/PRC1 pathway, and miR-766-3p may serve as a potential therapeutic target in HCC.
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Affiliation(s)
- Yu You
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010,
China
| | - Keting Que
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010,
China
| | - Yun Zhou
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010,
China
| | - Zhen Zhang
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010,
China
| | - Xiaoping Zhao
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010,
China
| | - Jianpin Gong
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010,
China
| | - Zuojin Liu
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010,
China
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36
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Hu W, Liu Q, Pan J, Sui Z. MiR-373-3p enhances the chemosensitivity of gemcitabine through cell cycle pathway by targeting CCND2 in pancreatic carcinoma cells. Biomed Pharmacother 2018; 105:887-898. [PMID: 30021382 DOI: 10.1016/j.biopha.2018.05.091] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 05/19/2018] [Accepted: 05/20/2018] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE This study aimed to detect the expression of miR-373-3p and CCND2 in gemcitabine-resistance pancreatic carcinoma (PC) cells, investigate the relationship between miR-373-3p and CCND2, and explore their effects on PC propagation, migration, invasion and apoptosis. METHODS R software was applied for analyzing differentially expressed genes (DEGs) in cell samples. The potential biological pathway was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, based on R software. The gemcitabine-resistance PC cells were screened out using MTT assay, and they were applied in the next experiments. MiR-373-3p and CCND2 expression in GEM-PANC-1 cells were measured by qRT-PCR. After transfection, the expression of CCND2 protein was examined via western blot assay. Cells viability and apoptosis were confirmed by MTT proliferation assay and Flow cytometry, whereas cells migration and invasion were analyzed by transwell assay. The targeting relationship between miR-373-3p and CCND2 was identified by dual-luciferase reporter assay. RESULTS MiR-373-3p was found to be low expressed in GEM-PANC-1 cells while CCND2 was highly expressed in GEM-PANC-1 cells. MiR-373-3p negatively regulated CCND2 expression through KEGG_Cell_Cycle_Signaling_Pathway. The targeted relationship between miR-373-3p and CCND2 could be verified using dual luciferase reporter assay. MTT proliferation assay, transwell assay and Annexin V assay demonstrated that miR-373-3p suppressed GEM-PANC-1 cells propagation and invasion and promoted cell apoptosis, while CCND2 showed totally reverse effects compared with miR-373-3p. All the results suggested that miR-373-3p could enhance the chemosensitivity of GEM-PANC-1 cells by regulating CCND2. CONCLUSION MiR-373-3p inhibited cell propagation, migration and invasion and boosted apoptosis in gemcitabine resistance pancreatic carcinoma cells by targeting CCND2.
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Affiliation(s)
- Wenjie Hu
- Department of Pharmacy, Qingdao Mental Health Center, Qingdao, 266034, Shandong, China
| | - Qilong Liu
- Department of Pharmacy, Qingdao Mental Health Center, Qingdao, 266034, Shandong, China
| | - Jie Pan
- Department of Pharmacy, Qingdao Mental Health Center, Qingdao, 266034, Shandong, China
| | - Zheng Sui
- Department of Pharmacy, Qingdao Mental Health Center, Qingdao, 266034, Shandong, China.
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Han X, Zheng J, Wang Y, Gao Z. miRNA-29a inhibits colon cancer growth by regulation of the PTEN/Akt/GSK3β and Wnt/β-catenin signaling pathways. Oncol Lett 2018; 16:2638-2644. [PMID: 30013659 DOI: 10.3892/ol.2018.8905] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Accepted: 03/19/2018] [Indexed: 12/13/2022] Open
Abstract
In the present study, the effects of microRNA-29a (miRNA-29a) on colon cancer cell viability and the molecular mechanisms underlying the effects were investigated. The expression of miRNA-29a in colon cancer serum samples was notably downregulated, compared with in the normal group. First, miRNA-29a mimic was used to increase the expression of miRNA-29a in HCT-116 cells. Furthermore, upregulation of miRNA-29a suppressed cell viability, increased lactate dehydrogenase levels and apoptosis, and promoted caspase-3/9 activities and B-cell lymphoma 2-associated X protein and phosphatase and tensin homolog (PTEN) protein expression in colon cancer cells. Furthermore, upregulation of miRNA-29a decreased phosphoinositide 3-kinase, phosphorylated (p)-protein kinase B (Akt) and p-glycogen synthase kinase 3β (GSK3β) protein expression and suppressed the Wnt/β-catenin signaling pathway in colon cancer cells. The results of the present study verified that the protective effects of miRNA-29a suppress the PTEN/Akt/GSK3β and Wnt/β-catenin signaling pathways in colon cancer.
