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Abdulla A, Sadida HQ, Jerobin J, Elfaki I, Mir R, Mirza S, Singh M, Macha MA, Uddin S, Fakhro K, Bhat AA, Akil ASAS. Unraveling molecular interconnections and identifying potential therapeutic targets of significance in obesity-cancer link. JOURNAL OF THE NATIONAL CANCER CENTER 2025; 5:8-27. [PMID: 40040878 PMCID: PMC11873641 DOI: 10.1016/j.jncc.2024.11.001] [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: 07/03/2024] [Revised: 08/16/2024] [Accepted: 11/11/2024] [Indexed: 03/06/2025] Open
Abstract
Obesity, a global health concern, is associated with severe health issues like type 2 diabetes, heart disease, and respiratory complications. It also increases the risk of various cancers, including melanoma, endometrial, prostate, pancreatic, esophageal adenocarcinoma, colorectal carcinoma, renal adenocarcinoma, and pre-and post-menopausal breast cancer. Obesity-induced cellular changes, such as impaired CD8+ T cell function, dyslipidemia, hypercholesterolemia, insulin resistance, mild hyperglycemia, and fluctuating levels of leptin, resistin, adiponectin, and IL-6, contribute to cancer development by promoting inflammation and creating a tumor-promoting microenvironment rich in adipocytes. Adipocytes release leptin, a pro-inflammatory substance that stimulates cancer cell proliferation, inflammation, and invasion, altering the tumor cell metabolic pathway. Adiponectin, an insulin-sensitizing adipokine, is typically downregulated in obese individuals. It has antiproliferative, proapoptotic, and antiangiogenic properties, making it a potential cancer treatment. This narrative review offers a comprehensive examination of the molecular interconnections between obesity and cancer, drawing on an extensive, though non-systematic, survey of the recent literature. This approach allows us to integrate and synthesize findings from various studies, offering a cohesive perspective on emerging themes and potential therapeutic targets. The review explores the metabolic disturbances, cellular alterations, inflammatory responses, and shifts in the tumor microenvironment that contribute to the obesity-cancer link. Finally, it discusses potential therapeutic strategies aimed at disrupting these connections, offering valuable insights into future research directions and the development of targeted interventions.
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Affiliation(s)
- Alanoud Abdulla
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar
| | - Hana Q. Sadida
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar
| | - Jayakumar Jerobin
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Imadeldin Elfaki
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia
| | - Rashid Mir
- Department of Medical Laboratory Technology, Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Sameer Mirza
- Department of Chemistry, College of Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Mayank Singh
- Department of Medical Oncology (Lab.), Dr. BRAIRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Muzafar A. Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Pulwama, Jammu and Kashmir, India
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Laboratory of Animal Research Center, Qatar University, Doha, Qatar
| | - Khalid Fakhro
- Department of Human Genetics, Sidra Medicine, Doha, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
- Department of Genetic Medicine, Weill Cornell Medicine, Doha, Qatar
| | - Ajaz A. Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar
| | - Ammira S. Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar
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Cuachirria-Espinoza RL, García-Miranda A, Hernández-Barragán R, Nava-Tapia DA, Olea-Flores M, Navarro-Tito N. Analysis of the relationship between resistin with prognosis, cell migration, and p38 and ERK1/2 activation in breast cancer. Biochimie 2025; 229:19-29. [PMID: 39369940 DOI: 10.1016/j.biochi.2024.10.001] [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: 11/30/2023] [Revised: 09/14/2024] [Accepted: 10/01/2024] [Indexed: 10/08/2024]
Abstract
Obesity increases the risk and mortality of breast cancer through dysregulated secretion of proinflammatory cytokines and tumor adipokines that induce an inflammatory breast microenvironment. Resistin is an adipokine secreted by adipocytes, immune cells, and predominantly macrophages, which contributes to cancer progression, but its molecular mechanism in cancer is not completely described. In this study, we analyzed the relationship of resistin on breast cancer prognosis and tumor progression and the effect in vitro of resistin on p38 and ERK1/2 activation in breast cancer cell lines. By bioinformatic analysis, we found that resistin is overexpressed in the basal subtype triple-negative breast cancer and is related to poor prognosis. In addition, we demonstrated a positive correlation between RETN and MAPK3 expression in basal triple-negative breast cancer. Importantly, we found amplifications of the RETN gene in at least 20 % of metastatic samples from patients with breast cancer. Most samples with RETN amplifications metastasized to bone and showed high expression of IL-8 (CXCL8) and IL-6 (IL6). Finally, resistin could be considered a prognostic marker for basal triple-negative breast cancer, and we also proposed the possibility that resistin-induced cell migration involves the activation of MAPK in breast cancer cells.
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Affiliation(s)
- Reyna L Cuachirria-Espinoza
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Chilpancingo, GRO, 39090, Mexico
| | - Alin García-Miranda
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Chilpancingo, GRO, 39090, Mexico
| | - Rafael Hernández-Barragán
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Chilpancingo, GRO, 39090, Mexico
| | - Dania A Nava-Tapia
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Chilpancingo, GRO, 39090, Mexico
| | - Monserrat Olea-Flores
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Chilpancingo, GRO, 39090, Mexico
| | - Napoleón Navarro-Tito
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Chilpancingo, GRO, 39090, Mexico.
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Gong W, Huang D, Zhou T, Zhu X, Huang Y, Lv Y, Zhang Y, Liu Z, Zeng F, Wu S. Decoding Resistin Gene Polymorphisms: Implications for Lung Cancer Risk and Clinical Outcomes of Platinum-Based Chemotherapy. Biomedicines 2025; 13:291. [PMID: 40002704 PMCID: PMC11852191 DOI: 10.3390/biomedicines13020291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/20/2025] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Resistin (RETN), an inflammatory cytokine exhibiting multifaceted roles in cancer progression, has emerged as a plausible mediator between inflammation and oncogenesis. Prior research from our group has highlighted the pivotal role of resistin in carcinogenesis and its impact on drug responsiveness. The present study delves into the relationship between resistin expression and genetic polymorphisms with cancer risk and clinical outcomes among lung cancer patients undergoing platinum-based chemotherapy. Methods: Immunohistochemical analysis was conducted to assess resistin expression levels in 104 tumor tissues derived from lung adenocarcinoma patients. Additionally, 498 lung cancer patients and 213 healthy controls were recruited for this study, with 467 patients undergoing at least two cycles of platinum-based chemotherapy. Unconditional logistical regression analysis was employed to evaluate the associations between RETN polymorphisms and lung cancer risk, as well as clinical outcomes. Genotyping of RETN polymorphisms (rs1862513 and rs3745367) was performed using the Sequenom MassARRAY System. Results: The findings revealed a positive correlation between resistin expression in tumor tissues and metastasis (particularly distant metastasis) and overall survival in lung adenocarcinoma. However, RETN polymorphisms were not significantly associated with overall survival in lung cancer patients. No substantial association was observed between RETN polymorphisms and lung cancer risk, chemotherapy response, or toxicities, except for rs1862513, which showed a link with severe gastrointestinal toxicity. Meta-analysis results further confirmed the absence of a significant association between RETN polymorphisms and cancer risk. Conclusions: Despite the pivotal role of resistin in carcinogenesis, only the RETN rs1862513 polymorphism emerges as a potential biomarker for gastrointestinal toxicity in lung cancer patients undergoing platinum-based chemotherapy. However, these findings necessitate validation through well-designed studies with larger sample sizes.
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Affiliation(s)
- Weijing Gong
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (T.Z.); (Y.H.); (Y.L.); (Y.Z.)
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, China
| | - Dandan Huang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
| | - Tao Zhou
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (T.Z.); (Y.H.); (Y.L.); (Y.Z.)
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, China
| | - Xinxin Zhu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
| | - Yifei Huang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (T.Z.); (Y.H.); (Y.L.); (Y.Z.)
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, China
| | - Yongning Lv
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (T.Z.); (Y.H.); (Y.L.); (Y.Z.)
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, China
| | - Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (T.Z.); (Y.H.); (Y.L.); (Y.Z.)
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, China
| | - Zhaoqian Liu
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410017, China;
| | - Fang Zeng
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (T.Z.); (Y.H.); (Y.L.); (Y.Z.)
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, China
| | - Sanlan Wu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (T.Z.); (Y.H.); (Y.L.); (Y.Z.)
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, China
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Hsu LA, Teng MS, Wu S, Liao MS, Chou HH, Ko YL. Circulating resistin levels and mutation burden of the RETN gene variants predict long-term mortality in a Taiwanese population. Sci Rep 2025; 15:564. [PMID: 39747951 PMCID: PMC11695976 DOI: 10.1038/s41598-024-84142-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 12/20/2024] [Indexed: 01/04/2025] Open
Abstract
Human resistin is a proinflammatory cytokine involving the development and progression of cancer and cardiovascular diseases. However, prediction of long-term outcome using circulating resistin level and its genetic determinants in a population-based study remain to be explored. After genome-wide association study (GWAS), DNA methylation (DNAm) analysis and functional assays of a RETN rs370006313 variant, we tested whether resistin level and its genetic determinants can be used to determine the long-term outcomes of 5678 Taiwan Biobank (TWB) participants. GWAS and DNAm analysis revealed RETN variants, rs3219175, rs370006313, and rs3745368, and DNAm sites, cg21271423 and cg09909011, independently associated with circulating resistin levels. Functional assays showed rs370006313 variant played a key role in affecting RETN promoter activity, whereas genotypes of rs3219175 and rs3745368, but not rs370006313, exhibited genome-wide significant associations with RETN promoter DNAm levels. Using Kaplan-Meier survival and Cox regression analyses, participants with progressively increasing resistin levels had a higher hazard ratio for all-cause mortality and cancer mortality compared to those with lower resistin levels. Participants with all three RETN variants (high mutation burden) also exhibited significantly higher hazard ratios for all-cause mortality and cancer mortality, at 3.99 and 5.55, respectively, compared to those without a high mutation burden. In conclusion, RETN rs370006313 is a functional variant affecting RETN promoter activity. Elevated circulating resistin levels and a high RETN mutation burden predict all-cause and cancer mortality in TWB participants. Both resistin levels and RETN variants may serve as biomarkers of long-term outcomes in the general Taiwanese populations.
