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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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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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Vannini I, Rossi T, Melloni M, Valgiusti M, Urbini M, Passardi A, Bartolini G, Gallio C, Azzali I, Bandini S, Ancarani V, Montanaro L, Frassineti GL, Fabbri F, Rapposelli IG. Analysis of EVs from patients with advanced pancreatic cancer identifies antigens and miRNAs with predictive value. Mol Ther Methods Clin Dev 2023; 29:473-482. [PMID: 37273899 PMCID: PMC10238807 DOI: 10.1016/j.omtm.2023.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 05/09/2023] [Indexed: 06/06/2023]
Abstract
The identification of predictive factors for treatment of pancreatic cancer (PC) is an unmet clinical need. In the present work, we analyzed blood-derived extracellular vesicles (EVs) from patients with advanced PC in order to find a molecular signature predictive of response to therapy. We analyzed samples from 21 patients with advanced PC, all receiving first-line treatment with gemcitabine + nab-paclitaxel. Isolated EVs have been analyzed, and the results of laboratory have been matched with clinical data in order to investigate possible predictive factors. EV concentration and size were similar between responder and non-responder patients. Analysis of 37 EV surface epitopes showed a decreased expression of SSEA4 and CD81 in responder patients. We detected more than 450 expressed miRNAs in EVs. A comparative survey between responder and non-responder patients showed that at least 44 miRNAs were differently expressed. Some of these miRNAs have already been observed in relation to the survival and gemcitabine sensitivity of tumor cells. In conclusion, we showed the ability of our approach to identify EV-derived biomarkers with predictive value for therapy response in PC. Our findings are worthy of further investigation, including the analysis of samples from patients treated with different schedules and in different settings.
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Affiliation(s)
- Ivan Vannini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Tania Rossi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Mattia Melloni
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Milena Urbini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Giulia Bartolini
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Chiara Gallio
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Irene Azzali
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Sara Bandini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Valentina Ancarani
- Immunotherapy-Cell Therapy and Biobank Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Lorenzo Montanaro
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna, Italy
- Departmental Program in Laboratory Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Francesco Fabbri
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Ilario Giovanni Rapposelli
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
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LncRNA MBNL1-AS1 Suppresses Cell Proliferation and Metastasis of Pancreatic Adenocarcinoma through Targeting Carcinogenic miR-301b-3p. Genet Res (Camb) 2023; 2023:6785005. [PMID: 36908851 PMCID: PMC9995204 DOI: 10.1155/2023/6785005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/20/2023] [Accepted: 02/13/2023] [Indexed: 03/05/2023] Open
Abstract
Pancreatic adenocarcinoma (PAAD) has been a huge challenge to public health due to its increasing incidence, frequent early metastasis, and poor outcome. The molecular basis of tumorigenesis and metastasis in PAAD is largely unclear. Here, we identified a novel tumor-suppressor long noncoding RNA (lncRNA) MBNL1-AS1, in PAAD and revealed its downstream mechanism. Quantitative real-time PCR (qRT-PCR) data showed that MBNL1-AS1 expression was significantly downregulated in PAAD tissues and cells, which was closely associated with metastasis and poor prognosis. Cell counting kit-8 (CCK-8) assay, transwell assay, and western blot verified that overexpression of MBNL1-AS1 suppressed cell proliferation, migration, and epithelial mesenchymal transformation (EMT) behavior in PAAD cells. By using a dual luciferase reporter gene system, we confirmed that miR-301b-3p was a direct target of MBNL1-AS1. Further mechanismic study revealed that upregulation of miR-301b-3p abolished the inhibitory effect of MBNL1-AS1 overexpression on cell proliferation, tumorigenesis, migration and EMT. Our results demonstrate that MBNL1-AS1 plays a tumor-suppressive role in PAAD mainly by downregulating miR-301b-3p, providing a novel therapeutic target for PAAD.