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Affiliation(s)
- Xiaofeng Han
- Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100043, P.R. China
| | - Jianwei Zheng
- Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100043, P.R. China
| | - Yunlei Wang
- Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100043, P.R. China
| | - Zhigang Gao
- Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100043, P.R. China
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38
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MiR-29a: a potential therapeutic target and promising biomarker in tumors. Biosci Rep 2018; 38:BSR20171265. [PMID: 29217524 PMCID: PMC5803495 DOI: 10.1042/bsr20171265] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 12/05/2017] [Accepted: 12/06/2017] [Indexed: 02/06/2023] Open
Abstract
MiRNAs, small non-coding RNA molecules, were recognized to be associated with the incidence and development of diverse neoplasms. MiRNAs were small non-coding RNAs that could regulate post-transcriptional level by binding to 3'-UTR of target mRNAs. Amongst which, miR-29a was demonstrated that it had significant impact on oncogenicity in various neoplasms through binding to critical genes which enhanced or inhibited the progression of cancers. MiR-29a participated in kinds of physiological and pathological processes, including virus replication, cell proliferation, differentiation, apoptosis, fibrosis, angiogenesis, tumorigenicity, metastasis, drug-resistance, and so on. According to its sufficient sensitivity and specificity, many studies showed that miR-29a might serve as a potential therapeutic target and promising biomarker in various tumors. In this review, we discussed the functions of miR-29a and its potential application in the diagnosis, treatment and stages of carcinoma, which could provide additional insight to develop a novel therapeutic strategy.
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39
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Ren L, Yu Y. The role of miRNAs in the diagnosis, chemoresistance, and prognosis of pancreatic ductal adenocarcinoma. Ther Clin Risk Manag 2018; 14:179-187. [PMID: 29416345 PMCID: PMC5790163 DOI: 10.2147/tcrm.s154226] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a very challenging malignancy with late presentation, metastatic potential, chemoresistance, and poor prognosis. Therefore, there is an urgent need for novel diagnostic and prognostic biomarkers. miRNAs are small noncoding RNAs that regulate the expression of multitude number of genes. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. A series of miRNAs have been defined as holding promise for early diagnostics, as indicators of therapy resistance, and even as markers for prognosis in PDAC patients. In this review, we summarize the current knowledge on the role of miRNAs in diagnosis, chemoresistance, and prognosis in PDAC patients.
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Affiliation(s)
- Le Ren
- Department of Gastroenterology, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China
| | - Yue Yu
- Department of Gastroenterology, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China
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40
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Liu J, Fei D, Xing J, Du J. Retracted: MicroRNA-29a inhibits proliferation and induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes by repressing STAT3. Biomed Pharmacother 2017; 96:173-181. [PMID: 28987940 DOI: 10.1016/j.biopha.2017.09.120] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 09/16/2017] [Accepted: 09/23/2017] [Indexed: 12/17/2022] Open
Abstract
Rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS) with aberrant expression of microRNA (miRNA) have been reported to be involved in the initiation, progression, and perpetuation of rheumatoid arthritis (RA). In this study, we explored the biological function and underlying mechanism of microRNA-29a (miR-29a) in cultured RA-FLS from RA patients. The expression of miR-29a in serum, synovial tissues, and FLS from RA patients and health donors was detected by real-time quantitative RT-PCR (qRT-PCR). The effects of miR-29a on cell proliferation, apoptosis, and inflammatory cytokine levels in RA-FLS were also determined using Counting Assay Kit-8 (CCK-8), flow cytometry, and enzyme-linked immunosorbent assay (ELISA) respectively. Luciferase reporter assay was carried out to identify the target genes of miR-29a. We observed that expression of miR-29a was markedly downregulated in serum, synovial tissues and FLS of RA patients. miR-29a overexpression in RA-FLS significantly inhibited proliferation, promoted apoptosis, and suppressed expression of inflammatory cytokines. Signal transducer and activator of transcription 3 (STAT3) was identified to be a direct target of miR-29a in RA-FLS. miR-29a overexpression suppressed the expression of STAT3, as well as phosphorylated STAT3(p-STAT3) and its downstream targets protein (Cyclin D1 and Bcl-2). In addition, the levels of miR-29a were inversely correlated with that of STAT3 in synovial tissues. Rescue experiments showed that overexpression of STAT3 effectively reversed the effect of miR-29a on proliferation and apoptosis in RA-FLS. These data indicate that miR-29a inhibits proliferation and induces apoptosis in RA-FLS by targeting STAT3, suggesting that promoting miR-29a expression may yield therapeutic benefits in the treatment of RA.