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Affiliation(s)
- Lung-An Hsu
- The First Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Ming-Sheng Teng
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Semon Wu
- Department of Life Science, Chinese Culture University, Taipei, Taiwan
| | - Mei-Siou Liao
- The Division of Cardiology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No.289, Jianguo Road, Xindian Dist., New Taipei City, 23142, Taiwan
| | - Hsin-Hua Chou
- The Division of Cardiology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No.289, Jianguo Road, Xindian Dist., New Taipei City, 23142, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Yu-Lin Ko
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan.
- The Division of Cardiology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No.289, Jianguo Road, Xindian Dist., New Taipei City, 23142, Taiwan.
- School of Medicine, Tzu Chi University, Hualien, Taiwan.
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Zhang J, Lu E, Deng L, Zhu Y, Lu X, Li X, Li F, Yan Y, Han JY, Li Y, Zhang Y. Immunological roles for resistin and related adipokines in obesity-associated tumors. Int Immunopharmacol 2024; 142:112911. [PMID: 39232363 DOI: 10.1016/j.intimp.2024.112911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 08/01/2024] [Accepted: 08/05/2024] [Indexed: 09/06/2024]
Abstract
Rationale Obesity is an independent risk factor for the occurrence and development of tumors. Obesity is influenced by signaling of adipokines, which are secreted factors from adipocytes and resident immune cells within adipose tissues that mediate lipid metabolism. More recently, adipokines have been implicated in chronic inflammation as well as in tumor formation and growth. Among them, resistin has received increasing attention in research related to the growth and expansion of solid tumors and hematological cancers through various signaling pathways. Objective and findings We reviewed the physiological, biochemical, and immune functions of adipose tissue, with a focus on the structure and expression of resistin and adipokines within multiple adipose cell types, their signaling pathways and putative effects on tumor cells, as well as their in vivo regulation. Current evidence indicates that adipokines such as resistin act as pro-inflammatory factors to stimulate immune cells which, in turn, promotes tumor angiogenesis, connective tissue proliferation, and matrix fibrosis. Concurrently, in states of metabolic dysfunction and lipotoxicity in obese individuals, the numbers and functions of immune cells are compromised, leading to an immunosuppressive environment that fosters tumor cell survival and weak cancer immune monitoring. Conclusion Adipokines such as resistin are important to the development of obesity-related tumors. Clarifying the roles for obesity-related factors in immune regulation and tumor progression may lead to the discovery of novel anti-tumor strategies for targeting obesity factors such as resistin to limit tumor growth and manage obesity, or both.
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Affiliation(s)
- Jingxin Zhang
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Enting Lu
- Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Lei Deng
- Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Yaoxuan Zhu
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Xiaoqing Lu
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Xinyuan Li
- School of Nursing, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Fangmei Li
- Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Yan Yan
- Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Jing-Yan Han
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Yin Li
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
| | - Yi Zhang
- Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China.
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Cai Q, Yang J, Shen H, Xu W. Cancer-associated adipocytes in the ovarian cancer microenvironment. Am J Cancer Res 2024; 14:3259-3279. [PMID: 39113876 PMCID: PMC11301307 DOI: 10.62347/xzri9189] [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: 03/30/2024] [Accepted: 07/02/2024] [Indexed: 08/10/2024] Open
Abstract
The tumor microenvironment (TME) plays a critical role in high energy metabolism during tumorigenesis, progression and metastasis. Among them, adipocytes, as an important component of the TME, can transform into cancer-associated adipocytes (CAAs) through dedifferentiation via interactions with tumor cells. These CAAs provide nutrients, growth factors, cytokines and metabolites to the tumor and later transdifferentiate into other stromal cells at a later stage to alter tumor growth, metastasis and the drug response and ultimately influence the treatment and prognosis of ovarian cancer. This review outlines the physiological functions of CAAs and discusses the progress in the use of CAAs as therapeutic targets in ovarian cancer.
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Affiliation(s)
- Qiuling Cai
- Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Jing Yang
- Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Huiling Shen
- Department of Oncology, The First Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Wenlin Xu
- Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu UniversityZhenjiang, Jiangsu, China
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Rompou AV, Bletsa G, Tsakogiannis D, Theocharis S, Vassiliu P, Danias N. An Updated Review of Resistin and Colorectal Cancer. Cureus 2024; 16:e65403. [PMID: 39184804 PMCID: PMC11344879 DOI: 10.7759/cureus.65403] [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] [Accepted: 07/25/2024] [Indexed: 08/27/2024] Open
Abstract
Resistin is one of the most important adipokines, and its role lies mainly in controlling insulin sensitivity and inflammation. However, over the last years, the study of resistin gained increased popularity since it was proved that there is a considerable relationship between high levels of resistin and obesity as well as obesity-induced diseases, including diabetes, cardiovascular disorders, and cancer. Regarding cancer risk, circulating resistin levels have been correlated with several types of cancer, including colorectal, breast, lung, endometrial, gastroesophageal, prostate, renal, and pancreatic cancer. Colorectal cancer is regarded as a multi-pathway disease. Several pathophysiological features seem to promote colorectal cancer (CRC) such as chronic inflammation, insulin resistance, and obesity. Even though the molecular mechanisms involved in CRC development remain rather vague, it is widely accepted that several biochemical factors promote CRC by releasing augmented pro-inflammatory cytokines, like IGF-I, insulin, sex-steroid hormones, and adipokines. A wide range of research studies has focused on evaluating the impact of circulating resistin levels on CRC risk and determining the efficacy of chemotherapy in CRC patients by measuring resistin levels. Moreover, significant outcomes have emerged regarding the association of specific single nucleotide polymorphisms (SNPs) in the resistin gene and CRC risk. The present study reviewed the role of circulating resistin levels in CRC development and shed light on specific resistin gene SNPs implicated in the disease's development. Finally, we analyzed the impact of resistin levels on the effectiveness of chemotherapy and further discussed whether resistin can be regarded as a valuable biomarker for CRC prognosis and treatment. Resistin is one of the most important adipokines, and its role lies mainly in controlling insulin sensitivity and inflammation. However, over the last years, the study of resistin gained increased popularity since it was proved that there is a considerable relationship between high levels of resistin and obesity as well as obesity-induced diseases, including diabetes, cardiovascular disorders, and cancer. This review discusses the aberrant expression of resistin and its receptors, its diverse downstream signaling, and its impact on tumor growth, metastasis, angiogenesis, and therapy resistance to support its clinical exploitation in biomarker and therapeutic development.
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Affiliation(s)
- Aliki Vaia Rompou
- Department of Colorectal Surgery, Guy's and St Thomas' NHS Foundation Trust, London, GBR
| | - Garyfalia Bletsa
- Department of Medicine, Research Center, Hellenic Anticancer Institute, Athens, GRC
| | | | - Stamatios Theocharis
- Department of Pathology, National and Kapodistrian University of Athens, Athens, GRC
| | - Panteleimon Vassiliu
- Fourth Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, GRC
| | - Nick Danias
- Fourth Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, GRC
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Wu R, Zhang J, Zou G, Li S, Wang J, Li X, Xu J. Diabetes Mellitus and Thyroid Cancers: Risky Correlation, Underlying Mechanisms and Clinical Prevention. Diabetes Metab Syndr Obes 2024; 17:809-823. [PMID: 38380275 PMCID: PMC10878320 DOI: 10.2147/dmso.s450321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 02/08/2024] [Indexed: 02/22/2024] Open
Abstract
The incidences of thyroid cancer and diabetes are rapidly increasing worldwide. The relationship between thyroid cancer and diabetes is a popular topic in medicine. Increasing evidence has shown that diabetes increases the risk of thyroid cancer to a certain extent. This mechanism may be related to genetic factors, abnormal thyroid-stimulating hormone secretion, oxidative stress injury, hyperinsulinemia, elevated insulin-like growth factor-1 levels, abnormal secretion of adipocytokines, and increased secretion of inflammatory factors and chemokines. This article reviews the latest research progress on the relationship between thyroid cancer and diabetes, including the association between diabetes and the risk of developing thyroid cancer, its underlying mechanisms, and potential anti-thyroid cancer effects of hypoglycemic drugs. It providing novel strategies for the prevention, treatment, and improving the prognosis of thyroid cancer.
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Affiliation(s)
- Rongqian Wu
- Department of Endocrinology and Metabolism, The 1 Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, People’s Republic of China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang, People’s Republic of China
| | - Junping Zhang
- Department of Endocrinology and Metabolism, The 1 Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, People’s Republic of China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang, People’s Republic of China
| | - Guilin Zou
- Department of Endocrinology and Metabolism, The 1 Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, People’s Republic of China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang, People’s Republic of China
| | - Shanshan Li
- Department of Endocrinology and Metabolism, The 1 Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
| | - Jinying Wang
- Department of Endocrinology and Metabolism, The 1 Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
| | - Xiaoxinlei Li
- Department of Endocrinology and Metabolism, The 1 Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
| | - Jixiong Xu
- Department of Endocrinology and Metabolism, The 1 Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, People’s Republic of China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang, People’s Republic of China
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Zhao Z, Luan T, Wan J, Du H, Hu J, Liu H, Gong X, Kuang G, Wang B. Elucidating Cuproptosis-Associated Genes in the Progression from Nash to HCC Using Bulk and Single-Cell RNA Sequencing Analyses and Experimental Validation. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1639. [PMID: 37763758 PMCID: PMC10536385 DOI: 10.3390/medicina59091639] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 09/03/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023]
Abstract
Background and Objectives: Non-alcoholic steatohepatitis (NASH) is a significant risk factor for hepatocellular carcinoma (HCC) development. Timely treatment during the NASH stage is essential to minimize the possibility of disease progression to HCC. Cuproptosis is a newly identified form of cellular death that could impact the progression of various diseases and cancers. Materials and Methods: Transcriptome and single-cell sequencing datasets were utilized to investigate the role of cuproptosis-related genes (CRGs) in NASH progression to HCC. FDX1, LIPT1, and PDHP were identified as CRGs in NASH patients, and FDX1, DBT, GCSH, SLC31A1, and DLAT were identified as CRGs in patients with NASH progressing to HCC. FDX1 was found to play a significant role in both NASH patients and patients with NASH progressing to HCC. This study constructed cuproptosis-related clusters (CRCs) using the Nonnegative Matrix Factorization algorithm, and they were linked to fatty acid metabolism and the PPAR signaling pathway in both NASH CRCs and HCC CRCs. The Weighted Correlation Network Analysis algorithm identified CRP, CRC, TAT, CXCL10, and ACTA1 as highly relevant genes in NASH CRCs and HCC CRCs. The expression of FDX1 was validated in both mouse models and human NASH samples. Results: The investigation highlights FDX1 as a pivotal CRG in both NASH and NASH progression to HCC. The comprehensive characterization of CRGs sheds light on their potential biofunctional importance in the context of NASH and HCC. Our experimental results show that FDX1 expression was significantly increased in NASH patients. Conclusions: The present study identified key CRGs, revealing their potential impact on NASH and HCC. Meanwhile, targeting FDX1 may prevent the progression of NASH to HCC.
