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Lin SY, Huang H, Yu JJ, Su F, Jiang T, Zhang SY, Lv L, Long T, Pan HW, Qi JQ, Zhou Q, Tang WF, Ding GW, Wang LM, Tan LJ, Yin J. Activin A receptor type 1C single nucleotide polymorphisms associated with esophageal squamous cell carcinoma risk in Chinese population. World J Gastrointest Oncol 2025; 17:96702. [PMID: 39817119 PMCID: PMC11664604 DOI: 10.4251/wjgo.v17.i1.96702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 09/01/2024] [Accepted: 10/14/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Transforming growth factor-β (TGF-β) superfamily plays an important role in tumor progression and metastasis. Activin A receptor type 1C (ACVR1C) is a TGF-β type I receptor that is involved in tumorigenesis through binding to different ligands. AIM To evaluate the correlation between single nucleotide polymorphisms (SNPs) of ACVR1C and susceptibility to esophageal squamous cell carcinoma (ESCC) in Chinese Han population. METHODS In this hospital-based cohort study, 1043 ESCC patients and 1143 healthy controls were enrolled. Five SNPs (rs4664229, rs4556933, rs77886248, rs77263459, rs6734630) of ACVR1C were assessed by the ligation detection reaction method. Hardy-Weinberg equilibrium test, genetic model analysis, stratified analysis, linkage disequilibrium test, and haplotype analysis were conducted. RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC, and those with rs77886248 TA mutant were related with higher risk, especially in older male smokers. In the haplotype analysis, ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC, while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC. CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC, which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.
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Affiliation(s)
- Si-Yun Lin
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Hou Huang
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Jin-Jie Yu
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Feng Su
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Tian Jiang
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Shao-Yuan Zhang
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Lu Lv
- Department of Cardiothoracic Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu Province, China
| | - Tao Long
- Department of Cardiothoracic Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu Province, China
| | - Hui-Wen Pan
- Department of Cardiothoracic Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu Province, China
| | - Jun-Qing Qi
- Department of Cardiothoracic Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu Province, China
| | - Qiang Zhou
- Department of Thoracic Surgery, Sichuan Cancer Hospital & Institute, Chengdu 610042, Sichuan Province, China
| | - Wei-Feng Tang
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, Jiangsu Province, China
| | - Guo-Wen Ding
- Department of Cardiothoracic Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu Province, China
| | - Li-Ming Wang
- Department of Respiratory and Critical Care Medicine, Shanghai Xuhui Central Hospital, Shanghai 200032, China
| | - Li-Jie Tan
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Jun Yin
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
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Du R, Wen L, Niu M, Zhao L, Guan X, Yang J, Zhang C, Liu H. Activin receptors in human cancer: Functions, mechanisms, and potential clinical applications. Biochem Pharmacol 2024; 222:116061. [PMID: 38369212 DOI: 10.1016/j.bcp.2024.116061] [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: 11/06/2023] [Revised: 01/18/2024] [Accepted: 02/15/2024] [Indexed: 02/20/2024]
Abstract
Activins are members of the transforming growth factor-β (TGF-β) superfamily and act as key regulators in various physiological processes, such as follicle and embryonic development, as well as in multiple human diseases, including cancer. They have been established to signal through three type I and two type II serine/threonine kinase receptors, which, upon ligand binding, form a final signal-transducing receptor complex that activates downstream signaling and governs gene expression. Recent research highlighted the dysregulation of the expression or activity of activin receptors in multiple human cancers and their critical involvement in cancer progression. Furthermore, expression levels of activin receptors have been associated with clinicopathological features and patient outcomes across different cancers. However, there is currently a paucity of comprehensive systematic reviews of activin receptors in cancer. Thus, this review aimed to consolidate existing knowledge concerning activin receptors, with a primary emphasis on their signaling cascade and emerging biological functions, regulatory mechanisms, and potential clinical applications in human cancers in order to provide novel perspectives on cancer prognosis and targeted therapy.