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Affiliation(s)
- Jinxiang Liu
- Department of Pediatric Rheumatology and Allergy, the First Affiliated Bethune Hospital, Jilin University, Changchun 130021, PR China
| | - Dan Fei
- Ultrasonographic Department, the China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, PR China
| | - Jie Xing
- Ultrasonographic Department, the China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, PR China
| | - Juan Du
- Department of Rheumatology and Immunology, the China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, PR China.
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41
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Peng Y, Zhang X, Feng X, Fan X, Jin Z. The crosstalk between microRNAs and the Wnt/β-catenin signaling pathway in cancer. Oncotarget 2017; 8:14089-14106. [PMID: 27793042 PMCID: PMC5355165 DOI: 10.18632/oncotarget.12923] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 10/21/2016] [Indexed: 12/16/2022] Open
Abstract
Mounting evidence has indicated microRNA (miR) dysregulation and the Wnt/β-catenin signaling pathway jointly drive carcinogenesis, cancer metastasis, and drug-resistance. The current review will focus on the role of the crosstalk between miRs and the Wnt/β-catenin signaling pathway in cancer development. MiRs were found to activate or inhibit the canonical Wnt pathway at various steps. On the other hand, Wnt activation increases expression of miR by directly binding to its promoter and activating transcription. Moreover, there are mutual feedback loops between some miRs and the Wnt/β-catenin signaling pathway. Clinical trials of miR-based therapeutic agents are investigated for solid and hematological tumors, however, challenges concerning low bioavailability and possible side effects must be overcome before the final clinical application. This review will describe current understanding of miR crosstalk with the Wnt/β-catenin signaling cascade. Better understanding of the regulatory network will provide insight into miR-based therapeutic development.
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Affiliation(s)
- Yin Peng
- Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.,Department of Pathology, Wuhan University School of Basic Medical Sciences, Hubei, People's Republic of China
| | - Xiaojing Zhang
- Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.,Shenzhen Key Laboratory of Translational Medicine in Tumors, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Xianling Feng
- Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Xinmim Fan
- Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Zhe Jin
- Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.,Shenzhen Key Laboratory of Micromolecule Innovatal Drugs, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.,Shenzhen Key Laboratory of Translational Medicine in Tumors, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
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42
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Mondal G, Almawash S, Chaudhary AK, Mahato RI. EGFR-Targeted Cationic Polymeric Mixed Micelles for Codelivery of Gemcitabine and miR-205 for Treating Advanced Pancreatic Cancer. Mol Pharm 2017; 14:3121-3133. [PMID: 28719220 DOI: 10.1021/acs.molpharmaceut.7b00355] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Gemcitabine (GEM), a first-line chemotherapy for pancreatic cancer undergoes rapid metabolism and develops chemoresistance after repeated administration. We previously demonstrated that the combination of GEM and miR-205 provides an effective therapeutic strategy to sensitize GEM-resistant pancreatic cancer cells. Since epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer cells, in this study, we aimed to deliver mixed micelles containing GEM and miR-205 decorated with EGFR-targeting cetuximab (C225) monoclonal antibody for targeted therapy. Cetuximab C225 was conjugated to malemido-poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (C225-PEG-PCD) to prepare mixed micelles with mPEG-b-PCC-g-GEM-g-DC-g-TEPA for targeted codelivery of GEM and miR-205. This mixed micelle formulation showed a significant enhancement in EGFR-mediated cellular uptake in GEM-resistant MIA PaCa-2R cells. Further, an enhanced tumor accumulation of C225-micelles conjugated with near-infrared fluorescent Cy7.5 dye and Dy677-labeled miR-205 in orthotopic pancreatic tumor bearing NSG mice was evident after systemic administration. In addition, inhibition of tumor growth was also observed with increased apoptosis and reduced EMT after treatment with C225-micelles containing GEM and miR-205. Therefore, we believe that the targeted delivery of GEM and miR-205 in combination could be a novel strategy for treating advanced pancreatic cancer.