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Affiliation(s)
- Zizuo Zhao
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China;
| | - Tiankuo Luan
- Department of Anatomy, Chongqing Medical University, Chongqing 400016, China; (T.L.); (X.G.)
| | - Jingyuan Wan
- Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China; (J.W.); (H.D.); (J.H.); (H.L.)
| | - Hui Du
- Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China; (J.W.); (H.D.); (J.H.); (H.L.)
| | - Jun Hu
- Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China; (J.W.); (H.D.); (J.H.); (H.L.)
| | - Hao Liu
- Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China; (J.W.); (H.D.); (J.H.); (H.L.)
| | - Xia Gong
- Department of Anatomy, Chongqing Medical University, Chongqing 400016, China; (T.L.); (X.G.)
| | - Ge Kuang
- Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China; (J.W.); (H.D.); (J.H.); (H.L.)
| | - Bin Wang
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China;
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10
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Abdalla MMI. Serum resistin and the risk for hepatocellular carcinoma in diabetic patients. World J Gastroenterol 2023; 29:4271-4288. [PMID: 37545641 PMCID: PMC10401662 DOI: 10.3748/wjg.v29.i27.4271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/11/2023] [Accepted: 06/27/2023] [Indexed: 07/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant type of liver cancer, is a major contributor to cancer-related fatalities across the globe. Diabetes has been identified as a significant risk factor for HCC, with recent research indicating that the hormone resistin could be involved in the onset and advancement of HCC in diabetic individuals. Resistin is a hormone that is known to be involved in inflammation and insulin resistance. Patients with HCC have been observed to exhibit increased resistin levels, which could be correlated with more severe disease stages and unfavourable prognoses. Nevertheless, the exact processes through which resistin influences the development and progression of HCC in diabetic patients remain unclear. This article aims to examine the existing literature on the possible use of resistin levels as a biomarker for HCC development and monitoring. Furthermore, it reviews the possible pathways of HCC initiation due to elevated resistin and offers new perspectives on comprehending the fundamental mechanisms of HCC in diabetic patients. Gaining a better understanding of these processes may yield valuable insights into HCC’s development and progression, as well as identify possible avenues for prevention and therapy.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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11
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Zhang Z, Du J, Xu Q, Li Y, Zhou S, Zhao Z, Mu Y, Zhao AZ, Cao SM, Li F. Resistin Promotes Nasopharyngeal Carcinoma Metastasis through TLR4-Mediated Activation of p38 MAPK/NF-κB Signaling Pathway. Cancers (Basel) 2022; 14:6003. [PMID: 36497484 PMCID: PMC9737889 DOI: 10.3390/cancers14236003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
NPC is a type of malignant tumor with a high risk of local invasion and early distant metastasis. Resistin is an inflammatory cytokine that is predominantly produced from the immunocytes in humans. Accumulating evidence has suggested a clinical association of circulating resistin with the risk of tumorigenesis and a relationship between blood resistin levels and the risk of cancer metastasis. In this study, we explored the blood levels and the role of resistin in NPC. High resistin levels in NPC patients were positively associated with lymph node metastasis, and resistin promoted the migration and invasion of NPC cells in vitro. These findings were also replicated in a mouse model of NPC tumor metastasis. We identified TLR4 as a functional receptor in mediating the pro-migratory effects of resistin in NPC cells. Furthermore, p38 MAPK and NF-κB were intracellular effectors that mediated resistin-induced EMT. Taken together, our results suggest that resistin promotes NPC metastasis by activating the TLR4/p38 MAPK/NF-κB signaling pathways.
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Affiliation(s)
- Zongmeng Zhang
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Jinlin Du
- Department of Epidemiology and Health Statistics, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Qihua Xu
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Yuyu Li
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Sujin Zhou
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Zhenggang Zhao
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Yunping Mu
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Allan Z. Zhao
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Su-Mei Cao
- Department of Cancer Prevention Research, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Fanghong Li
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
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12
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Adipokines as Regulators of Autophagy in Obesity-Linked Cancer. Cells 2022; 11:cells11203230. [PMID: 36291097 PMCID: PMC9600294 DOI: 10.3390/cells11203230] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/02/2022] [Accepted: 10/12/2022] [Indexed: 11/16/2022] Open
Abstract
Excess body weight and obesity have become significant risk factors for cancer development. During obesity, adipose tissue alters its biological function, deregulating the secretion of bioactive factors such as hormones, cytokines, and adipokines that promote an inflammatory microenvironment conducive to carcinogenesis and tumor progression. Adipokines regulate tumor processes such as apoptosis, proliferation, migration, angiogenesis, and invasion. Additionally, it has been found that they can modulate autophagy, a process implicated in tumor suppression in healthy tissue and cancer progression in established tumors. Since the tumor-promoting role of autophagy has been well described, the process has been suggested as a therapeutic target in cancer. However, the effects of targeting autophagy might depend on the tumor type and microenvironmental conditions, where circulating adipokines could influence the role of autophagy in cancer. Here, we review recent evidence related to the role of adipokines in cancer cell autophagy in an effort to understand the tumor response in the context of obesity under the assumption of an autophagy-targeting treatment.
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13
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Ahsan H, Islam SU, Ahmed MB, Lee YS. Role of Nrf2, STAT3, and Src as Molecular Targets for Cancer Chemoprevention. Pharmaceutics 2022; 14:1775. [PMID: 36145523 PMCID: PMC9505731 DOI: 10.3390/pharmaceutics14091775] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/23/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer is a complex and multistage disease that affects various intracellular pathways, leading to rapid cell proliferation, angiogenesis, cell motility, and migration, supported by antiapoptotic mechanisms. Chemoprevention is a new strategy to counteract cancer; to either prevent its incidence or suppress its progression. In this strategy, chemopreventive agents target molecules involved in multiple pathways of cancer initiation and progression. Nrf2, STAT3, and Src are promising molecular candidates that could be targeted for chemoprevention. Nrf2 is involved in the expression of antioxidant and phase II metabolizing enzymes, which have direct antiproliferative action as well as indirect activities of reducing oxidative stress and eliminating carcinogens. Similarly, its cross-talk with NF-κB has great anti-inflammatory potential, which can be utilized in inflammation-induced/associated cancers. STAT3, on the other hand, is involved in multiple pathways of cancer initiation and progression. Activation, phosphorylation, dimerization, and nuclear translocation are associated with tumor cell proliferation and angiogenesis. Src, being the first oncogene to be discovered, is important due to its convergence with many upstream stimuli, its cross-talk with other potential molecular targets, such as STAT3, and its ability to modify the cell cytoskeleton, making it important in cancer invasion and metastasis. Therefore, the development of natural/synthetic molecules and/or design of a regimen that can reduce oxidative stress and inflammation in the tumor microenvironment and stop multiple cellular targets in cancer to stop its initiation or retard its progression can form newer chemopreventive agents.
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Affiliation(s)
- Haseeb Ahsan
- Department of Pharmacy, Faculty of Life and Environmental Sciences, University of Peshawar, Peshawar 25120, Pakistan
| | - Salman Ul Islam
- Department of Pharmacy, CECOS University, Peshawar 25000, Pakistan
| | - Muhammad Bilal Ahmed
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Korea
| | - Young Sup Lee
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Korea
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14
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Yao Q, Zhang X, Chen D. The emerging potentials of lncRNA DRAIC in human cancers. Front Oncol 2022; 12:867670. [PMID: 35992823 PMCID: PMC9386314 DOI: 10.3389/fonc.2022.867670] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Long non-coding RNA (lncRNA) is a subtype of noncoding RNA that has more than 200 nucleotides. Numerous studies have confirmed that lncRNA is relevant during multiple biological processes through the regulation of various genes, thus affecting disease progression. The lncRNA DRAIC, a newly discovered lncRNA, has been found to be abnormally expressed in a variety of diseases, particularly cancer. Indeed, the dysregulation of DRAIC expression is closely related to clinicopathological features. It was also reported that DRAIC is key to biological functions such as cell proliferation, autophagy, migration, and invasion. Furthermore, DRAIC is of great clinical significance in human disease. In this review, we discuss the expression signature, clinical characteristics, biological functions, relevant mechanisms, and potential clinical applications of DRAIC in several human diseases.