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Affiliation(s)
- Ruochen Du
- First Clinical Medical College of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Department of Laboratory Animal Center, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Liqi Wen
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Min Niu
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Liting Zhao
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Xiaoya Guan
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Jiao Yang
- Department of Anatomy, the Basic Medical School of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Chunming Zhang
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China.
| | - Hongliang Liu
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; First Clinical Medical College of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Department of Cell Biology and Genetics, the Basic Medical School of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China.
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Rengganaten V, Huang CJ, Wang ML, Chien Y, Tsai PH, Lan YT, Ong HT, Chiou SH, Choo KB. Circular RNA ZNF800 (hsa_circ_0082096) regulates cancer stem cell properties and tumor growth in colorectal cancer. BMC Cancer 2023; 23:1088. [PMID: 37950151 PMCID: PMC10636831 DOI: 10.1186/s12885-023-11571-1] [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: 04/06/2023] [Accepted: 10/26/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Cancer stem cells form a rare cell population in tumors that contributes to metastasis, recurrence and chemoresistance in cancer patients. Circular RNAs (circRNAs) are post-transcriptional regulators of gene expression that sponge targeted microRNA (miRNAs) to affect a multitude of downstream cellular processes. We previously showed in an expression profiling study that circZNF800 (hsa_circ_0082096) was up-regulated in cancer stem cell-enriched spheroids derived from colorectal cancer (CRC) cell lines. METHODS Spheroids were generated in suspension spheroidal culture. The ZNF800 mRNA, pluripotency stem cell markers and circZNF800 levels were determined by quantitative RT-PCR. CircZNF800-miRNA interactions were shown in RNA pulldown assays and the miRNA levels determined by stem-loop qRT-PCR. The effects of circZNF800 on cell proliferation were tested by EdU staining followed by flowcytometry. Expression of stem cell markers CD44/CD133, Lgr5 and SOX9 was demonstrated in immunofluorescence microscopy. To manipulate the cellular levels of circZNF800, circZNF800 over-expression was achieved via transfection of in vitro synthesized and circularized circZNF800, and knockdown attained using a CRISPR-Cas13d-circZNF800 vector system. Xenografted nude mice were used to demonstrate effects of circZNF800 over-expression and knockdown on tumor growth in vivo. RESULTS CircZNF800 was shown to be over-expressed in late-stage tumor tissues of CRC patients. Data showed that circZNF800 impeded expression of miR-140-3p, miR-382-5p and miR-579-3p while promoted the mRNA levels of ALK/ACVR1C, FZD3 and WNT5A targeted by the miRNAs, as supported by alignments of seed sequences between the circZNF800-miRNA, and miRNA-mRNA paired interactions. Analysis in CRC cells and biopsied tissues showed that circZNF800 positively regulated the expression of intestinal stem cell, pluripotency and cancer stem cell markers, and promoted CRC cell proliferation, spheroid and colony formation in vitro, all of which are cancer stem cell properties. In xenografted mice, circZNF800 over-expression promoted tumor growth, while circZNF800 knockdown via administration of CRISPR Cas13d-circZNF800 viral particles at the CRC tumor sites impeded tumor growth. CONCLUSIONS CircZNF800 is an oncogenic factor that regulate cancer stem cell properties to lead colorectal tumorigenesis, and may be used as a predictive marker for tumor progression and the CRISPR Cas13d-circZNF800 knockdown strategy for therapeutic intervention of colorectal cancer.