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Affiliation(s)
- Goutam Mondal
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States
| | - Saud Almawash
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States
| | - Amit Kumar Chaudhary
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States
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43
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Xiao Y, Deng T, Su C, Shang Z. MicroRNA 217 inhibits cell proliferation and enhances chemosensitivity to doxorubicin in acute myeloid leukemia by targeting KRAS. Oncol Lett 2017; 13:4986-4994. [PMID: 28599501 DOI: 10.3892/ol.2017.6076] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 01/19/2017] [Indexed: 01/21/2023] Open
Abstract
Acute myeloid leukemia (AML) is a heterogeneous malignant disorder derived from the myeloid hematopoietic cells that accounts for ~80% of all adult acute leukemia. Numerous studies have shown that drug resistance not only exists against conventional chemotherapeutic drugs, but also limits the efficacy of new biological agents. Therefore, it is important to identify the mechanisms behind chemoresistance and seek therapeutic strategies to enhance efficacy in AML chemotherapy. MicroRNA (miR)-217 has been recognized as a tumor suppressor that is downregulated in various types of cancer, however the mechanisms behind the expression and function of miR-217 in AML have not yet been recognized. The expression of miR-217 was determined by quantitative polymerase chain reaction (qPCR). Following transfection with miR-217 mimics, an MTT assay, chemosensitivity assay, cell apoptosis assay and western blot analysis were performed in AML cell lines. Functional assays were also performed to explore the effects of endogenous Kirsten rat sarcoma viral oncogene homolog (KRAS) in AML. The results revealed that miR-217 was downregulated in patients with AML. Overexpression of miR-217 inhibited cellular proliferation and enhanced cell chemosensitivity to doxorubicin by the cell apoptosis pathway in AML cells. A dual-luciferase reporter assay demonstrated that KRAS was a direct target gene of miR-217 in vitro. qPCR and western blot analysis revealed that miR-217 negatively regulated KRAS protein expression, but had no impact on KRAS mRNA expression. Knockdown of KRAS expression markedly suppressed AML cellular proliferation, and enhanced cell chemosensitivity to doxorubicin via the cell apoptosis pathway. These findings indicate that miR-217 functions as a tumor suppressor in AML by directly targeting KRAS. Therefore, miR-217-based therapeutic strategies may provide a novel strategy for the enhancement of efficacy in the treatment of AML.
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Affiliation(s)
- Yi Xiao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Taoran Deng
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Changliang Su
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Zhen Shang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Zhang Y, Liu Y, Xu X. Upregulation of miR-142-3p Improves Drug Sensitivity of Acute Myelogenous Leukemia through Reducing P-Glycoprotein and Repressing Autophagy by Targeting HMGB1. Transl Oncol 2017; 10:410-418. [PMID: 28445844 PMCID: PMC5406584 DOI: 10.1016/j.tranon.2017.03.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 03/06/2017] [Accepted: 03/06/2017] [Indexed: 01/22/2023] Open
Abstract
miR-142-3p was reported to be downregulated in acute myelogenous leukemia (AML) and acted as a novel diagnostic marker. However, the regulatory effect of miR-142-3p on drug resistance of AML cells and its underlying mechanism have not been elucidated. Here, we found that miR-142-3p was significantly downregulated and high mobility group box 1 (HMGB1) was dramatically upregulated in AML samples and cells, as well as drug-resistant AML cells. P-gp level and autophagy were markedly enhanced in HL-60/ADR and HL-60/ATRA cells. miR-142-3p overexpression improved drug sensitivity of AML cells by inhibiting cell viability and promoting apoptosis, and inhibited P-gp level and autophagy in drug-resistant AML cells, whereas HMGB1 overexpression obviously reversed these effect. HMGB1 was demonstrated to be a target of miR-142-3p, and miR-142-3p negatively regulated HMGB1 expression. In conclusion, our study elucidated that upregulation of miR-142-3p improves drug sensitivity of AML through reducing P-glycoprotein and repressing autophagy by targeting HMGB1, contributing to better understanding the molecular mechanism of drug resistance in AML.