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He YG, Huang XB, Li YM, Li J, Peng XH, Huang W, Tang YC, Zheng L. Efficacy and safety of laparoscopic radical resection following neoadjuvant therapy for pancreatic ductal adenocarcinoma: A retrospective study. World J Gastrointest Oncol 2022; 14:1785-1797. [PMID: 36187398 PMCID: PMC9516639 DOI: 10.4251/wjgo.v14.i9.1785] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/16/2022] [Accepted: 08/15/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Multiple studies have demonstrated that neoadjuvant chemotherapy (NACT) can prolong the overall survival of pancreatic ductal adenocarcinoma (PDAC) patients. However, most studies have focused on open surgery following NACT. AIM To investigate the efficacy and safety of laparoscopic radical resection following NACT for PDAC. METHODS We retrospectively analyzed the clinical data of 15 patients with pathologically confirmed PDAC who received NACT followed by laparoscopic radical surgery in our hospital from December 2019 to April 2022. All patients underwent abdominal contrast-enhanced computed tomography (CT) and positron emission tomography-CT before surgery to accurately assess tumor stage and exclude distant metastasis. RESULTS All 15 patients with pancreatic cancer were successfully converted to surgical resection after NACT, including 8 patients with pancreatic head cancer and 7 patients with pancreatic body and tail cancer. Among them, 13 patients received the nab-paclitaxel plus gemcitabine regimen (gemcitabine 1000 mg/m2 plus nab-paclitaxel 125 mg/m2 on days 1, 8, and 15 every 4 wk) and 2 patients received the modified FOLFIRINOX regimen (intravenous oxaliplatin 68 mg/m2, irinotecan 135 mg/m2, and leucovorin 400 mg/m2 on day 1 and fluorouracil 400 mg/m2 on day 1, followed by 46-h continuous infusion of fluorouracil 2400 mg/m2). After each treatment cycle, abdominal CT, tumor markers, and circulating tumor cell counts were reviewed to evaluate the treatment efficacy. All 15 patients achieved partial remission. The surgical procedures included laparoscopic pancreaticoduodenectomy (LPD, n = 8) and laparoscopic radical antegrade modular pancreatosplenectomy (L-RAMPS, n = 7). None of them were converted to a laparotomy. One patient with pancreatic head carcinoma was found to have portal vein involvement during the operation, and LPD combined with vascular resection and reconstruction was performed. The amount of blood loss and operation times of L-RAMPS vs LPD were 435.71 ± 32.37 mL vs 343.75 ± 145.01 mL and 272.52 ± 49.14 min vs 444.38 ± 68.63 min, respectively. The number of dissected lymph nodes was 16.87 ± 4.10, and 3 patients had positive lymph nodes. One patient developed grade B postoperative pancreatic fistula (POPF) after L-RAMPS, and one patient experienced jaundice after LPD. None of the patients died after surgery. As of April 2022, progressive disease was noted in 4 patients, 2 patients had liver metastasis, and one had both liver metastasis and lymph node metastasis and died during the follow-up period. CONCLUSION Laparoscopic radical resection of PDAC after NACT is safe and effective if it is performed by a surgeon with rich experience in LPD and in a large center of pancreatic surgery.
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Affiliation(s)
- Yong-Gang He
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Xiao-Bing Huang
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Yu-Ming Li
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Jing Li
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Xue-Hui Peng
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Wen Huang
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Yi-Chen Tang
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Lu Zheng
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
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Nisar M, Paracha RZ, Adil S, Qureshi SN, Janjua HA. An Extensive Review on Preclinical and Clinical Trials of Oncolytic Viruses Therapy for Pancreatic Cancer. Front Oncol 2022; 12:875188. [PMID: 35686109 PMCID: PMC9171400 DOI: 10.3389/fonc.2022.875188] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/12/2022] [Indexed: 12/12/2022] Open
Abstract
Chemotherapy resistance and peculiar tumor microenvironment, which diminish or mitigate the effects of therapies, make pancreatic cancer one of the deadliest malignancies to manage and treat. Advanced immunotherapies are under consideration intending to ameliorate the overall patient survival rate in pancreatic cancer. Oncolytic viruses therapy is a new type of immunotherapy in which a virus after infecting and lysis the cancer cell induces/activates patients’ immune response by releasing tumor antigen in the blood. The current review covers the pathways and molecular ablation that take place in pancreatic cancer cells. It also unfolds the extensive preclinical and clinical trial studies of oncolytic viruses performed and/or undergoing to design an efficacious therapy against pancreatic cancer.