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Affiliation(s)
- Vimalan Rengganaten
- Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, 43000, Kajang, Selangor, Malaysia
- Postgraduate Program, M. Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, 43000, Kajang, Malaysia
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | - Chiu-Jung Huang
- Department of Animal Science & Graduate Institute of Biotechnology, Chinese Culture University, Taipei, 11221, Taiwan
| | - Mong-Lien Wang
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11221, Taiwan
- Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | - Yueh Chien
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11221, Taiwan
| | - Ping-Hsing Tsai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11221, Taiwan
| | - Yuan-Tzu Lan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, 11221, Taiwan
| | - Hooi Tin Ong
- Centre for Cancer Research, Universiti Tunku Abdul Rahman, 43000, Kajang, Selangor, Malaysia
- Department of Preclinical Sciences, M. Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Sg Long, 43000, Kajang, Selangor, Malaysia
| | - Shih-Hwa Chiou
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11221, Taiwan.
| | - Kong Bung Choo
- Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, 43000, Kajang, Selangor, Malaysia.
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11221, Taiwan.
- Department of Preclinical Sciences, M. Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Sg Long, 43000, Kajang, Selangor, Malaysia.
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Medina EJ, Zohdy YM, Porto E, Revuelta Barbero JM, Bray D, Maldonado J, Rodas A, Mayol M, Morales B, Neill S, Read W, Pradilla G, Ioachimescu A, Garzon-Muvdi T. Therapeutic response to pazopanib: case report and literature review on molecular abnormalities of aggressive prolactinomas. Front Endocrinol (Lausanne) 2023; 14:1195792. [PMID: 37529607 PMCID: PMC10388536 DOI: 10.3389/fendo.2023.1195792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/27/2023] [Indexed: 08/03/2023] Open
Abstract
Introduction Aggressive prolactinomas (APRLs) pose a significant clinical challenge due to their high rate of regrowth and potentially life-threatening complications. In this study, we present a case of a patient with an APRL who had a trial of multiple therapeutic modalities with the aim to provide a review of molecular abnormalities and management of APRLs by corroborating our experience with previous literature. Methods A total of 268 articles were reviewed and 46 were included. Case reports and series, and studies that investigated the molecular and/or genetic analysis of APRLs were included. Special care was taken to include studies describing prolactinomas that would fall under the APRL subtype according to the European Society of Endocrinology guidelines; however, the author did not label the tumor as "aggressive" or "atypical". Addiontionally, we present a case report of a 56-year-old man presented with an invasive APRL that was resistant to multiple treatment modalities. Results Literature review revealed multiple molecular abnormalities of APRLs including mutations in and/or deregulation of ADAMTS6, MMP-9, PITX1, VEGF, POU6F2, CDKN2A, and Rb genes. Mismatch repair genes, downregulation of microRNAs, and hypermethylation of specific genes including RASSF1A, p27, and MGMT were found to be directly associated with the aggressiveness of prolactinomas. APRL receptor analysis showed that low levels of estrogen receptor (ER) and an increase in somatostatin receptors (SSTR5) and epidermal growth factor receptors (EGFR) were associated with increased invasiveness and higher proliferation activity. Our patient had positive immunohistochemistry staining for PD-L1, MSH2, and MSH6, while microarray analysis revealed mutations in the CDKN2A and POU6F2 genes. Despite undergoing two surgical resections, radiotherapy, and taking dopamine agonists, the tumor continued to progress. The patient was administered pazopanib, which resulted in a positive response and the patient remained progression-free for six months. However, subsequent observations revealed tumor progression. The patient was started on PD-L1 inhibitor pembrolizumab, yet the tumor continued to progress. Conclusion APRLs are complex tumors that require a multidisciplinary management approach. Knowledge of the molecular underpinnings of these tumors is critical for understanding their pathogenesis and identifying potential targets for precision medical therapy.