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Affiliation(s)
- Qinfan Yao
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- National Key Clinical Department of Kidney Diseases, Institute of Nephrology, Zhejiang University, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Xiuyuan Zhang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- National Key Clinical Department of Kidney Diseases, Institute of Nephrology, Zhejiang University, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Dajin Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- National Key Clinical Department of Kidney Diseases, Institute of Nephrology, Zhejiang University, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- *Correspondence: Dajin Chen,
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15
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Feng L, Cheng P, Feng Z, Zhang X. Transmembrane p24 trafficking protein 2 regulates inflammation through the TLR4/NF-κB signaling pathway in lung adenocarcinoma. World J Surg Oncol 2022; 20:32. [PMID: 35135563 PMCID: PMC8826716 DOI: 10.1186/s12957-021-02477-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 12/06/2021] [Indexed: 02/07/2023] Open
Abstract
Background To investigate the role of transmembrane p24 trafficking protein 2 (TMED2) in lung adenocarcinoma (LUAD) and determine whether TMED2 knockdown could inhibit LUAD in vitro and in vivo. Methods TIMER2.0, Kaplan-Meier plotter, gene set enrichment analysis (GSEA), Target Gene, and pan-cancer systems were used to predict the potential function of TMED2. Western blotting and immunohistochemistry were performed to analyze TMED2 expression in different tissues or cell lines. The proliferation, development, and apoptosis of LUAD were observed using a lentivirus-mediated TMED2 knockdown. Bioinformatics and western blot analysis of TMED2 against inflammation via the TLR4/NF-κB signaling pathway were conducted. Results TMED2 expression in LUAD tumor tissues was higher than that in normal tissues and positively correlated with poor survival in lung cancer and negatively correlated with apoptosis in LUAD. The expression of TMED2 was higher in tumors or HCC827 cells. TMED2 knockdown inhibited LUAD development in vitro and in vivo and increased the levels of inflammatory factors via the TLR4/NF-κB signaling pathway. TMED2 was correlated with TME, immune score, TME-associated immune cells, their target markers, and some mechanisms and pathways, as determined using the TIMER2.0, GO, and KEGG assays. Conclusions TMED2 may regulate inflammation in LUAD through the TLR4/NF-κB signaling pathway and enhance the proliferation, development, and prognosis of LUAD by regulating inflammation, which provide a new strategy for treating LUAD by regulating inflammation.
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Affiliation(s)
- Longhua Feng
- Department of Respiratory, Qianjiang Central Hospital of Chongqing, Chongqing, 409000, People's Republic of China
| | - Pengjiang Cheng
- Department of Respiratory, Qianjiang Central Hospital of Chongqing, Chongqing, 409000, People's Republic of China
| | - Zhengyun Feng
- Department of Respiratory, Qianjiang Central Hospital of Chongqing, Chongqing, 409000, People's Republic of China
| | - Xiaoyu Zhang
- Department of Intensive Care Unit, Qianjiang Central Hospital of Chongqing, No.63, Chengxijiu Road, Qianjiang District, Chongqing, 409000, People's Republic of China.
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16
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Han L, Shi H, Ma S, Luo Y, Sun W, Li S, Zhang N, Jiang X, Gao Y, Huang Z, Xie C, Gong Y. Agrin Promotes Non-Small Cell Lung Cancer Progression and Stimulates Regulatory T Cells via Increasing IL-6 Secretion Through PI3K/AKT Pathway. Front Oncol 2022; 11:804418. [PMID: 35111682 PMCID: PMC8801576 DOI: 10.3389/fonc.2021.804418] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 12/23/2021] [Indexed: 01/04/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) has high mortality rates worldwide. Agrin contributes to immune synapse information and is involved in tumor metastasis. However, its roles in NSCLC and tumor immune microenvironment remain unclear. This study examined the effects and the underlying mechanisms of Agrin in NSCLC and tumor-infiltrated immune cells. Clinical tissue samples were used to confirm the bioinformatic predictions. NSCLC cells were used to investigate the effects of Agrin on cell cycle and proliferation, as well as invasion and migration. Tumor xenograft mouse model was used to confirm the effects of Agrin on NSCLC growth and tumor-infiltrated regulatory T cells (Tregs) in vivo. Agrin levels in NSCLC cells were closely related to tumor progression and metastasis, and its function was enriched in the PI3K/AKT pathway. In vitro assays demonstrated that Agrin knockdown suppressed NSCLC cell proliferation and metastasis, while PI3K/AKT activators reversed the inhibitory effects of Agrin deficiency on NSCLC cell behaviors. Agrin expression was negatively associated with immunotherapy responses in NSCLC patients. Agrin knockdown suppressed Tregs, as well as interleukin (IL)-6 expression and secretion, while PI3K/AKT activators and exogenous IL-6 rescued the inhibitory effects. In the mouse model, Agrin downregulation alleviated NSCLC cell growth and Treg infiltration in vivo. Our results indicated that Agrin promotes tumor cell growth and Treg infiltration via increasing IL-6 expression and secretion through PI3K/AKT pathway in NSCLC. Our studies suggested Agrin as a therapeutically potential target to increase the efficacy of immunotherapy in NSCLC patients.
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Affiliation(s)
- Linzhi Han
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hongjie Shi
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shijing Ma
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yuan Luo
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wenjie Sun
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shuying Li
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Nannan Zhang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xueping Jiang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yanping Gao
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhengrong Huang
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.,Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Conghua Xie
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yan Gong
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.,Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China
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17
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Zhou Y, Qiao Y, Adcock IM, Zhou J, Yao X. FIZZ2 as a Biomarker for Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Lung 2021; 199:629-638. [PMID: 34677666 DOI: 10.1007/s00408-021-00483-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 09/20/2021] [Indexed: 11/30/2022]
Abstract
PURPOSE Found in inflammatory zone 2 (FIZZ2) is associated with lung inflammation. The aim of the study was to investigate the expression and utility of FIZZ2 as a marker for chronic obstructive pulmonary disease (COPD). METHODS Immunohistochemistry was used to detect the expression of FIZZ2 in COPD. The serum concentration of FIZZ2 was measured by enzyme-linked immunosorbent assay and the episodes of acute exacerbations of COPD (AECOPD) in the following year were recorded. RESULTS FIZZ2 expression was elevated in bronchial epithelial cells (0.217 ± 0.021 vs 0.099 ± 0.010, p < 0.0001) and negatively correlated with the pulmonary function (FEV1/FVC%) (p = 0.0149) and positively correlated with the smoking index (p = 0.0241). Serum level of FIZZ2 in COPD were significantly higher than that in healthy controls (561.6 ± 70.71 vs 52.24 ± 20.52 pg/ml, p < 0.0001) and increased with the COPD severity. Serum levels of FIZZ2 negatively correlated with the pulmonary function [Forced Vital Capacity (FVC), Forced Expiratory Volume (FEV1), FEV1%, FEV1/FVC) (r = - 0.3086, - 0.3529, - 0.3343, and - 0.2676, respectively, p = 0.0003, p < 0.0001, p < 0.0001, p = 0.0014). The expression of human serum FIZZ2 was positively correlated with the smoking index (r = 0.2749, p = 0.0015). There was a positive correlation between the FIZZ2 concentration and the frequency of AECOPD episodes in the following year (r = 0.7291, p < 0.0001). CONCLUSION FIZZ2 expression was elevated in patients with COPD and its serum concentration might be a potential biomarker for AECOPD.
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Affiliation(s)
- Ying Zhou
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.,Department of Respiratory Medicine, Nanjing Gulou Group Anqing Petrochemical Hospital, 11 Shihua First Road, Anqing, 246002, China
| | - Yingying Qiao
- Department of Respiratory Medicine, The Third Affiliated Hospital of Suzhou University, 185 Juqian Street, Changzhou, 213003, China
| | - Ian M Adcock
- Airway Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK
| | - Jun Zhou
- Department of Respiratory Medicine, The Third Affiliated Hospital of Suzhou University, 185 Juqian Street, Changzhou, 213003, China.
| | - Xin Yao
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
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18
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Taouis M, Benomar Y. Is resistin the master link between inflammation and inflammation-related chronic diseases? Mol Cell Endocrinol 2021; 533:111341. [PMID: 34082045 DOI: 10.1016/j.mce.2021.111341] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/25/2021] [Accepted: 05/28/2021] [Indexed: 01/07/2023]
Abstract
Resistin has been firstly discovered in mice and was identified as an adipose tissue-secreted hormone or adipokine linking obesity and insulin resistance. In humans, resistin has been characterized as a hormone expressed and secreted by Immune cells especially by macrophages, and was linked to many inflammatory responses including inflammation of adipose tissue due to macrophages' infiltration. Human and mouse resistin display sequence and structural similarities and also dissimilarities that could explain their different expression pattern. In mice, strong pieces of evidence clearly associated high resistin plasma levels to obesity and insulin resistance suggesting that resistin could play an important role in the onset and progression of obesity and insulin resistance via resistin-induced inflammation. In humans, the link between resistin and obesity/insulin resistance is still a matter of debate and needs more epidemiological studies. Also, resistin has been linked to other chronic diseases such as cardiovascular diseases and cancers where resistin has been proposed in many studies as a biological marker.