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Affiliation(s)
- Yuan Zhang
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China
| | - Yufeng Liu
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China.
| | - Xueju Xu
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China
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45
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Vesel M, Rapp J, Feller D, Kiss E, Jaromi L, Meggyes M, Miskei G, Duga B, Smuk G, Laszlo T, Karner I, Pongracz JE. ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling. Respir Res 2017; 18:52. [PMID: 28340578 PMCID: PMC5364604 DOI: 10.1186/s12931-017-0537-6] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 03/14/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Lung cancer (LC) is still the most common cause of cancer related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all LC cases but is not a single entity. It is now accepted that, apart from the characteristic driver mutations, the unique molecular signatures of adeno- (AC) and squamous cell carcinomas (SCC), the two most common NSCLC subtypes should be taken into consideration for their management. Therapeutic interventions, however, frequently lead to chemotherapy resistance highlighting the need for in-depth analysis of regulatory mechanisms of multidrug resistance to increase therapeutic efficiency. METHODS Non-canonical Wnt5a and canonical Wnt7b and ABC transporter expressions were tested in primary human LC (n = 90) resections of AC and SCC. To investigate drug transporter activity, a three dimensional (3D) human lung aggregate tissue model was set up using differentiated primary human lung cell types. Following modification of the canonical, beta-catenin dependent Wnt pathway or treatment with cisplatin, drug transporter analysis was performed at mRNA, protein and functional level using qRT-PCR, immunohistochemistry, immune-fluorescent staining and transport function analysis. RESULTS Non-canonical Wnt5a is significantly up-regulated in SCC samples making the microenvironment different from AC, where the beta-catenin dependent Wnt7b is more prominent. In primary cancer tissues ABCB1 and ABCG2 expression levels were different in the two NSCLC subtypes. Non-canonical rhWnt5a induced down-regulation of both ABCB1 and ABCG2 transporters in the primary human lung aggregate tissue model recreating the SCC-like transporter pattern. Inhibition of the beta-catenin or canonical Wnt pathway resulted in similar down-regulation of both ABC transporter expression and function. In contrast, cisplatin, the frequently used adjuvant chemotherapeutic agent, activated beta-catenin dependent signaling that lead to up-regulation of both ABCB1 and ABCG2 transporter expression and activity. CONCLUSIONS The difference in the Wnt microenvironment in AC and SCC leads to variations in ABC transporter expression. Cisplatin via induction of canonical Wnt signaling up-regulates ABCB1 and ABCG2 drug transporters that are not transporters for cisplatin itself but are transporters for drugs that are frequently used in combination therapy with cisplatin modulating drug response.
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Affiliation(s)
- M Vesel
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
- Scientific Unit, Osijek University Hospital, Huttlerova 4, Osijek, HR31000, Croatia
| | - J Rapp
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
- Humeltis Ltd, Pecs, Hungary
| | - D Feller
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
- Humeltis Ltd, Pecs, Hungary
| | - E Kiss
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
- Humeltis Ltd, Pecs, Hungary
| | - L Jaromi
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
| | - M Meggyes
- Department of Microbiology and Immunology, School of Medicine, University of Pecs, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
- Humeltis Ltd, Pecs, Hungary
| | - G Miskei
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
| | - B Duga
- Humeltis Ltd, Pecs, Hungary
| | - G Smuk
- Department of Pathology, School of Medicine, University of Pecs, Pecs, Hungary
| | - T Laszlo
- Department of Pathology, School of Medicine, University of Pecs, Pecs, Hungary
| | - I Karner
- Department of Pathophysiology, Faculty of Medicine, University of Osijek, Cara Hadrijana 10, Osijek, HR31300, Croatia
| | - J E Pongracz
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary.
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary.
- Humeltis Ltd, Pecs, Hungary.