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Affiliation(s)
- Eduardo J. Medina
- Department of Neurosurgery, Emory University, Atlanta, GA, United States
| | - Youssef M. Zohdy
- Department of Neurosurgery, Emory University, Atlanta, GA, United States
| | - Edoardo Porto
- Department of Neurosurgery, Emory University, Atlanta, GA, United States
- Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | | | - David Bray
- Department of Neurosurgery, Emory University, Atlanta, GA, United States
| | - Justin Maldonado
- Department of Neurosurgery, Emory University, Atlanta, GA, United States
| | - Alejandra Rodas
- Department of Otolaryngology, Emory University, Atlanta, GA, United States
| | - Miguel Mayol
- Department of Neurosurgery, Emory University, Atlanta, GA, United States
| | - Bryan Morales
- Department of Pathology, Emory University, Atlanta, GA, United States
| | - Stewart Neill
- Department of Pathology, Emory University, Atlanta, GA, United States
| | - William Read
- Department of Oncology, Emory University, Atlanta, GA, United States
| | - Gustavo Pradilla
- Department of Neurosurgery, Emory University, Atlanta, GA, United States
| | | | - Tomas Garzon-Muvdi
- Department of Neurosurgery, Emory University, Atlanta, GA, United States
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Zhao Z, Lu Y, Wang H, Gu X, Zhu L, Guo H, Li N. ALK7 Inhibition Protects Osteoblast Cells Against High Glucoseinduced ROS Production via Nrf2/HO-1 Signaling Pathway. Curr Mol Med 2022; 22:354-364. [PMID: 34126915 DOI: 10.2174/1566524021666210614144337] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Some studies demonstrated that under high-glucose (HG) condition, osteoblasts develop oxidative stress, which will impair their normal functions. The effects of activin receptor-like kinase 7 (ALK7) silencing on HG-induced osteoblasts remained unclear. OBJECTIVE The aim of this study was to explore the effect of ALK7 on HG-induced osteoblasts. METHODS MC3T3-E1 cells were treated with different concentrations of HG (0, 50, 100, 200 and 300mg/dL), and the cell viability was detected using cell counting kit-8 (CCK-8). HG-treated MC3T3-E1 cells were transfected with siALK7 or ALK7 overexpression plasmid or siNrf2, and then the viability and apoptosis were detected by CCK-8 and flow cytometry. The levels of Reactive Oxygen Species (ROS), collagen I and calcification nodule were determined by oxidative stress kits, Enzyme-linked immunosorbent assay and Alizarin red staining. The expressions of NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and osteoblast-associated genes were determined by quantitative real-time PCR (qRT-PCR) and Western blot. RESULTS Cell viability was reduced with HG treatment. Silencing ALK7 inhibited the effect of HG on increasing cell apoptosis and ROS production, reduced cell viability, mineralized nodules, and downregulated collagen I and osteoblast-associated genes expression in MC3T3-E1 cells. ALK7 silencing activated the Nrf2/HO-1 signaling pathway by affecting expressions of HO-1 and Nrf2. ALK7 overexpression had the opposite effects. In addition, siNrf2 partially reversed the effects of ALK7 silencing on HG-induced MC3T3-E1 cells. CONCLUSION ALK7 silencing protected osteoblasts under HG condition possibly through activating the Nrf2/HO-1 pathway.
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Affiliation(s)
- Zhen Zhao
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, 100050, China
| | - Yu Lu
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, 100050, China
| | - Huan Wang
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, 100050, China
| | - Xiang Gu
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, 100050, China
| | - Luting Zhu
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, 100050, China
| | - Hong Guo
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, 100050, China
| | - Nan Li
- Department of Endocrinology, The Second Medical Center & National Clinical Research Center, Chinese PLA General Hospital, Haidian District, Beijing, 100853, China
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Ibáñez CF. Regulation of metabolic homeostasis by the TGF-β superfamily receptor ALK7. FEBS J 2021; 289:5776-5797. [PMID: 34173336 DOI: 10.1111/febs.16090] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/28/2021] [Accepted: 06/11/2021] [Indexed: 12/13/2022]
Abstract
ALK7 (Activin receptor-like kinase 7) is a member of the TGF-β receptor superfamily predominantly expressed by cells and tissues involved in endocrine functions, such as neurons of the hypothalamus and pituitary, pancreatic β-cells and adipocytes. Recent studies have begun to delineate the processes regulated by ALK7 in these tissues and how these become integrated with the homeostatic regulation of mammalian metabolism. The picture emerging indicates that ALK7's primary function in metabolic regulation is to limit catabolic activities and preserve energy. Aside of the hypothalamic arcuate nucleus, the function of ALK7 elsewhere in the brain, particularly in the cerebellum, where it is abundantly expressed, remains to be elucidated. Although our understanding of the basic molecular events underlying ALK7 signaling has benefited from the vast knowledge available on TGF-β receptor mechanisms, how these connect to the physiological functions regulated by ALK7 in different cell types is still incompletely understood. Findings of missense and nonsense variants in the Acvr1c gene, encoding ALK7, of some mouse strains and human subjects indicate a tolerance to ALK7 loss of function. Recent discoveries suggest that specific inhibitors of ALK7 may have therapeutic applications in obesity and metabolic syndrome without overt adverse effects.
