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Zehtabi M, Ghaedrahmati F, Dari MAG, Moramezi F, Kempisty B, Mozdziak P, Farzaneh M. Emerging biologic and clinical implications of miR-182-5p in gynecologic cancers. Clin Transl Oncol 2024:10.1007/s12094-024-03822-9. [PMID: 39661239 DOI: 10.1007/s12094-024-03822-9] [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: 06/10/2024] [Accepted: 11/28/2024] [Indexed: 12/12/2024]
Abstract
MicroRNAs (miRNAs) have emerged as important regulators of gene expression in various biological processes, including cancer. miR-182-5p has gained attention for its potential implications in gynecologic cancers, including breast, ovarian, endometrial, and cervical cancers. miR-182-5p dysregulation has been associated with multiple facets of tumor biology in gynecologic cancers, including tumor initiation, progression, metastasis, and therapeutic response. Studies have highlighted its involvement in key signaling pathways and cellular processes that contribute to cancer development and progression. In addition, miR-182-5p has shown potential as a diagnostic and prognostic biomarker, with studies demonstrating its correlation with clinicopathological features and patient outcomes. Furthermore, the therapeutic potential of miR-182-5p is being explored in gynecologic cancers. Strategies such as miRNA mimics or inhibitors targeting miR-182-5p have shown promise in preclinical and early clinical studies. These approaches aim to modulate miR-182-5p expression, restoring normal cellular functions and potentially enhancing treatment responses. Understanding the biologic and clinical implications of miR-182-5p in gynecologic cancers is crucial for the development of targeted therapeutic strategies and personalized medicine approaches. Further investigations are needed to unravel the specific target genes and pathways regulated by miR-182-5p. It is important to consider the emerging biologic and clinical implications of miR-182-5p in gynecologic cancers.
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Affiliation(s)
- Mojtaba Zehtabi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhoodeh Ghaedrahmati
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahrokh Abouali Gale Dari
- Department of Obstetrics and Gynecology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Farideh Moramezi
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Bartosz Kempisty
- Department of Human Morphology and Embryology, Division of Anatomy, Faculty of Medicine, Wrocław Medical University, Wrocław, Poland
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University, Torun, Poland
- Physiology Graduate Faculty North, Carolina State University, Raleigh, NC, 27695, USA
- Center of Assisted Reproduction Department of Obstetrics and Gynecology, University Hospital and Masaryk University, Brno, Czech Republic
| | - Paul Mozdziak
- Physiology Graduate Faculty North, Carolina State University, Raleigh, NC, 27695, USA
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Clinical Research Development Unit, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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2
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Lotfi M, Maharati A, Hamidi AA, Taghehchian N, Moghbeli M. MicroRNA-532 as a probable diagnostic and therapeutic marker in cancer patients. Mutat Res 2024; 829:111874. [PMID: 38986233 DOI: 10.1016/j.mrfmmm.2024.111874] [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: 08/18/2023] [Revised: 07/01/2024] [Accepted: 07/05/2024] [Indexed: 07/12/2024]
Abstract
The high mortality rate in cancer patients is always one of the main challenges of the health systems globally. Several factors are involved in the high rate of cancer related mortality, including late diagnosis and drug resistance. Cancer is mainly diagnosed in the advanced stages of tumor progression that causes the failure of therapeutic strategies and increases the death rate in these patients. Therefore, assessment of the molecular mechanisms associated with the occurrence of cancer can be effective to introduce early tumor diagnostic markers. MicroRNAs (miRNAs) as the stable non-coding RNAs in the biological body fluids are involved in regulation of cell proliferation, migration, and apoptosis. MiR-532 deregulation has been reported in different tumor types. Therefore, in the present review we discussed the role of miR-532 during tumor growth. It has been shown that miR-532 has mainly a tumor suppressor role through the regulation of transcription factors, chemokines, and signaling pathways such as NF-kB, MAPK, PI3K/AKT, and WNT. In addition to the independent role of miR-532 in regulation of cellular processes, it also functions as a mediator of lncRNAs and circRNAs. Therefore, miR-532 can be considered as a non-invasive diagnostic/prognostic marker as well as a therapeutic target in cancer patients.