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Affiliation(s)
- Maryum Nisar
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Rehan Zafar Paracha
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Sidra Adil
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | | | - Hussnain Ahmed Janjua
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad, Pakistan
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Gu J, Huang W, Wang X, Zhang J, Tao T, Zheng Y, Liu S, Yang J, Chen ZS, Cai CY, Li J, Wang H, Fan Y. Hsa-miR-3178/RhoB/PI3K/Akt, a novel signaling pathway regulates ABC transporters to reverse gemcitabine resistance in pancreatic cancer. Mol Cancer 2022; 21:112. [PMID: 35538494 PMCID: PMC9088115 DOI: 10.1186/s12943-022-01587-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 04/27/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Although gemcitabine has been considered as the first-line drug for advanced pancreatic cancer (PC), development of resistance to gemcitabine severely limits the effectiveness of this chemotherapy, and the underlying mechanism of gemcitabine resistance remains unclear. Various factors, such as ATP binding cassette (ABC) transporters, microRNAs and their downstream signaling pathways are included in chemoresistance to gemcitabine. This study investigated the potential mechanisms of microRNAs and ABC transporters related signaling pathways for PC resistance to gemcitabine both in vivo and in vitro. METHODS Immunohistochemistry and Western blotting were applied to detect the expression of ABC transporters. Molecular docking analysis was performed to explore whether gemcitabine interacted with ABC transporters. Gain-of-function and loss-of-function analyses were performed to investigate the functions of hsa-miR-3178 in vitro and in vivo. Bioinformatics analysis, Western blotting and dual-luciferase reporter assay were used to confirm the downstream regulatory mechanisms of hsa-miR-3178. RESULTS We found that P-gp, BCRP and MRP1 were highly expressed in gemcitabine-resistant PC tissues and cells. Molecular docking analysis revealed that gemcitabine can bind to the ABC transporters. Hsa-miR-3178 was upregulated in gemcitabine resistance PANC-1 cells as compared to its parental PANC-1 cells. Moreover, we found that hsa-miR-3178 promoted gemcitabine resistance in PC cells. These results were also verified by animal experiments. RhoB was down-regulated in gemcitabine-resistant PC cells and it was a downstream target of hsa-miR-3178. Kaplan-Meier survival curve showed that lower RhoB expression was significantly associated with poor overall survival in PC patients. Rescue assays demonstrated that RhoB could reverse hsa-miR-3178-mediated gemcitabine resistance. Interestingly, hsa-miR-3178 promoted gemcitabine resistance in PC by activating the PI3K/Akt pathway-mediated upregulation of ABC transporters. CONCLUSIONS Our results indicate that hsa-miR-3178 promotes gemcitabine resistance via RhoB/PI3K/Akt signaling pathway-mediated upregulation of ABC transporters. These findings suggest that hsa-miR-3178 could be a novel therapeutic target for overcoming gemcitabine resistance in PC.