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Affiliation(s)
- Mohammed Taouis
- Molecular Neuroendocrinology of Food Intake (NMPA), UMR 9197, University of Paris-Saclay, Orsay, France; NMPA, Dept. Development, Evolution and Cell Signaling, Paris-Saclay Institute of Neurosciences (NeuroPSI) CNRS UMR 9197, Orsay, France.
| | - Yacir Benomar
- Molecular Neuroendocrinology of Food Intake (NMPA), UMR 9197, University of Paris-Saclay, Orsay, France; NMPA, Dept. Development, Evolution and Cell Signaling, Paris-Saclay Institute of Neurosciences (NeuroPSI) CNRS UMR 9197, Orsay, France
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19
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Pintha K, Chaiwangyen W, Yodkeeree S, Suttajit M, Tantipaiboonwong P. Suppressive Effects of Rosmarinic Acid Rich Fraction from Perilla on Oxidative Stress, Inflammation and Metastasis Ability in A549 Cells Exposed to PM via C-Jun, P-65-Nf-Κb and Akt Signaling Pathways. Biomolecules 2021; 11:1090. [PMID: 34439757 PMCID: PMC8392772 DOI: 10.3390/biom11081090] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/13/2022] Open
Abstract
Particulate matter from forest fires (PMFF) is an environmental pollutant causing oxidative stress, inflammation, and cancer cell metastasis due to the presence of polycyclic aromatic hydrocarbons (PAHs). Perilla seed meal contains high levels of polyphenols, including rosmarinic acid (RA). The aim of this study is to determine the anti-oxidative stress, anti-inflammation, and anti-metastasis actions of rosmarinic acid rich fraction (RA-RF) from perilla seed meal and its underlying molecular mechanisms in A549 cells exposed to PMFF. PMFF samples were collected via the air sampler at the University of Phayao, Thailand, and their PAH content were analyzed using GC-MS. Fifteen PAH compounds were detected in PMFF. The PMFF significantly induced intracellular reactive oxygen species (ROS) production, the mRNA expression of pro-inflammatory cytokines, MMP-9 activity, invasion, migration, the overexpression of c-Jun and p-65-NF-κB, and Akt phosphorylation. Additionally, the RA-RF significantly reduced ROS production, IL-6, IL-8, TNF-α, and COX-2. RA-RF could also suppress MMP-9 activity, migration, invasion, and the phosphorylation activity of c-Jun, p-65-NF-κB, and Akt. Our findings revealed that RA-RF has antioxidant, anti-inflammatory, and anti-metastasis properties via c-Jun, p-65-NF-κB, and Akt signaling pathways. RA-RF may be further developed as an inhalation agent for the prevention of lung inflammation and cancer metastasis induced by PM exposure.
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Affiliation(s)
- Komsak Pintha
- Division of Biochemistry, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand; (K.P.); (W.C.); (M.S.)
| | - Wittaya Chaiwangyen
- Division of Biochemistry, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand; (K.P.); (W.C.); (M.S.)
| | - Supachai Yodkeeree
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Maitree Suttajit
- Division of Biochemistry, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand; (K.P.); (W.C.); (M.S.)
| | - Payungsak Tantipaiboonwong
- Division of Biochemistry, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand; (K.P.); (W.C.); (M.S.)
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20
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Deb A, Deshmukh B, Ramteke P, Bhati FK, Bhat MK. Resistin: A journey from metabolism to cancer. Transl Oncol 2021; 14:101178. [PMID: 34293684 PMCID: PMC8319804 DOI: 10.1016/j.tranon.2021.101178] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 06/23/2021] [Accepted: 07/09/2021] [Indexed: 12/11/2022] Open
Abstract
Resistin levels have been associated with several pathological disorders such as metabolic disorders, cancers etc. Resistin exists in three isoforms namely RELM-α, β and γ. High resistin level activates inflammatory pathways, promotes metabolic disorders and is associated with carcinogenesis. Increase in the resistin level impairs the therapeutic response by inducing stemness or resistance, in cancer cells. Conventional drugs which alter resistin level could have therapeutic implications in several pathological disorders. Resistin, a small secretory molecule, has been implicated to play an important role in the development of insulin resistance under obese condition. For the past few decades, it has been linked to various cellular and metabolic functions. It has been associated with diseases like metabolic disorders, cardiovascular diseases and cancers. Numerous clinical studies have indicated an increased serum resistin level in pathological disorders which have been reported to increase mortality rate in comparison to low resistin expressing subjects. Various molecular studies suggest resistin plays a pivotal role in proliferation, metastasis, angiogenesis, inflammation as well as in regulating metabolism in cancer cells. Therefore, understanding the role of resistin and elucidating its’ associated molecular mechanism will give a better insight into the management of these disorders. In this article, we summarize the diverse roles of resistin in pathological disorders based on the available literature, clinicopathological data, and a compiled study from various databases. The article mainly provides comprehensive information of its role as a target in different treatment modalities in pre as well as post-clinical studies.
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Affiliation(s)
- Ankita Deb
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411007, India
| | - Bhavana Deshmukh
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411007, India
| | - Pranay Ramteke
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411007, India
| | - Firoz Khan Bhati
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411007, India
| | - Manoj Kumar Bhat
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411007, India.
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21
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Gong WJ, Zhou T, Xu JQ, Huang YF, Xiang LP, Zeng F, Han Y, Lv YN, Zhang Y, Wu SL. Resistin increases cisplatin-induced cytotoxicity in lung adenocarcinoma A549 cells via a mitochondria-mediated pathway. Med Oncol 2021; 38:65. [PMID: 33929634 DOI: 10.1007/s12032-021-01511-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/16/2021] [Indexed: 12/19/2022]
Abstract
Lung cancer is the most commonly diagnosed cancer with a high mortality rate. Cisplatin is one of the most important chemotherapeutic agents for the treatment of lung cancer patients, especially in advanced stages. Recent studies show that cisplatin may interact with mitochondria to induce apoptosis, which may partly account for its cytotoxicity. In the study, we explored the effect of resistin on cisplatin-induced cytotoxicity in A549 cells and assessed whether mitochondria-dependent apoptosis was involved. Our results found that 25 ng/ml resistin could significantly increase cisplatin-induced apoptosis and G2/M phase arrest, enhance reactive oxygen species generation, exacerbate the collapse of mitochondrial membrane potential, promote the distribution of cytochrome C in the cytoplasm from mitochondria, and activate caspase 3. Therefore, the results suggested that resistin might increase cisplatin-induced cytotoxicity via a mitochondria-mediated pathway in A549 cells. However, the precise mechanism remains to be explored in the future.
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Affiliation(s)
- Wei-Jing Gong
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Tao Zhou
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Jia-Qiang Xu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Yi-Fei Huang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Li-Ping Xiang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Fang Zeng
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Yong Han
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Yong-Ning Lv
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - San-Lan Wu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China.
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22
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Cheng W, Lu J, Wang B, Sun L, Zhu B, Zhou F, Ding Z. Inhibition of inflammation-induced injury and cell migration by coelonin and militarine in PM 2.5-exposed human lung alveolar epithelial A549 cells. Eur J Pharmacol 2021; 896:173931. [PMID: 33549578 DOI: 10.1016/j.ejphar.2021.173931] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 01/27/2021] [Accepted: 01/29/2021] [Indexed: 12/22/2022]
Abstract
Accumulating studies suggest that fine particulate matter (PM2.5) pollutants in the air are easily enter into alveoli and even the bloodstream, resulting in an inflammatory response that not only triggers respiratory disorders but also causes permanent damage to various organs. Recent findings suggest that coelonin and militarine enriched in orchids can inhibit inflammation-induced injury against respiratory diseases. Here, we evaluated the anti-inflammatory properties of coelonin and militarine and examined their underlying molecular mechanisms in A549 cells exposed to PM2.5. PM2.5 induced significant intracellular reactive oxidative stress accumulation at a concentration of 250 μg/ml, as determined using the dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence assay. Cell viability was assessed via the MTS assay to determine the concentrations of compounds appropriate for use in subsequent experiments. Data from the enzyme-linked immunosorbent assay (ELISA) showed that both coelonin (10 and 20 μg/ml) and militarine (5 and 10 μg/ml) mitigated PM2.5-induced inflammation by reducing the generation of inflammatory factors, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Quantitative real-time PCR (qRT-PCR) analysis revealed a remarkable decrease in IL-6, TNF-α, cyclooxygenase-2 (COX-2) and interleukin-1β (IL-1β) mRNA levels in the coelonin and militarine-pretreated groups. In Western blot analysis, expression of inhibitor of NF-κB (IκBα) protein in the coelonin and militarine pretreatment groups was significantly increased compared with the PM2.5 (only) treatment group (P < 0.05), concomitant with a significant decrease in phospho-IκB kinase β/IκB kinase β (p-IKKβ/IKKβ), phospho-nuclear factor of kappa B p65/nuclear factor of kappa B p65 (p-NF-κBp65/NF-κBp65) and COX-2 proteins (P < 0.05). Both coelonin and militarine inhibited migration and inflammation by suppressing PM2.5-induced IKK phosphorylation, and followed by IκBα protein degradation and NF-κB activation. Our collective data strongly supported the utility of coelonin and militarine as novel sources for development of treatments for PM2.5-induced lung diseases.
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Affiliation(s)
- Wen Cheng
- College of Life Sciences, Zhejiang Chinese Medical University, No.548, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Jingjing Lu
- College of Life Sciences, Zhejiang Chinese Medical University, No.548, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Bixu Wang
- College of Medical Technology, Zhejiang Chinese Medical University, No.548, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Ling Sun
- College of Medical Technology, Zhejiang Chinese Medical University, No.548, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Bingqi Zhu
- College of Medical Technology, Zhejiang Chinese Medical University, No.548, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Fangmei Zhou
- College of Medical Technology, Zhejiang Chinese Medical University, No.548, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Zhishan Ding
- College of Medical Technology, Zhejiang Chinese Medical University, No.548, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China.
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23
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Yu L, Qiao R, Xu J, Han B, Zhong R. FAM207BP, a pseudogene-derived lncRNA, facilitates proliferation, migration and invasion of lung adenocarcinoma cells and acts as an immune-related prognostic factor. Life Sci 2021; 268:119022. [PMID: 33434533 DOI: 10.1016/j.lfs.2021.119022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 12/28/2020] [Accepted: 01/05/2021] [Indexed: 12/11/2022]
Abstract
AIMS This study aimed to characterize the functions of pseudogene-derived long non-coding RNA (lncRNA) FAM207BP in lung adenocarcinoma (LUAD). MATERIALS AND METHODS Through the Cancer Genome Atlas (TCGA)-Genotype Tissue Expression (GTEx) database, FAM207BP expression was detected in LUAD and normal tissues. Overall survival (OS) and disease-free survival (DFS) analysis was presented using log-rank test or univariate Cox regression analysis. The relationships between FAM207BP expression and clinical features were analyzed. FAM207BP expression was validated in LUAD tissues and cells using RT-qPCR. Cell viability of LUAD cells was evaluated after silencing or overexpressing FAM207BP. Furthermore, migrated and invasive abilities were examined by Transwell and scratch assays. The correlation between FAM207BP expression and the immune infiltration levels was analyzed. Gene Set Enrichment Analysis (GSEA) was performed for high- and low-expression of FAM207BP using C2 collection in the Molecular Signatures Database (MSigDB) database. KEY FINDINGS FAM207BP expression was distinctly higher in LUAD than normal tissues. Patients with its high expression indicated worse OS and DFS time. FAM207BP expression was significantly related to gender. RT-qPCR results confirmed that FAM207BP was significantly highly expressed in LUAD tissues and cells. Knockdown of FAM207BP distinctly suppressed cellular viability, migration and invasion for LUAD cells. Also, its expression was negatively related to B cell infiltration levels. GSEA results indicated that high FAM207BP expression was involved in regulation of gene expression. Its low expression was related to immune response. SIGNIFICANCE Pseudogene-derived lncRNA FAM207BP could induce proliferation and migration of LUAD cells, which could act as an immune-related prognostic factor.