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Affiliation(s)
- Malihe Lotfi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Abbas Hamidi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Taghehchian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Trojniak J, Sendera A, Banaś-Ząbczyk A, Kopańska M. The MicroRNAs in the Pathophysiology of Osteoporosis. Int J Mol Sci 2024; 25:6240. [PMID: 38892426 PMCID: PMC11172499 DOI: 10.3390/ijms25116240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/26/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024] Open
Abstract
Globally, osteoporosis is the most common systemic skeletal disease. There are many factors that influence osteoporosis' development and progression. During the pathogenesis of this disease, bone turnover is imbalanced between resorption and the formation of bone tissue. A growing interest has been devoted to the role that microRNA (miRNA) plays in osteoporosis regulation. A microRNA (miRNA) is a group of small single-stranded RNA molecules involved in regulating gene expression in eukaryotic organisms. As microRNAs (miRNAs) are key regulators of gene expression and can modulate processes related to bone metabolism, they have become increasingly important for studying osteoporosis pathogenesis. The available research suggests that miRNAs play an important role in regulating processes associated with bone metabolism, especially by influencing bone resorption and synthesis. Furthermore, microRNAs can also serve as potential therapeutic targets for osteoporosis, besides being a rapid and specific biomarker.
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Affiliation(s)
- Julia Trojniak
- Student Research Club “Reh-Tech”, Medical College of Rzeszow University, 35-959 Rzeszow, Poland;
| | - Anna Sendera
- Department of Biology, Institute of Medical Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland; (A.S.); (A.B.-Z.)
| | - Agnieszka Banaś-Ząbczyk
- Department of Biology, Institute of Medical Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland; (A.S.); (A.B.-Z.)
| | - Marta Kopańska
- Department of Pathophysiology, Institute of Medical Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
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4
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Ouyang X, Li K, Wang J, Zhu W, Yi Q, Zhong J. HMGA2 promotes nasopharyngeal carcinoma progression and is associated with tumor resistance and poor prognosis. Front Oncol 2024; 13:1271080. [PMID: 38304037 PMCID: PMC10830841 DOI: 10.3389/fonc.2023.1271080] [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: 08/01/2023] [Accepted: 12/27/2023] [Indexed: 02/03/2024] Open
Abstract
Nasopharyngeal carcinoma (NPC), as one of the most prevalent malignancies in the head and neck region, still lacks a complete understanding of its pathogenesis. Presently, radiotherapy, concurrent chemoradiotherapy, and targeted therapy stand as the primary modalities for treating NPC. With advancements in medicine, the cure rates for nasopharyngeal carcinoma have been steadily increasing. Nevertheless, recurrence and metastasis persist as the primary reasons for treatment failure. Consequently, a profound exploration of the molecular mechanisms underlying the occurrence and progression of nasopharyngeal carcinoma, along with the exploration of corresponding therapeutic approaches, becomes particularly imperative in the quest for comprehensive solutions to combat this disease. High mobility group AT-hook 2 (HMGA2) is a pivotal protein capable of altering chromatin structure, regulating gene expression, and influencing transcriptional activity. In the realm of cancer research, HMGA2 exhibits widespread dysregulation, playing a crucial role in nearly all malignant tumors. It is implicated in various tumorigenic processes, including cell cycle regulation, cell proliferation, epithelial-mesenchymal transition, angiogenesis, tumor invasion, metastasis, and drug resistance. Additionally, HMGA2 serves as a molecular marker and an independent prognostic factor in certain malignancies. Recent studies have increasingly unveiled the critical role of HMGA2 in nasopharyngeal carcinoma (NPC), particularly in promoting malignant progression, correlating with tumor resistance, and serving as an independent adverse prognostic factor. This review focuses on elucidating the oncogenic role of HMGA2 in NPC, suggesting its potential association with chemotherapy resistance in NPC, and proposing its candidacy as an independent factor in nasopharyngeal carcinoma prognosis assessment.
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Affiliation(s)
| | - Kangxin Li
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jiaqi Wang
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Weijian Zhu
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Qiang Yi
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jinghua Zhong
- Department of Oncology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
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Abd El Fattah YK, Abulsoud AI, AbdelHamid SG, AbdelHalim S, Hamdy NM. CCDC144NL-AS1/hsa-miR-143-3p/HMGA2 interaction: In-silico and clinically implicated in CRC progression, correlated to tumor stage and size in case-controlled study; step toward ncRNA precision. Int J Biol Macromol 2023; 253:126739. [PMID: 37690651 DOI: 10.1016/j.ijbiomac.2023.126739] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 08/06/2023] [Accepted: 08/25/2023] [Indexed: 09/12/2023]
Abstract
Unravel the regulatory mechanism of lncRNA CCDC144NL-AS1 in CRC hsa-miR-143-3p, downstream protein HMGA2 interaction arm, association with clinicopathological characteristics. Using peripheral blood as liquid biopsy from 60 CRC patients and 30 controls. The expression levels of CCDC144NL-AS1 and hsa-miR-143-3p detected by qRT-PCR. CCDC144NL-AS1 expression was significantly upregulated in CRC patients' sera, associated with worse CRC clinicopathological features regarding the depth of tumor invasion and highly significant difference between tumor stages 3 and 4 and tumor stages 2 and 4. While, hsa-miR-143-3p expression was downregulated in CRC patients by 4.5-fold change when compared to the control subjects (p < 0.0001) and HMGA2 increased in CRC patients than controls 19.59 ng/μL and 5.377 ng/μL, respectively (p < 0.0001) with significant difference between tumor stages 3 and 4 as well as tumor stages 2 and 4. CRC patients with large tumor size showed upregulation in CCDC144NL-AS1 expression and HMGA2 levels compared to those with small tumor size (p-value = 0.0365 and 0.013, respectively). CCDC144NL-AS1 and HMGA2 were positively correlated, whereas lncRNA CCDC144NL-AS1 and hsa-miR-143-3p were negatively correlated. Conclusion: As an interaction arm CCDC144NL-AS1/hsa-miR-143-3p/HMGA2 were correlated to CRC stages 2-4. Therefore, this interaction arm expression clinically and in silico approved, would direct treatment precision in the near future.