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Affiliation(s)
- Jianyou Gu
- Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, People's Republic of China
| | - Wenjie Huang
- Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, People's Republic of China
| | - Xianxing Wang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, People's Republic of China
| | - Junfeng Zhang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, People's Republic of China
| | - Tian Tao
- Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Yao Zheng
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, People's Republic of China
| | - Songsong Liu
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, People's Republic of China
| | - Jiali Yang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, People's Republic of China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Chao-Yun Cai
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Jinsui Li
- Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Huaizhi Wang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, People's Republic of China.
| | - Yingfang Fan
- Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
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Gulla A, Andriusaityte U, Zdanys GT, Babonaite E, Strupas K, Kelly H. The Impact of Epithelial-Mesenchymal Transition and Metformin on Pancreatic Cancer Chemoresistance: A Pathway towards Individualized Therapy. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:467. [PMID: 35454306 PMCID: PMC9032206 DOI: 10.3390/medicina58040467] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/14/2022] [Accepted: 03/21/2022] [Indexed: 12/26/2022]
Abstract
Globally, pancreatic ductal adenocarcinoma remains among the most aggressive forms of neoplastic diseases, having a dismal prognostic outcome. Recent findings elucidated that epithelial-mesenchymal transition (EMT) can play an important role in pancreatic tumorigenic processes, as it contributes to the manifestation of malignant proliferative masses, which impede adequate drug delivery. An organized literature search with PubMed, Scopus, Microsoft Academic and the Cochrane library was performed for articles published in English from 2011 to 2021 to review and summarize the latest updates and knowledge on the current understanding of EMT and its implications for tumorigenesis and chemoresistance. Furthermore, in the present paper, we investigate the recent findings on metformin as a possible neoadjuvant chemotherapy agent, which affects EMT progression and potentially provides superior oncological outcomes for PDAC patients. Our main conclusions indicate that selectively suppressing EMT in pancreatic cancer cells has a promising therapeutic utility by selectively targeting the chemotherapy-resistant sub-population of cancer stem cells, inhibiting tumor growth via EMT pathways and thereby improving remission in PDAC patients. Moreover, given that TGF-β1-driven EMT generates the migration of tumor-initiating cells by directly linking the acquisition of abnormal cellular motility with the maintenance of tumor initiating potency, the chemoprevention of TGF-β1-induced EMT may have promising clinical applications in the therapeutic management of PDAC outcomes.
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Affiliation(s)
- Aiste Gulla
- Institute of Clinical Medicine, Clinic of Gastroenterology, Surgery, Nephrology, Faculty of Medicine, Vilnius University, Santariskiu Str. 2, 08661 Vilnius, Lithuania;
- Center of Visceral Medicine and Translational Research, Department of Surgery, Georgetown University Hospital, 3800 Reservoir Road Northwest BLES Building 1st. Floor, Washington, DC 20007, USA
| | - Urte Andriusaityte
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Gabrielius Tomas Zdanys
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Elena Babonaite
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Kestutis Strupas
- Institute of Clinical Medicine, Clinic of Gastroenterology, Surgery, Nephrology, Faculty of Medicine, Vilnius University, Santariskiu Str. 2, 08661 Vilnius, Lithuania;
| | - Helena Kelly
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, 123 St. Stephen’s Green, D02 YN77 Dublin, Ireland;
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Forika G, Kiss E, Petovari G, Danko T, Gellert AB, Krenacs T. Modulated Electro-Hyperthermia Supports the Effect of Gemcitabine Both in Sensitive and Resistant Pancreas Adenocarcinoma Cell Lines. Pathol Oncol Res 2021; 27:1610048. [PMID: 34955688 PMCID: PMC8702438 DOI: 10.3389/pore.2021.1610048] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/17/2021] [Indexed: 12/09/2022]