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Affiliation(s)
- Lian Yu
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Rong Qiao
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Jianlin Xu
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Baohui Han
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
| | - Runbo Zhong
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
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24
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Combined High Resistin and EGFR Expression Predicts a Poor Prognosis in Breast Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8835398. [PMID: 33313320 PMCID: PMC7719526 DOI: 10.1155/2020/8835398] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/27/2020] [Accepted: 11/18/2020] [Indexed: 12/14/2022]
Abstract
Elevated levels of resistin and epidermal growth factor receptor (EGFR) facilitate the development of breast cancer, although there are no reports of any correlation between these proteins. This study analyzed 392 human breast cancer tissue specimens and 42 samples of adjacent normal tissue. Rates of positive and strongly positive resistin expression were significantly higher in breast cancer tissue than in the adjacent nontumor tissue (83.2% vs. 23.8% and 20.9% vs. 0.0%, respectively; P < 0.001 for both comparisons). Positive resistin expression was significantly associated with tumor size, grade, stage, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, and molecular classification; strongly positive resistin expression was associated with tumor grade, ER, PR, HER2 status, and molecular classification. Significantly positive correlations were observed between positive and strongly positive resistin expression and corresponding levels of EGFR expression. Relapse-free and overall survival was worse for patients with high levels of both proteins than for those with high levels of only one protein or normal levels of both proteins. Our evidence suggests that combined high levels of resistin and EGFR expression correlate with survival in patients with breast cancer.
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25
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Bonaventura A, Grossi F, Carbone F, Vecchié A, Minetti S, Bardi N, Elia E, Ansaldo AM, Ferrara D, Rijavec E, Dal Bello MG, Rossi G, Biello F, Tagliamento M, Alama A, Coco S, Spallarossa P, Dallegri F, Genova C, Montecucco F. Resistin is associated with overall survival in non-small cell lung cancer patients during nivolumab treatment. Clin Transl Oncol 2020; 22:1603-1610. [PMID: 32048158 DOI: 10.1007/s12094-020-02305-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 01/18/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE Since the role of resistin was evaluated only in patients with non-small cell lung cancer (NSCLC) not treated with immunotherapy, we aimed to evaluate levels of resistin during immunotherapy (nivolumab) and its prognostic role with regard to OS. METHODS/PATIENTS From a cohort of 78 patients with advanced NSCLC enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 43 patients have been considered for this sub-analysis because of the availability of samples. Before and during nivolumab administration, clinical information and blood samples were collected and resistin, matrix metalloproteinase (MMP)-8, MMP-9, and myeloperoxidase were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS Median age was 71 with a prevalence of males and former smokers. Median resistin levels presented a peak at cycle 2 and then dropped down until the last cycle. Resistin correlated with all neutrophil degranulation products at cycle 1 (except for MMP-9) and at cycle 2 as well as with white blood cells and neutrophils. By a ROC curve analysis, a resistin value at cycle 2 of 19 ng/mL was tested as the best cut-off point for OS. Kaplan-Meier analysis demonstrated that patients above the resistin cut-off experienced a reduced OS (median OS 242.5 vs. 470 days, p = 0.0073), as confirmed by Cox proportional hazards regression analysis. CONCLUSIONS Resistin levels > 19 ng/mL at the time of the second cycle of nivolumab treatment independently predict a reduced OS in patients with advanced NSCLC.
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Affiliation(s)
- A Bonaventura
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy.
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1200 E Marshall St, Richmond, VA, 23298, USA.
| | - F Grossi
- Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Medical Oncology, Milan, Italy
| | - F Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genova-Italian Cardiovascular Network, Largo R. Benzi 10, 16132, Genoa, Italy
| | - A Vecchié
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1200 E Marshall St, Richmond, VA, 23298, USA
| | - S Minetti
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy
| | - N Bardi
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy
| | - E Elia
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy
| | - A M Ansaldo
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy
| | - D Ferrara
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy
| | - E Rijavec
- IRCCS Ospedale Policlinico San Martino, UOS Tumori Polmonari, Largo R. Benzi 10, 16132, Genoa, Italy
| | - M G Dal Bello
- IRCCS Ospedale Policlinico San Martino, UOS Tumori Polmonari, Largo R. Benzi 10, 16132, Genoa, Italy
| | - G Rossi
- IRCCS Ospedale Policlinico San Martino, UOS Tumori Polmonari, Largo R. Benzi 10, 16132, Genoa, Italy
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - F Biello
- Azienda Ospedaliero-Universitaria Maggiore Della Carità, Novara, Italy
| | - M Tagliamento
- IRCCS Ospedale Policlinico San Martino, UOS Tumori Polmonari, Largo R. Benzi 10, 16132, Genoa, Italy
| | - A Alama
- IRCCS Ospedale Policlinico San Martino, UOS Tumori Polmonari, Largo R. Benzi 10, 16132, Genoa, Italy
| | - S Coco
- IRCCS Ospedale Policlinico San Martino, UOS Tumori Polmonari, Largo R. Benzi 10, 16132, Genoa, Italy
| | - P Spallarossa
- Cardiovascular Diseases Unit, IRCCS Ospedale Policlinico San Martino-Italian Cardiovascular Network, Genoa, Italy
| | - F Dallegri
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genova-Italian Cardiovascular Network, Largo R. Benzi 10, 16132, Genoa, Italy
| | - C Genova
- IRCCS Ospedale Policlinico San Martino Genova-Italian Cardiovascular Network, Largo R. Benzi 10, 16132, Genoa, Italy
| | - F Montecucco
- IRCCS Ospedale Policlinico San Martino Genova-Italian Cardiovascular Network, Largo R. Benzi 10, 16132, Genoa, Italy
- First Clinic of Internal Medicine, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy
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26
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Sudan SK, Deshmukh SK, Poosarla T, Holliday NP, Dyess DL, Singh AP, Singh S. Resistin: An inflammatory cytokine with multi-faceted roles in cancer. Biochim Biophys Acta Rev Cancer 2020; 1874:188419. [PMID: 32822824 DOI: 10.1016/j.bbcan.2020.188419] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/04/2020] [Accepted: 08/05/2020] [Indexed: 12/11/2022]
Abstract
Systemic and organ-confined inflammation has been associated with cancer development and progression. Resistin, initially described as an adipocyte-derived cytokine in mice, is mostly expressed by the macrophages in humans. It has potent pro-inflammatory properties, and its elevated serum levels are detected in cancer patients. Aberrant expression of resistin receptors is also reported in several malignancies and associated with aggressive clinicopathological features. Several lines of evidence demonstrate that resistin, acting through its different receptors, promotes tumor growth, metastasis, and chemoresistance by influencing a variety of cellular phenotypes as well as by modulating the tumor microenvironment. Racially disparate expression of resistin has also attracted much interest, considering prevalent cancer health disparities. This review discusses the aberrant expression of resistin and its receptors, its diverse downstream signaling and impact on tumor growth, metastasis, angiogenesis, and therapy resistance to support its clinical exploitation in biomarker and therapeutic development.
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Affiliation(s)
- Sarabjeet Kour Sudan
- Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA; Department of Pathology, University of South Alabama, Mobile, AL 36617, USA
| | - Sachin Kumar Deshmukh
- Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA; Department of Pathology, University of South Alabama, Mobile, AL 36617, USA
| | - Teja Poosarla
- Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
| | | | - Donna Lynn Dyess
- Department of Surgery, University of South Alabama, Mobile, AL 36617, USA
| | - Ajay Pratap Singh
- Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA; Department of Pathology, University of South Alabama, Mobile, AL 36617, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
| | - Seema Singh
- Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA; Department of Pathology, University of South Alabama, Mobile, AL 36617, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
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27
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Dimitrakopoulos FID, Kottorou AE, Kalofonou M, Kalofonos HP. The Fire Within: NF-κB Involvement in Non-Small Cell Lung Cancer. Cancer Res 2020; 80:4025-4036. [PMID: 32616502 DOI: 10.1158/0008-5472.can-19-3578] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 04/01/2020] [Accepted: 06/29/2020] [Indexed: 11/16/2022]
Abstract
Thirty-four years since its discovery, NF-κB remains a transcription factor with great potential for cancer therapy. However, NF-κB-targeted therapies have yet to find a way to be clinically translatable. Here, we focus exclusively on the role of NF-κB in non-small cell lung cancer (NSCLC) and discuss its contributing effect on cancer hallmarks such as inflammation, proliferation, survival, apoptosis, angiogenesis, epithelial-mesenchymal transition, metastasis, stemness, metabolism, and therapy resistance. In addition, we present our current knowledge of the clinical significance of NF-κB and its involvement in the treatment of patients with NSCLC with chemotherapy, targeted therapies, and immunotherapy.
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Affiliation(s)
- Foteinos-Ioannis D Dimitrakopoulos
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Anastasia E Kottorou
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Melpomeni Kalofonou
- Institute of Biomedical Engineering, Imperial College London, London, United Kingdom
| | - Haralabos P Kalofonos
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece.