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Xu W, Jiang H, Zhang F, Gao J, Hou J. MicroRNA-330 inhibited cell proliferation and enhanced chemosensitivity to 5-fluorouracil in colorectal cancer by directly targeting thymidylate synthase. Oncol Lett 2017; 13:3387-3394. [PMID: 28521444 PMCID: PMC5431319 DOI: 10.3892/ol.2017.5895] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 01/06/2017] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in males and the second most common in females, worldwide. Currently, 5-fluorouracil (5-FU)-mediated chemotherapy is the adjuvant treatment for patients with CRC following surgical resection. However, a number of patients with CRC develop 5-FU resistance, which is a major challenge for the effective treatment of cancer. Therefore, it is important to investigate the molecular mechanisms underlying chemoresistance and the therapeutic treatments that may improve the treatment of CRC. The present study demonstrated that microRNA (miR)-330 was significantly downregulated in CRC tissues and cell lines. Ectopic miR-330 expression decreased cell proliferation and enhanced cell chemosensitivity to 5-FU via the cell apoptosis pathway in CRC. In addition, thymidylate synthase (TYMS) was revealed to be a direct target gene of miR-330 in CRC. Knockdown of TYMS inhibited CRC cell proliferation, and enhanced cell chemosensitivity to 5-FU by promoting cell apoptosis. In conclusion, the results of the present study indicated that miR-330 targeted TYMS to inhibit the proliferation and enhance the chemosensitivity of CRC cells to 5-FU by promoting cell apoptosis. The present study provided important insight into the molecular mechanism underlying 5-FU-mediated chemoresistance and a novel therapeutic strategy for the enhancement of efficacy in CRC treatment.
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Affiliation(s)
- Weidong Xu
- Department of Radiation Oncology, The Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Huayong Jiang
- Department of Radiation Oncology, The Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Fuli Zhang
- Department of Radiation Oncology, The Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Junmao Gao
- Department of Radiation Oncology, The Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Jun Hou
- Department of Radiation Oncology, The Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
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The underlying mechanisms of non-coding RNAs in the chemoresistance of pancreatic cancer. Cancer Lett 2017; 397:94-102. [PMID: 28254409 DOI: 10.1016/j.canlet.2017.02.020] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/08/2017] [Accepted: 02/21/2017] [Indexed: 12/21/2022]
Abstract
Pancreatic cancer, which is often asymptomatic, is currently one of the most common causes of cancer-related death. This phenomenon is most likely due to a lack of early diagnosis, a high metastasis rate and a disappointing chemotherapy outcome. Thus, improving treatment outcomes by overcoming chemotherapy resistance may be a useful strategy in pancreatic cancer. Various underlying mechanisms involved in the chemoresistance of pancreatic cancer have been investigated. Notably, non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a pivotal role in regulating sensitivity to chemotherapy in pancreatic cancer. In this review, we highlight recent evidence regarding the role of miRNAs and lncRNAs in the chemoresistance of pancreatic cancer, including their expression levels, targets, biological functions and the regulation of chemoresistance, and discuss the potential clinical application of miRNAs and lncRNAs in the treatment of pancreatic cancer.