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Affiliation(s)
- Carlos F Ibáñez
- Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.,Peking-Tsinghua Center for Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University School of Life Sciences and Chinese Institute for Brain Research, Beijing, China.,Department of Physiology and Life Sciences Institute, National University of Singapore, Singapore
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Mapping a Circular RNA-microRNA-mRNA-Signaling Regulatory Axis That Modulates Stemness Properties of Cancer Stem Cell Populations in Colorectal Cancer Spheroid Cells. Int J Mol Sci 2020; 21:ijms21217864. [PMID: 33114016 PMCID: PMC7672619 DOI: 10.3390/ijms21217864] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/19/2020] [Accepted: 10/20/2020] [Indexed: 02/08/2023] Open
Abstract
Spheroidal cancer cell cultures have been used to enrich cancer stem cells (CSC), which are thought to contribute to important clinical features of tumors. This study aimed to map the regulatory networks driven by circular RNAs (circRNAs) in CSC-enriched colorectal cancer (CRC) spheroid cells. The spheroid cells established from two CRC cell lines acquired stemness properties in pluripotency gene expression and multi-lineage differentiation capacity. Genome-wide sequencing identified 1503 and 636 circRNAs specific to the CRC parental and spheroid cells, respectively. In the CRC spheroids, algorithmic analyses unveiled a core network of mRNAs involved in modulating stemness-associated signaling pathways, driven by a circRNA–microRNA (miRNA)–mRNA axis. The two major circRNAs, hsa_circ_0066631 and hsa_circ_0082096, in this network were significantly up-regulated in expression levels in the spheroid cells. The two circRNAs were predicted to target and were experimentally shown to down-regulate miR-140-3p, miR-224, miR-382, miR-548c-3p and miR-579, confirming circRNA sponging of the targeted miRNAs. Furthermore, the affected miRNAs were demonstrated to inhibit degradation of six mRNA targets, viz. ACVR1C/ALK7, FZD3, IL6ST/GP130, SKIL/SNON, SMAD2 and WNT5, in the CRC spheroid cells. These mRNAs encode proteins that are reported to variously regulate the GP130/Stat, Activin/Nodal, TGF-β/SMAD or Wnt/β-catenin signaling pathways in controlling various aspects of CSC stemness. Using the CRC spheroid cell model, the novel circRNA–miRNA–mRNA axis mapped in this work forms the foundation for the elucidation of the molecular mechanisms of the complex cellular and biochemical processes that determine CSC stemness properties of cancer cells, and possibly for designing therapeutic strategies for CRC treatment by targeting CSC.