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Affiliation(s)
- Yasmine K Abd El Fattah
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, El Salam City, 11785, Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, El Salam City, 11785, Cairo, Egypt; Biochemistry Department, Faculty of Pharmacy (Boy's Branch), Al-Azhar University, Nasr City, 11884, Cairo, Egypt
| | - Sherihan G AbdelHamid
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt
| | - Sherif AbdelHalim
- Department of General surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt.
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Li S, Zhao J, Wen S, Li M, Yu F, Wang W, Shao H, Jiang D. CircRNA High Mobility Group At-hook 2 regulates cell proliferation, metastasis and glycolytic metabolism of nonsmall cell lung cancer by targeting miR-331-3p to upregulate High Mobility Group At-hook 2. Anticancer Drugs 2023; 34:81-91. [PMID: 36066399 DOI: 10.1097/cad.0000000000001343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Increasing circular RNAs (circRNAs) have been identified as pivotal players in nonsmall cell lung cancer (NSCLC). The study will explore the function and mechanism of circRNA High Mobility Group AT-hook 2 (circHMGA2) in NSCLC. The circHMGA2, microRNA-331-3p (miR-331-3p) and HMGA2 expression analyses were performed via quantitative real-time PCR. Cell proliferation was assessed via Cell Counting Kit-8 and colony formation assays. Transwell migration/invasion assays were used for measuring cell metastasis. Glucose consumption and lactate production were determined for glycolytic evaluation. Western blot was used to detect the protein expression of HMGA2 and glycolytic markers. Target analysis was performed by dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. Xenograft tumor assay in mice was conducted for the investigation of circHMGA2 in vivo . CircHMGA2 was overexpressed in NSCLC, and high circHMGA2 level might be related to NSCLC metastasis and poor prognosis. In-vitro assays suggested that NSCLC cell growth, metastasis and glycolysis were retarded by downregulation of circHMGA2. Upregulation of HMGA2 was shown to return the anticancer response of circHMGA2 knockdown in NSCLC cells. Through interacting with miR-331-3p, circHMGA2 could regulate the expression of HMGA2. In addition, circHMGA2/miR-331-3p and miR-331-3p/HMGA2 axes were affirmed in NSCLC regulation. In-vivo analysis indicated that circHMGA2 inhibition also reduced tumorigenesis and glycolysis of NSCLC via the miR-331-3p/HMGA2 axis. This study disclosed the oncogenic role of circHMGA2 and the regulatory circHMGA2/miR-331-3p/HMGA2 axis in NSCLC.