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48
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Calatayud D, Dehlendorff C, Boisen MK, Hasselby JP, Schultz NA, Werner J, Immervoll H, Molven A, Hansen CP, Johansen JS. Tissue MicroRNA profiles as diagnostic and prognostic biomarkers in patients with resectable pancreatic ductal adenocarcinoma and periampullary cancers. Biomark Res 2017; 5:8. [PMID: 28239461 PMCID: PMC5320745 DOI: 10.1186/s40364-017-0087-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 02/03/2017] [Indexed: 12/20/2022] Open
Abstract
Background The aim of this study was to validate previously described diagnostic and prognostic microRNA expression profiles in tissue samples from patients with pancreatic cancer and other periampullary cancers. Methods Expression of 46 selected microRNAs was studied in formalin-fixed paraffin-embedded tissue from patients with resected pancreatic ductal adenocarcinoma (n = 165), ampullary cancer (n=59), duodenal cancer (n = 6), distal common bile duct cancer (n = 21), and gastric cancer (n = 20); chronic pancreatitis (n = 39); and normal pancreas (n = 35). The microRNAs were analyzed by PCR using the Fluidigm platform. Results Twenty-two microRNAs were significantly differently expressed in patients with pancreatic cancer when compared to healthy controls and chronic pancreatitis patients; 17 miRNAs were upregulated (miR-21-5p, −23a-3p, −31-5p, −34c-5p, −93-3p, −135b-3p, −155-5p, −186-5p, −196b-5p, −203, −205-5p, −210, −222-3p, −451, −492, −614, and miR-622) and 5 were downregulated (miR-122-5p, −130b-3p, −216b, −217, and miR-375). MicroRNAs were grouped into diagnostic indices of varying complexity. Ten microRNAs associated with prognosis were identified (let-7 g, miR-29a-5p, −34a-5p, −125a-3p, −146a-5p, −187, −205-5p, −212-3p, −222-5p, and miR-450b-5p). Prognostic indices based on differences in expression of 2 different microRNAs were constructed for pancreatic and ampullary cancer combined and separately (30, 5, and 21 indices). Conclusion The study confirms that pancreatic cancer tissue has a microRNA expression profile that is different from that of other periampullary cancers, chronic pancreatitis, and normal pancreas. We identified prognostic microRNAs and microRNA indices that were associated with shorter overall survival in patients with radically resected pancreatic cancer. Electronic supplementary material The online version of this article (doi:10.1186/s40364-017-0087-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Dan Calatayud
- Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.,Department of Oncology, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark
| | | | - Mogens K Boisen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Jane Preuss Hasselby
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Nicolai Aagaard Schultz
- Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, LMU, University of Munich, Munich, Germany
| | - Heike Immervoll
- Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.,Department of Pathology, Ålesund Hospital, Ålesund, Norway
| | - Anders Molven
- Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Carsten Palnæs Hansen
- Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Julia S Johansen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Muluhngwi P, Krishna A, Vittitow SL, Napier JT, Richardson KM, Ellis M, Mott JL, Klinge CM. Tamoxifen differentially regulates miR-29b-1 and miR-29a expression depending on endocrine-sensitivity in breast cancer cells. Cancer Lett 2016; 388:230-238. [PMID: 27986463 DOI: 10.1016/j.canlet.2016.12.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 12/05/2016] [Accepted: 12/06/2016] [Indexed: 12/21/2022]
Abstract
Endocrine-resistance develops in ∼40% of breast cancer patients after tamoxifen (TAM) therapy. Although microRNAs are dysregulated in breast cancer, their contribution to endocrine-resistance is not yet understood. Previous microarray analysis identified miR-29a and miR-29b-1 as repressed by TAM in MCF-7 endocrine-sensitive breast cancer cells but stimulated by TAM in LY2 endocrine-resistant breast cancer cells. Here we examined the mechanism for the differential regulation of these miRs by TAM in MCF-7 versus TAM-resistant LY2 and LCC9 breast cancer cells and the functional role of these microRNAs in these cells. Knockdown studies revealed that ERα is responsible for TAM regulation of miR-29b-1/a transcription. We also demonstrated that transient overexpression of miR-29b-1/a decreased MCF-7, LCC9, and LY2 proliferation and inhibited LY2 cell migration and colony formation but did not sensitize LCC9 or LY2 cells to TAM. Furthermore, TAM reduced DICER1 mRNA and protein in LY2 cells, a known target of miR-29. Supporting this observation, anti-miR-29b-1 or anti-miR-29a inhibited the suppression of DICER by 4-OHT. These results suggest miR-29b-1/a has tumor suppressor activity in TAM-resistant cells and does not appear to play a role in mediating TAM resistance.
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Affiliation(s)
- Penn Muluhngwi
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Abirami Krishna
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Stephany L Vittitow
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Joshua T Napier
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Kirsten M Richardson
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Mackenzie Ellis
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Justin L Mott
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Carolyn M Klinge
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
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MicroRNA-29a contributes to drug-resistance of breast cancer cells to adriamycin through PTEN/AKT/GSK3β signaling pathway. Gene 2016; 593:84-90. [DOI: 10.1016/j.gene.2016.08.016] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 08/02/2016] [Accepted: 08/08/2016] [Indexed: 11/19/2022]
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