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New insights into human prolactin pathophysiology: genomics and beyond. Curr Opin Obstet Gynecol 2019; 31:207-211. [DOI: 10.1097/gco.0000000000000545] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Ilie MD, Lasolle H, Raverot G. Emerging and Novel Treatments for Pituitary Tumors. J Clin Med 2019; 8:jcm8081107. [PMID: 31349718 PMCID: PMC6723109 DOI: 10.3390/jcm8081107] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 07/21/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
A subset of pituitary neuroendocrine tumors (PitNETs) have an aggressive behavior, showing resistance to treatment and/or multiple recurrences in spite of the optimal use of standard therapies (surgery, conventional medical treatments, and radiotherapy). To date, for aggressive PitNETs, temozolomide (TMZ) has been the most used therapeutic option, and has resulted in an improvement in the five-year survival rate in responders. However, given the fact that roughly only one third of patients showed a partial or complete radiological response on the first course of TMZ, and even fewer patients responded to a second course of TMZ, other treatment options are urgently needed. Emerging therapies consist predominantly of peptide receptor radionuclide therapy (20 cases), vascular endothelial growth factor receptor-targeted therapy (12 cases), tyrosine kinase inhibitors (10 cases), mammalian target of rapamycin (mTOR) inhibitors (six cases), and more recently, immune checkpoint inhibitors (one case). Here, we present the available clinical cases published in the literature for each of these treatments. The therapies that currently show the most promise (based on the achievement of partial radiological response in a certain number of cases) are immune checkpoint inhibitors, peptide receptor radionuclide therapy, and vascular endothelial growth factor receptor-targeted therapy. In the future, further improvement of these therapies and the development of other novel therapies, their use in personalized medicine, and a better understanding of combination therapies, will hopefully result in better outcomes for patients bearing aggressive PitNETs.
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Affiliation(s)
- Mirela Diana Ilie
- INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, 28 Laennec Street, 69008 Lyon, France
- "Claude Bernard" Lyon 1 University, University of Lyon, 43 "11 Novembre 1918" Boulevard, 69100 Villeurbanne, France
- Endocrinology Department, "C.I.Parhon" National Institute of Endocrinology, 34-36 Aviatorilor Boulevard, 011863 Bucharest, Romania
| | - Hélène Lasolle
- INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, 28 Laennec Street, 69008 Lyon, France
- "Claude Bernard" Lyon 1 University, University of Lyon, 43 "11 Novembre 1918" Boulevard, 69100 Villeurbanne, France
- "Groupement Hospitalier Est" Hospices Civils de Lyon, Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, 59 Pinel Boulevard, 69677 Bron, France
| | - Gérald Raverot
- INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, 28 Laennec Street, 69008 Lyon, France.
- "Claude Bernard" Lyon 1 University, University of Lyon, 43 "11 Novembre 1918" Boulevard, 69100 Villeurbanne, France.
- "Groupement Hospitalier Est" Hospices Civils de Lyon, Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, 59 Pinel Boulevard, 69677 Bron, France.
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Lapa RML, Barros-Filho MC, Marchi FA, Domingues MAC, de Carvalho GB, Drigo SA, Kowalski LP, Rogatto SR. Integrated miRNA and mRNA expression analysis uncovers drug targets in laryngeal squamous cell carcinoma patients. Oral Oncol 2019; 93:76-84. [PMID: 31109699 DOI: 10.1016/j.oraloncology.2019.04.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/20/2019] [Accepted: 04/24/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVES The current treatment of laryngeal squamous cell carcinoma (LSCC) is based on radical surgery and radiotherapy resulting in high morbidity. Chemoradiotherapy has been used as alternative to organ sparing; however, several advanced cases presented resistance to treatment, which contributes to a high risk of recurrence and mortality. Coding RNAs and miRNAs have potential to be used as biomarkers or targets for cancer therapy. MATERIALS AND METHODS In this study, 36 LSCC and 5 non-neoplastic control samples were investigated using miRNA and mRNA large-scale expression analysis and a cross-validation was performed using the TCGA database (116 LSCC and 12 surrounding normal tissues). RESULTS The large-scale profiling revealed the involvement of 28 miRNAs and 817 genes differentially expressed in LSCC. An integrative analysis comprising predicted and experimentally validated miRNA/mRNA interactions (negatively correlated), resulted in 28 miRNAs and 543 mRNAs. Decreased expression of miR-199b was significantly associated with shorter disease-free survival in LSCC (internal and TCGA datasets). The expression levels of selected miRNAs (miR-199b-5p, miR-29c-3p, miR-204-5p, miR-125b-5p and miR-92a-3p) and genes (COL3A1, COL10A1, ERBB4, HMGA2, HLF, TOP2A, MMP3, MMP13, MMP10 and PPP1R3) were confirmed as altered in LSCC by RT-qPCR. Additionally, a drug target prediction analysis revealed drug combinations based on miRNA and mRNA expression, pointing out novel alternatives to optimize the LSCC treatment. CONCLUSION Collectively, these findings provide new insights in the LSCC transcriptional deregulation and potential drug targets.