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28
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Lin Q, Johns RA. Resistin family proteins in pulmonary diseases. Am J Physiol Lung Cell Mol Physiol 2020; 319:L422-L434. [PMID: 32692581 DOI: 10.1152/ajplung.00040.2020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The family of resistin-like molecules (RELMs) consists of four members in rodents (RELMα/FIZZ1/HIMF, RELMβ/FIZZ2, Resistin/FIZZ3, and RELMγ/FIZZ4) and two members in humans (Resistin and RELMβ), all of which exhibit inflammation-regulating, chemokine, and growth factor properties. The importance of these cytokines in many aspects of physiology and pathophysiology, especially in cardiothoracic diseases, is rapidly evolving in the literature. In this review article, we attempt to summarize the contribution of RELM signaling to the initiation and progression of lung diseases, such as pulmonary hypertension, asthma/allergic airway inflammation, chronic obstructive pulmonary disease, fibrosis, cancers, infection, and other acute lung injuries. The potential of RELMs to be used as biomarkers or risk predictors of these diseases also will be discussed. Better understanding of RELM signaling in the pathogenesis of pulmonary diseases may offer novel targets or approaches for the development of therapeutics to treat or prevent a variety of inflammation, tissue remodeling, and fibrosis-related disorders in respiratory, cardiovascular, and other systems.
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Affiliation(s)
- Qing Lin
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Roger A Johns
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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29
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Zhao Y, Zheng R, Ning D, Xie F. MiR-625 Inhibits Tumor Cell Invasion, Migration and EMT by Negatively Regulating the Expression of Resistin in Non-Small Cell Lung. Cancer Manag Res 2020; 12:4171-4180. [PMID: 32581589 PMCID: PMC7276317 DOI: 10.2147/cmar.s248251] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/27/2020] [Indexed: 01/02/2023] Open
Abstract
PURPOSE To investigate the role of miR-625 on the invasion, migration, and epithelial-mesenchymal transition (EMT) of non-small cell lung carcinoma (NSCLC) cells, and the related mechanisms. MATERIALS AND METHODS The expression levels of miR-625 and Resistin mRNA in 80 pairs of NSCLC and para-cancerous lung tissues were analyzed by RT-PCR. The relationship between miR-625 and Resistin was predicted by bioinformatics and verified by a dual-luciferase gene reporter assay. NSCLC cells were transfected with Resistin plasmids, si-Resistin plasmids, miR-625 mimics, or miR-625 inhibitors, and proliferation, invasion, and migration were determined by CCK-8, Transwell, and wound scratch assays, respectively. EMT-related proteins were determined by Western blot assay. A xenograft model of NSCLC was established in nude mice to validate the in vitro findings. RESULTS MiR-625 was significantly downregulated in NSCLC tissue compared to paired para-cancerous lung tissues, while Resistin was markedly increased in tumor tissue. The expression levels of miR-625 and Resistin were negatively correlated in NSCLC tissues, and high levels of Resistin correlated with greater tumor differentiation, more advanced clinical staging, and lymph node metastasis. Furthermore, Resistin was a target gene of miR-625, and the latter downregulated Resistin to inhibit the EMT, proliferation, invasion, and migration of NSCLC cells in vitro, likely via the PI3K/AKT/Snail signaling pathway. Finally, miR-625 also inhibited the tumorigenic effect of NSCLC cells in vivo by downregulating Resistin. CONCLUSION MiR-625 acts as a tumor suppressor in NSCLC and inhibits tumor cell invasion and metastasis by blocking the Resistin/PI3K/AKT/Snail pathway and by decreasing EMT.
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Affiliation(s)
- Yongsheng Zhao
- Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong637000, Sichuan
| | - Renyan Zheng
- Department of Integrated Western and Chinese Colorectal and Anal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong637000, Sichuan
| | - Dong Ning
- Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong637000, Sichuan
| | - Fei Xie
- Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong637000, Sichuan
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30
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Ju H, Hu Z, Lu Y, Wu Y, Zhang L, Wei D, Guo W, Xia W, Liu S, Ren G, Hu J. TLR4 activation leads to anti-EGFR therapy resistance in head and neck squamous cell carcinoma. Am J Cancer Res 2020; 10:454-472. [PMID: 32195020 PMCID: PMC7061757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 12/22/2019] [Indexed: 06/10/2023] Open
Abstract
Epidermal growth factor receptor (EGFR) is highly expressed in head and neck squamous cell carcinoma (HNSCC) and related to cancer progression. The resistance to anti-EGFR therapy remains a major clinical problem in HNSCC. In this study, we found that TOLL-like receptor 4 (TLR4) was highly expressed in 50% of EGFR overexpressed HNSCC biopsies, which correlated to worse prognosis in patients. In HNSCC cell lines, activation of TLR4 reversed cetuximab-induced the inhibition of proliferation, migration and invasion. LPS induced of TLR4 signaling was potentiated under cetuximab treatment, showing increased activation of downstream NF-κB and MAPK pathways. Accordingly, cetuximab treatment also increased expression of TNF-α, COX2, and other molecules involved in TLR4 induced tumor inflammation. Mechanistically, we found inhibition of EGFR by cetuximab led to decreased phosphorylation of Src and sequentially Src-medicated activation of Cbl-b. This inhibited Cbl-b-mediated degradation of the key TLR4 adaptor protein MyD88 and activated TLR4 signaling. TLR4 or MyD88 overexpressed CAL27 and SCC4 cells grew faster and were more resistant to cetuximab and gefitinib both in vitro and in vivo. Out study delineates a crosstalk between EGFR and TLR4 pathways and identified TLR4 as a potential biomarker as well as a therapeutic target in overcoming the resistance to anti-EGFR therapy of HNSCC.
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Affiliation(s)
- Houyu Ju
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of StomatologyShanghai, China
| | - Zhenrong Hu
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of StomatologyShanghai, China
| | - Yusheng Lu
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of StomatologyShanghai, China
| | - Yunteng Wu
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of StomatologyShanghai, China
| | - Liming Zhang
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of StomatologyShanghai, China
| | - Dongliang Wei
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of StomatologyShanghai, China
| | - Wei Guo
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of StomatologyShanghai, China
| | - Weiya Xia
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas
| | - Shuli Liu
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of StomatologyShanghai, China
| | - Guoxin Ren
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of StomatologyShanghai, China
| | - Jingzhou Hu
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of StomatologyShanghai, China
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31
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Mao Y, Xu R. Circular RNA CDR1-AS contributes to pemetrexed and cisplatin chemoresistance through EGFR/PI3K signaling pathway in lung adenocarcinoma. Biomed Pharmacother 2019; 123:109771. [PMID: 31881486 DOI: 10.1016/j.biopha.2019.109771] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 11/30/2019] [Accepted: 12/04/2019] [Indexed: 12/24/2022] Open
Abstract
Recent studies found circRNAs were involved in tumorigenesis and became new tumor biomarkers and therapeutic targets in lung adenocarcinoma (LUAD), which played a critical role in various biological processes and had been implicated in resistance to chemotherapeutic drugs. However, the role of CDR1-AS in chemoresistance of LUAD to pemetrexed (PTX) and cisplatin (CDDP) is poorly understood. Here, we found that CDR1-AS was up-regulated in LUAD tissues and cell lines, its high-expression was relevant to smoking history, T stage and neoadjuvant chemotherapy (PTX and CDDP) of LUAD patients. CDR1-AS was an independent prognostic biomarker for LUAD patients. CDR1-AS was highly expressed in PTX and CDDP resistant LUAD tissues and cell line (A549/CR). Silence of CDR1-AS re-sensitized A549/CR cells to PTX and CDDP. CDR1-AS was closely related with EGFR/PI3K signaling pathway in A549/CR cells. The activating of EGFR/PI3K pathway mostly restored the effecting of CDR1-AS silence on PTX and CDDP sensitivity in A549/CR cells, CDR1-AS contributed to PTX and CDDP chemoresistance through EGFR/PI3K signaling pathway in LUAD. In conclusion, the CDR1-AS is high-expressed in LUAD and is an independent prognostic biomarker for LUAD patients. The high-expression of CDR1-AS is related with the PTX and CDDP insensitivity of LUAD patients, CDR1-AS promotes PTX and CDDP chemoresistance through EGFR/PI3K signaling pathway in LUAD.
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Affiliation(s)
- Yuqiang Mao
- Department of Thoracic Surgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China
| | - Ran Xu
- Department of Thoracic Surgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China.
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32
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Zhang Y, Wang Y, Xu Q, Zhu J, Lin Y. Molecular and expression characteristics of resistin (RETN) and its effects on the differentiation of intramuscular preadipocyte in goat. Anim Biotechnol 2019; 32:113-120. [PMID: 31516062 DOI: 10.1080/10495398.2019.1664564] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Resistin (RETN) is a hormone secreted by adipocytes, which plays an important role in glucose and lipid metabolism. The aim of this study is to clone and obtain the full length open reading frame (ORF) of goat RETN gene sequence, and to reveal its molecular and expression characteristics. Simultaneously, we explore its effect on the differentiation of intramuscular preadipocytes in goat. The full length ORF sequence of goat RETN gene was cloned by RT-PCR technique, and bioinformatics analysis was performed though relevant biological softwares. In this study, the expression of RETN mRNA in goat tissues and intramuscular preadipocytes during differentiation was detected by qPCR technique. Furthermore, RNA interference was used to explore the effects of RETN on intramuscular preadipocytes differentiation in goat. The results showed that the cloned goat RETN gene sequence was 428 bp in length, of which the ORF was 330 bp, encoding 109 amino acids. Sequence analysis revealed that it had 12 phosphorylation sites and an O-glycosylation site, and its protein contained a signal peptide sequence. Also, the RETN gene is expressed in goat various analyzed tissues, and the results showed that the expression of RETN gene in lung tissue was higher than that in other analyzed tissues of goat (p < .01). Moreover, the expression level of RETN gene in the goat's intramuscular preadipocytes decreased first and then increased, and reached the highest on the fifth day, which was significantly higher than that of undifferentiated intramuscular preadipocytes (p < .001). After transfecting intramuscular preadipocyte with siRNA, we found that the mRNA level of RETN was significantly down-regulated by 70% and 87% (p < .01). Oil red O staining results showed that the interference of RETN gene can promote the differentiation of intramuscular preadipocytes. After knockdown of RETN with siRNA, the PPARγ, AP2, C/EBPα, C/EBPβ and SREBP1 genes were significantly up-regulated (p < .01). Thus, it can be inferred that RETN inhibits the differentiation of goat intramuscular preadipocytes, probably through regulating the expression of C/EBPα, C/EBPβ, PPARγ, AP2 and SREBP-1 genes.