Abstract
The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is frequently associated to high treatment resistance. Gemcitabine (GEM) alone or in combination is the most used chemotherapy for unresecable PDACs. Here we studied whether modulated electro-hyperthermia (mEHT), a non-invasive complementary treatment, can support the effect of GEM on PDAC cells in vitro. The LD20 for the GEM-resistant Panc1 cells proved to be 200× higher than for the drug-sensitive Capan1. The mEHT alone caused significant apoptosis in Capan1 cultures as confirmed by the elevated SubG1 phase cell fraction and increased number of cleaved Caspase-3 positive cells 48 h after treatment, with an additive effect when GEM was used after hyperthermia. These were accompanied by reduced number of G1, S, and G2/M phase cells and elevated expression of the cyclin-dependent kinase inhibitor p21waf1 protein. In GEM-resistant Panc1 cells, an initial apoptosis was detected by flow cytometry 24 h after mEHT ± GEM treatment, which however diminished by 48 h at persistent number of cleaved Caspase-3 positive tumor cells. Though GEM monotherapy reduced the number of tumor progenitor colonies in Capan1 cell line, an additive colony inhibitory effect of mEHT was observed after mEHT + GEM treatment. The heat shock induced Hsp27 and Hsp70 proteins, which are known to sensitize PDAC cells to GEM were upregulated in both Capan1 and Panc1 cells 24 h after mEHT treatment. The level of E-Cadherin, a cell adhesion molecule, increased in Capan1 cells after mEHT + GEM treatment. In conclusion, in GEM-sensitive PDAC cells mEHT treatment alone induced cell death and cell cycle inhibition and improved GEM efficiency in combination, which effects were milder and short-term up to 24 h in the GEM-resistant Panc1 cells. Our data further support the inclusion of hyperthermia, in particular of mEHT, into the traditional oncotherapy regimens of PDAC.
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Affiliation(s)
- Gertrud Forika
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Eva Kiss
- 1st Department of Internal Medicine and Oncology, Oncology Profile, Semmelweis University, Budapest, Hungary
| | - Gabor Petovari
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Titanilla Danko
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Aron Bertram Gellert
- Department of Thoracic Surgery, National Institute of Oncology and Semmelweis University, Budapest, Hungary
| | - Tibor Krenacs
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
- *Correspondence: Tibor Krenacs,
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10
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Pan G, Liu Y, Shang L, Zhou F, Yang S. EMT-associated microRNAs and their roles in cancer stemness and drug resistance. Cancer Commun (Lond) 2021; 41:199-217. [PMID: 33506604 PMCID: PMC7968884 DOI: 10.1002/cac2.12138] [Citation(s) in RCA: 211] [Impact Index Per Article: 52.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/30/2020] [Accepted: 01/18/2021] [Indexed: 12/15/2022] Open
Abstract
Epithelial‐to‐mesenchymal transition (EMT) is implicated in a wide array of malignant behaviors of cancers, including proliferation, invasion, and metastasis. Most notably, previou studies have indicated that both cancer stem‐like properties and drug resistance were associated with EMT. Furthermore, microRNAs (miRNAs) play a pivotal role in the regulation of EMT phenotype, as a result, some miRNAs impact cancer stemness and drug resistance. Therefore, understanding the relationship between EMT‐associated miRNAs and cancer stemness/drug resistance is beneficial to both basic research and clinical treatment. In this review, we preliminarily looked into the various roles that the EMT‐associated miRNAs play in the stem‐like nature of malignant cells. Then, we reviewed the interaction between EMT‐associated miRNAs and the drug‐resistant complex signaling pathways of multiple cancers including lung cancer, gastric cancer, gynecologic cancer, breast cancer, liver cancer, colorectal cancer, pancreatic cancer, esophageal cancer, and nasopharyngeal cancer. We finally discussed the relationship between EMT, cancer stemness, and drug resistance, as well as looked forward to the potential applications of miRNA therapy for malignant tumors.