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Affiliation(s)
- Rainer Marco Lopez Lapa
- International Research Center, CIPE - A.C.Camargo Cancer Center, São Paulo, Brazil; Department of Genetics, Institute of Bioscience, São Paulo State University - UNESP, Botucatu, SP, Brazil
| | | | | | | | | | - Sandra Aparecida Drigo
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University - UNESP, Botucatu, SP, Brazil
| | - Luiz Paulo Kowalski
- Department of Head and Neck Surgery and Otorhinolaryngology, A.C.Camargo Cancer Center, São Paulo Brazil
| | - Silvia Regina Rogatto
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University - UNESP, Botucatu, SP, Brazil; Department of Clinical Genetics, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Denmark.
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Olarescu NC, Perez-Rivas LG, Gatto F, Cuny T, Tichomirowa MA, Tamagno G, Gahete MD. Aggressive and Malignant Prolactinomas. Neuroendocrinology 2019; 109:57-69. [PMID: 30677777 DOI: 10.1159/000497205] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 01/24/2019] [Indexed: 11/19/2022]
Abstract
Prolactin-secreting tumors (prolactinomas) represent the most common pituitary tumor type, accounting for 47-66% of functional pituitary tumors. Prolactinomas are usually benign and controllable tumors as they express abundant levels of dopamine type 2 receptor (D2), and can be treated with dopaminergic drugs, effectively reducing prolactin levels and tumor volume. However, a proportion of prolactinomas exhibit aggressive features (including invasiveness, relevant growth despite adequate dopamine agonist treatment, and recurrence potential) and few may exhibit metastasizing potential (carcinomas). In this context, the clinical, pathological, and molecular definitions of malignant and aggressive prolactinomas remain to be clearly defined, as primary prolactin-secreting carcinomas are similar to aggressive adenomas until the presence of metastases is detected. Indeed, standard molecular and histological analyses do not reflect differences between carcinomas and adenomas at a first glance and have limitations in prediction of the aggressive progression of prolactinomas, wherein the causes underlying the aggressive behavior remain unknown. Herein we present a comprehensive, multidisciplinary review of the most relevant epidemiological, clinical, pathological, genetic, biochemical, and molecular aspects of aggressive and malignant prolactinomas.
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Affiliation(s)
- Nicoleta Cristina Olarescu
- Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Oslo, Norway
| | - Luis G Perez-Rivas
- Medizinische Klinik und Poliklinik IV, Klinikum der LMU, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Federico Gatto
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Thomas Cuny
- Service d'Endocrinologie, Hôpital de la Conception, Inserm U1251, Marseille Medical Genetics, APHM, Aix-Marseille University, Marseille, France
| | - Maria A Tichomirowa
- Service d'Endocrinologie, Centre Hospitalier du Nord, Ettelbruck, Luxembourg
| | - Gianluca Tamagno
- Department of Endocrinology/Diabetes Mellitus, Mater Misericordiae University Hospital, Dublin, Ireland
- Department of Medicine, Wexford General Hospital, Wexford, Ireland
| | - Manuel D Gahete
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain,
- Universidad de Córdoba, Cordoba, Spain,
- Reina Sofia University Hospital, Cordoba, Spain,
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Cordoba, Spain,
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