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Affiliation(s)
- Yanan Zhang
- School of Life Science and Technology, Southwest Minzu University, Chengdu, Sichuan, China.,Ministry of Education, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Chengdu, Sichuan, China
| | - Yong Wang
- Ministry of Education, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Chengdu, Sichuan, China.,Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
| | - Qing Xu
- School of Life Science and Technology, Southwest Minzu University, Chengdu, Sichuan, China.,Ministry of Education, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Chengdu, Sichuan, China
| | - Jiangjiang Zhu
- Ministry of Education, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Chengdu, Sichuan, China.,Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
| | - Yaqiu Lin
- School of Life Science and Technology, Southwest Minzu University, Chengdu, Sichuan, China.,Ministry of Education, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Chengdu, Sichuan, China
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Deng F, Miller J. A review on protein markers of exosome from different bio-resources and the antibodies used for characterization. J Histotechnol 2019; 42:226-239. [PMID: 31432761 DOI: 10.1080/01478885.2019.1646984] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Exosomes are small membrane vesicles (ranging from 30 nm to 150 nm), secreted by different cell types upon fusion of multivesicular bodies (MVB) to the cell plasma membrane under a variety of normal and pathological conditions. Through transferring their cargos such as proteins, lipids and nucleic acids from donor cells to recipient cells, exosomes play a crucial role in cell-to-cell communication. Due to their presence in most body fluids (such as blood, breast milk, saliva, urine, bile, pancreatic juice, cerebrospinal and peritoneal fluids), and their role in carrying bioactive molecules from the cells of origin, exosomes have attracted great interest in their diagnostic and prognostic value for various diseases and therapeutic approaches. Although a large body of literature has documented the importance of exosomes over the past decade, there is no article systematically summarizing protein markers of exosome from different resources and the antibodies that are suited to characterize exosomes. In this review, we briefly summarize the exosome marker proteins, exosomal biomarkers for different diseases, and the antibodies suitable for different bio-resources exosomes characterization.
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Affiliation(s)
- Fengyan Deng
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, MO, USA
| | - Josh Miller
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, MO, USA
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Zhang L, Tao X, Fu Q, Ge C, Li R, Li Z, Zhu Y, Tian H, Li Q, Liu M, Hu H, Zeng B, Lin Z, Li C, Luo R, Song X. Curcumin inhibits cell proliferation and migration in NSCLC through a synergistic effect on the TLR4/MyD88 and EGFR pathways. Oncol Rep 2019; 42:1843-1855. [PMID: 31432177 PMCID: PMC6775800 DOI: 10.3892/or.2019.7278] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 05/31/2019] [Indexed: 02/07/2023] Open
Abstract
Despite the increasing number of available therapeutic methods, the prognosis of non-small cell lung cancer (NSCLC) remains poor. Furthermore, side effects are an important limiting factor in the treatment of NSCLC. Therefore, developing an efficacious, safe, affordable and easily accessible chemotherapeutic agent is necessary for NSCLC treatment. As a natural chemical produced by Zingiberaceae plants, curcumin exerts distinct antitumor effects on several tumor types. In the present study, curcumin was observed to inhibit not only cell proliferation and cell cycle transition, but also cell migration in NSCLC, as determined by a series of experiments (such as MTS assay, colony formation assay, flow cytometric analysis, Transwell migration assay and western blotting). Mechanistically, curcumin induced G2/M phase arrest by controlling cell cycle- and epithelial-mesenchymal transition (EMT)-related checkpoints. Furthermore, curcumin significantly inhibited the expression of Toll-like receptor 4 (TLR4)/MyD88 and EGFR in a dose- and time-dependent manner. Conversely, EGF reversed the inhibitory action of curcumin on TLR4/MyD88. In clinical specimens, TLR4 and MyD88 were highly expressed in NSCLC tissues, and a significant positive association was observed between TLR4 and MyD88 expression. These data suggested that curcumin may control the EGFR and TLR4/MyD88 pathways to synergistically downregulate downstream cell cycle- and EMT-related regulators, in order to block cell proliferation and metastasis in NSCLC. These findings provide evidence for the clinical application of curcumin.
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Affiliation(s)
- Lanfeng Zhang
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510315, P.R. China
| | - Xingyu Tao
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510315, P.R. China
| | - Qiaofen Fu
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 510118, P.R. China
| | - Chunlei Ge
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 510118, P.R. China
| | - Ruilei Li
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 510118, P.R. China
| | - Zhen Li
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 510118, P.R. China
| | - Ye Zhu
- Department of Medical Oncology, The Central Hospital of Hengyang, Hengyang, Hunan 421000, P.R. China
| | - Hui Tian
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 510118, P.R. China
| | - Qiaolin Li
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 510118, P.R. China
| | - Min Liu
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 510118, P.R. China
| | - Hongyan Hu
- Department of Pathology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 510118, P.R. China
| | - Baozhen Zeng
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 510118, P.R. China
| | - Zhuyin Lin
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, P.R. China
| | - Chunyan Li
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 510118, P.R. China
| | - Rongcheng Luo
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510315, P.R. China
| | - Xin Song
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510315, P.R. China
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35
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Dioscin-6’-O-acetate impairs migration of lung cancer cells through attenuations of MMP-2 and MMP-9 via NF-κB suppression. Med Chem Res 2018. [DOI: 10.1007/s00044-018-2257-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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36
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Zhao CC, Chen J, Niu RF, Liu Y, Zhang CG. Increased resistin suggests poor prognosis and promotes development of lung adenocarcinoma. Oncol Rep 2018; 40:3392-3404. [PMID: 30272365 PMCID: PMC6196645 DOI: 10.3892/or.2018.6736] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 09/17/2018] [Indexed: 12/27/2022] Open
Abstract
Resistin is considered to be a risk factor for several types of cancer, but its functions are controversial and not well studied in lung cancer. The present study is aimed to investigate the expression of resistin in lung adenocarcinoma tissues, in order to evaluate its association with the clinicopathological characteristics of cancer patients and to investigate the effects of resistin in lung adenocarcinoma cells. A total of 70 pairs of lung adenocarcinoma tissues and normal tissues were collected and immunohistochemistry was performed to examine resistin expression. Resistin overexpressed cells were established by plasmid transfection in A549 or H1975 cells. Alterations in cell proliferation, apoptosis, migration and invasion were analyzed in vitro. A nude mouse tumorigenicity assay was used to test the effect of resistin in vivo. High expression of resistin was predominantly observed in lung adenocarcinoma tissues but not in adjacent normal lung tissues. Resistin expression was significantly associated with increased tumor size, clinical stage as well as lymph node metastasis while negatively associated with progression-free survival (PFS) and overall survival (OS). Expression of resistin was an independent risk factor for PFS and OS. Overexpression of resistin promoted significant proliferation, migration and invasion, while also inhibited apoptosis in vitro. Resistin also promoted tumor formation in nude mice. The potential molecular mechanism was also investigated by in vitro experiments. In conclusion, the present study revealed that a high level of resistin expression in lung adenocarcinoma tissues is associated with poor clinicopathological status and survival. Resistin, which promotes the development of lung adenocarcinoma in vitro and in vivo may be a novel target for lung adenocarcinoma.
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Affiliation(s)
- Cui-Cui Zhao
- Department of VIP Ward, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| | - Jing Chen
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| | - Rui-Fang Niu
- Department of Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| | - Yan Liu
- Department of VIP Ward, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| | - Chuan-Gui Zhang
- Department of VIP Ward, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
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37
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Gong WJ, Liu JY, Yin JY, Cui JJ, Xiao D, Zhuo W, Luo C, Liu RJ, Li X, Zhang W, Zhou HH, Liu ZQ. Resistin facilitates metastasis of lung adenocarcinoma through the TLR4/Src/EGFR/PI3K/NF-κB pathway. Cancer Sci 2018; 109:2391-2400. [PMID: 29927028 PMCID: PMC6113506 DOI: 10.1111/cas.13704] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 06/14/2018] [Indexed: 12/21/2022] Open
Abstract
Metastasis is the main cause of lung cancer‐related death. The tumor microenvironment greatly contributes to tumor metastasis. Resistin, mainly secreted by tumor‐associated macrophages in tumor tissues, is a 12.5‐kDa cysteine‐rich secretory protein that is found at significantly higher levels in the serum or plasma of cancer patients compared with healthy controls. In this study, we explored the expression and role of resistin in lung adenocarcinoma. Our study showed that resistin was strongly expressed in lung adenocarcinoma tissues and promoted the migration and invasion of lung adenocarcinoma cells in a dose‐dependent manner. Toll‐like receptor 4 (TLR4) was the functional receptor of resistin for migration and invasion in A549 cells. Src/epidermal growth factor receptor (EGFR) was involved in resistin‐induced migration and invasion. Resistin increased the phosphorylation of EGFR through the TLR4/Src pathway. We also found that PI3K/nuclear factor (NF)‐κB were the intracellular downstream effectors mediating resistin‐induced migration and invasion. Taken together, our results suggested that resistin promoted lung adenocarcinoma metastasis through the TLR4/Src/EGFR/PI3K/NF‐κB pathway.
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Affiliation(s)
- Wei-Jing Gong
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun-Yan Liu
- Department of orthopaedics, The First Affiliated Hospital of the University of South China, Hengyang, China
| | - Ji-Ye Yin
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Jia-Jia Cui
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Di Xiao
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Zhuo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Chao Luo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Rui-Jie Liu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Xi Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
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