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Affiliation(s)
- Guangtao Pan
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P. R. China
| | - Yuhan Liu
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P. R. China
| | - Luorui Shang
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P. R. China
| | - Fangyuan Zhou
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P. R. China
| | - Shenglan Yang
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P. R. China
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11
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Li C, Li J, Xu Y, Zhan Y, Li Y, Song T, Zheng J, Yang H. Application of Phage-Displayed Peptides in Tumor Imaging Diagnosis and Targeting Therapy. Int J Pept Res Ther 2020; 27:587-595. [PMID: 32901205 PMCID: PMC7471523 DOI: 10.1007/s10989-020-10108-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 08/07/2020] [Accepted: 08/14/2020] [Indexed: 12/11/2022]
Abstract
Phage display is an effective and powerful technique that provides a route to discovery unique peptides targeting to tumor cells. Specifically binding peptides are considered as the valuable target directing molecule fragments with potential efficiency to improve the current tumor clinic, and offer new approaches for tumor prevention, diagnosis and treatment. We focus on the recent advances in the isolation of tumor-targeting peptides by biopanning methods, with particular emphasis on molecular imaging, and pharmaceutical targeting therapy.
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Affiliation(s)
- Chunyan Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Air Force Medical University, 127 West ChangLe Road, Xi'an, 710032 Shaanxi China
| | - Jia Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Air Force Medical University, 127 West ChangLe Road, Xi'an, 710032 Shaanxi China
| | - Ying Xu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Air Force Medical University, 127 West ChangLe Road, Xi'an, 710032 Shaanxi China
| | - Ying Zhan
- 518 Hospital of PLA, Xi'an, 710043 Shaanxi China
| | - Yu Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Air Force Medical University, 127 West ChangLe Road, Xi'an, 710032 Shaanxi China
| | - Tingting Song
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Air Force Medical University, 127 West ChangLe Road, Xi'an, 710032 Shaanxi China
| | - Jiao Zheng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Air Force Medical University, 127 West ChangLe Road, Xi'an, 710032 Shaanxi China
| | - Hong Yang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Air Force Medical University, 127 West ChangLe Road, Xi'an, 710032 Shaanxi China
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12
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Huang GJ, Yang BB. Identification of core miRNA prognostic markers in patients with laryngeal cancer using bioinformatics analysis. Eur Arch Otorhinolaryngol 2020; 278:1613-1626. [PMID: 32789639 DOI: 10.1007/s00405-020-06275-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 08/04/2020] [Indexed: 12/19/2022]
Abstract
PURPOSE Lots of studies indicated that many microRNAs (miRNAs) are associated with the prognosis of patients with laryngeal cancer (LC). The objective of our study is to identify potential core miRNAs associated with the pathogenesis and prognosis of LC. METHODS Using the Cancer Genome Atlast database, we identified 70 differentially expressed miRNAs between LC tumor specimens and non-tumor specimens. Then Cox regression analyses and the least absolute shrinkage and selection operator regression signature were performed to detect miRNA prognostic markers. A nomogram integrating miRNA prognostic markers was constructed to predict overall survival (OS) for LC patients. The potential target genes of the key miRNA were predicted by miRTarBase and miRDB databases. Subsequently, their potential functions were revealed by gene ontology annotation and kyoto encyclopedia of genes and genomes pathway enrichment analysis. Related biological pathways of the key target gene involved in LC were detected through gene set enrichment analysis (GSEA). RESULTS A prognostic miRNA signature was constructed. The up-regulated miR-105-1 was related to a worse OS (p = 0.043), which suggested that miR-105-1 may likely be the key miRNA prognostic marker. Survival analyses and paired expression analyses of target genes indicated that ENDOU may be the key target gene. Finally, we conducted GSEA to elucidate the pathways enriched between low- and high-ENDOU expression datasets. CONCLUSION Our findings might bring some new light on the pathogenesis of LC. Then, it might facilitate doctors to predict the prognosis and improve treatment outcomes for LC patients. However, the behaviors of LC are relatively heterogeneous, and the TCGA database cannot provide detailed information about the subsites and treatment modalities of LC. Further molecular biological experiments and clinical investigations would be required to confirm this conclusion.
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Affiliation(s)
- Guan-Jiang Huang
- Department of Otorhinolaryngology, School of Medicine, The Second Affiliated Hospital, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang, 310009, China
| | - Bei-Bei Yang
- Department of Otorhinolaryngology, School of Medicine, The Second Affiliated Hospital, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang, 310009, China.
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13
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Zhang X, Xie K, Zhou H, Wu Y, Li C, Liu Y, Liu Z, Xu Q, Liu S, Xiao D, Tao Y. Role of non-coding RNAs and RNA modifiers in cancer therapy resistance. Mol Cancer 2020; 19:47. [PMID: 32122355 PMCID: PMC7050132 DOI: 10.1186/s12943-020-01171-z] [Citation(s) in RCA: 177] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 02/24/2020] [Indexed: 02/08/2023] Open
Abstract
As the standard treatments for cancer, chemotherapy and radiotherapy have been widely applied to clinical practice worldwide. However, the resistance to cancer therapies is a major challenge in clinics and scientific research, resulting in tumor recurrence and metastasis. The mechanisms of therapy resistance are complicated and result from multiple factors. Among them, non-coding RNAs (ncRNAs), along with their modifiers, have been investigated to play key roles in regulating tumor development and mediating therapy resistance within various cancers, such as hepatocellular carcinoma, breast cancer, lung cancer, gastric cancer, etc. In this review, we attempt to elucidate the mechanisms underlying ncRNA/modifier-modulated resistance to chemotherapy and radiotherapy, providing some therapeutic potential points for future cancer treatment.
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Affiliation(s)
- Xinyi Zhang
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, School of Basic Medicine, Central South University, Changsha, 410078, Hunan, China
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Cardiovascular Medicine, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Kai Xie
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Honghua Zhou
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Cardiovascular Medicine, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Yuwei Wu
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Cardiovascular Medicine, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Chan Li
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Yating Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, School of Basic Medicine, Central South University, Changsha, 410078, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Zhaoya Liu
- Department of Geriatrics, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Qian Xu
- Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Shuang Liu
- Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Desheng Xiao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, School of Basic Medicine, Central South University, Changsha, 410078, Hunan, China.
| | - Yongguang Tao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, School of Basic Medicine, Central South University, Changsha, 410078, Hunan, China.
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China.
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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14
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Gu J, Zhang J, Huang W, Tao T, Huang Y, Yang L, Yang J, Fan Y, Wang H. Activating miRNA-mRNA network in gemcitabine-resistant pancreatic cancer cell associates with alteration of memory CD4 + T cells. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:279. [PMID: 32355723 PMCID: PMC7186712 DOI: 10.21037/atm.2020.03.53] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background To identify key microRNAs (miRNAs) and their target mRNAs related to gemcitabine-resistant pancreatic cancer (PC) and investigate the association between gemcitabine-resistant-related miRNAs and mRNAs and immune infiltration. Methods Expression profiles of miRNAs and mRNAs were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed miRNAs and mRNAs (referred to as "DEmiRNAs" and "DEmRNAs", respectively) were distinguished between gemcitabine-resistant PC cells and its parental cells. The DEmRNAs targeted by the DEmiRNAs were retrieved using miRDB, microT, and Targetscan. Furthermore, GO and KEGG pathway enrichment analysis and GSEA were performed. The Kaplan-Meier plotter was used to analyze the prognosis of key DEmiRNAs and DEmRNAs on PC patients. The relationship between the key DEmRNAs and tumor-infiltrating immune cells in PC was investigated using CIBERSORT method using the LM22 signature as reference. Key infiltrating immune cells were further analyzed for the associations with prognosis of TCGA PAAD patients. Results Four DEmiRNAs, including hsa-miR-3178, hsa-miR-485-3p, hsa-miR-574-5p, and hsa-miR-584-5p, were identified to target seven DEmRNAs, including MSI2, TEAD1, GNPDA1, RND3, PRKACB, TRIM68, and YKT6, individually, in gemcitabine-resistant PC cells versus parental cells. Gemcitabine-resistant PC cells were enriched in proteasome-related, immune-related, and memory CD4+ T cell-related pathways, indicating a gemcitabine therapeutic effect on PC cells. All four DEmiRNAs and almost all DEmRNAs had an impact on the prognosis of PC patients. All seven DEmRNAs had remarkable effects on CD4+ memory T cells, which were affected by the gemcitabine therapeutic effect. Effector memory CD4+ T cells rather than central memory CD4+ T cells predicted a good prognosis according to the TCGA PAAD dataset. Conclusions Gemcitabine resistance can alter the fraction of memory CD4+ T cells via hsa-miR-3178, hsa-miR-485-3p, hsa-miR-574-5p and hsa-miR-584-5p targeted MSI2, TEAD1, GNPDA1, RND3, PRKACB, TRIM68, and YKT6 network in PC.
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Affiliation(s)
- Jianyou Gu
- Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Junfeng Zhang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Wenjie Huang
- Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.,Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510000, China
| | - Tian Tao
- Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Yaohuan Huang
- Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Ludi Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China
| | - Jiali Yang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Yingfang Fan
- Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Huaizhi Wang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 400038, China
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15
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Zhou J, Zhang L, Zheng H, Ge W, Huang Y, Yan Y, Zhou X, Zhu W, Kong Y, Ding Y, Wang W. Identification of chemoresistance-related mRNAs based on gemcitabine-resistant pancreatic cancer cell lines. Cancer Med 2019; 9:1115-1130. [PMID: 31823522 PMCID: PMC6997050 DOI: 10.1002/cam4.2764] [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: 09/10/2019] [Revised: 11/07/2019] [Accepted: 11/24/2019] [Indexed: 12/18/2022] Open
Abstract
Gemcitabine (GEM) alone and GEM-based chemotherapy are the preferred regimens for treating advanced unresectable and metastatic pancreatic cancer (PC). However, these treatments have limited efficacy due to acquired resistance of cancer cells to chemotherapy, the mechanisms of which are not fully understood. In this study, we established two stable multidrug-resistant cell lines, BxPC-3-GR and CFPAC-1-GR, from their corresponding parental cells through exposure to GEM following a stepwise incremental dosing strategy. The GEM IC50 values of BxPC-3-GR and CFPAC-1-GR increased 112-fold and 210-fold, respectively, compared to parental cell lines. In vitro and in vivo experiments confirmed that both GEM-resistant cell subgroups declined in proliferative capacity, but were more resistant to GEM. Unlike CFPAC-1-GR, BxPC-3-GR exhibited enhanced migratory and invasive properties compared with BxPC-3 in vitro. We also compared differentially expressed mRNA profiles between parental and GEM-resistant cells using transcriptome sequencing. RRM1, STIM1, and TRIM21 were significantly upregulated in both GEM-resistant cell lines and confirmed to be associated with the degree of GEM resistance by quantitative reverse-transcription polymerase chain reaction and western blot analysis. These three genes were more highly expressed in PC tissues and potentially regarded as prognostic biomarkers through database mining. Thus, our findings provide chemo-resistant cell models to better understand the underlying mechanisms of chemoresistance, and to explore potential biomarkers for GEM response in PC patients.
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Affiliation(s)
- Jiarong Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Linshi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Huilin Zheng
- School of Biological & Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, Zhejiang, China
| | - Wenhao Ge
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yu Huang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yingcai Yan
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xiaohu Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Wei Zhu
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yang Kong
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yuan Ding
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, China.,Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, China.,Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Diseases of Zhejiang University, Hangzhou, Zhejiang, China.,Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Weilin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, China.,Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang, China.,Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Diseases of Zhejiang University, Hangzhou, Zhejiang, China.,Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
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