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Affiliation(s)
- Shenke Li
- Department of Respiratory, Puyang Oilfield General Hospital, Puyang
| | - Jun Zhao
- Department of Respiratory, Xinxiang Medical University, Puyang oilfield General Hospital, Puyang
| | - Song Wen
- Department of Respiratory, Xinxiang Medical University, Puyang oilfield General Hospital, Puyang
| | - Min Li
- Department of Respiratory, Xinxiang Medical University, Puyang oilfield General Hospital, Puyang
| | - Faming Yu
- Department of Respiratory, Puyang Oilfield General Hospital, Puyang
| | - Wenhui Wang
- Department of Respiratory, Xinxiang Medical University, Puyang oilfield General Hospital, Puyang
| | - Huamin Shao
- Department of Respiratory, Xinxiang Medical University, Puyang oilfield General Hospital, Puyang
| | - Dongliang Jiang
- Department of Respiratory, Puyang Oilfield General Hospital, Puyang
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Liu Y, Lv G, Bai J, Song L, Ding E, Liu L, Tian Y, Chen Q, Li K, Liu X, Ding Y. Effects of HMGA2 on the epithelial-mesenchymal transition-related genes in ACHN renal cell carcinoma cells-derived xenografts in nude mice. BMC Cancer 2022; 22:421. [PMID: 35439951 PMCID: PMC9016978 DOI: 10.1186/s12885-022-09537-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 04/12/2022] [Indexed: 11/30/2022] Open
Abstract
Background The architectural transcriptional regulator high-mobility group AT-hook 2 (HMGA2) is an oncofetal protein which has been reported to be ectopically expressed in a variety of cancers. A high expression of HMGA2 in human renal cell carcinoma (RCC) is related with tumor invasiveness and poor prognosis. Recent in vitro studies have shown that HMGA2 knockdown was able to decrease cell proliferation and migration, and regulate the gene expression related to epithelial-mesenchymal transition (EMT). Methods To understand the HMGA2’s effect in vivo, HMGA2 expression was knocked down in ACHN cells using small hairpin RNA (shRNA), then the HMGA2-deficient ACHN cells were xenografted into the BALB/c nude mice. Tumor growth was monitored and the expression of EMT-related genes was analyzed. Results HMGA2 expression was confirmed to be knocked down in the cultured and xenografted ACHN cells. The xenograft tumor of HMGA2-deficient cells demonstrated a retarded growth pattern compared with the control. The expression of E-cadherin was increased, whereas N-cadherin and Snail were decreased in the HMGA2-deficient xenograft tumors. Conclusions In conclusion, to the best of our knowledge, for the first time, we have successfully developed an in vivo experiment using HMGA2-silencing ACHN cells to be grown as xenografts in nude mice. Our findings show that HMGA2 deficiency was sufficient to suppress the xenograft tumor growth in vivo, which support our hypothesis that HMGA2-induced renal carcinogenesis occurs at least in part through the regulation of tumor associated EMT genes. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09537-w.
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Affiliation(s)
- Ying Liu
- Department of Urology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China.
| | - Guangyao Lv
- Department of Urology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Jianxin Bai
- Department of Intervention, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Lingling Song
- Department of Urology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Elizabeth Ding
- Department of Neuroscience, Brown University, Providence, RI, 02912, USA
| | - Lin Liu
- Navy Qingdao Special Care Center, Qingdao, 266071, China
| | - Yuqin Tian
- Department of Surgical Operations, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qian Chen
- Department of Urology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Kai Li
- Department of Urology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Xianfeng Liu
- Department of Urology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Yan Ding
- The Institute for Translational Medicine Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China. .,Department of Pediatrics, Children's Hospital of Boston, Harvard Medical School, Boston, MA, 02115, USA.
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Abstract
High Mobility Group A2 gene (HMGA2), an oncofetal protein, is normally expressed in fetal development and completely shuts down in almost all organs and tissue types during adulthood. It is upregulated or overexpressed again in certain mesenchymal neoplasms due to chromosomal translocations and in malignant epithelial tumors through transcription regulation. HMGA2 overexpression can either drive tumor development or promote the aggressiveness of tumor growth. Many gynecologic neoplasms, including uterine smooth muscle tumors and ovarian cancer, are associated with HMGA2 overexpression. In this article, we review recent developments in the study of HMGA2 and its expression as a potential biomarker for gynecologic neoplasms and clinic application.
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Affiliation(s)
- Jian-Jun Wei
- Correspondence to: Jian-Jun Wei, Department of Pathology, Northwestern University, School of Medicine, Feinberg 7-334, 251 East Huron Street, Chicago, IL 60611, USA. Tel: +1-312-926-1815, Fax: +1-312-926-3127,
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Yan J, Dai P, Qin X, He Y, Zhang Y. HMGA2 promotes the migration and invasion of gallbladder cancer cells and HMGA2 knockdown inhibits angiogenesis via targeting VEGFA. Mol Med Rep 2021; 25:54. [PMID: 34913073 PMCID: PMC8711027 DOI: 10.3892/mmr.2021.12570] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/17/2021] [Indexed: 11/26/2022] Open
Abstract
The high mobility group AT-hook 2 (HMGA2) protein has been found to be upregulated in the majority of tumor types and is associated with a poor prognosis. Previous studies have suggested the oncogenic role of HMGA2 in gallbladder cancer (GBC). The present study aimed to investigate the effects of HMGA2 on the invasion, migration and angiogenesis of GBC cells. To achieve this aim, HMGA2 was overexpressed or silenced in the GBC cell line, EH-GB1, and then the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) abilities of EH-GB1 cells were investigated using Cell Counting Kit-8, wound healing, Transwell and western blotting assays. In addition, the expression levels of VEGFA were determined in EH-GB1 cells using western blotting and reverse transcription-quantitative PCR following HMGA2 overexpression or silencing. Furthermore, HMGA2-silenced EH-GB1 cells were transfected with VEGFA overexpression plasmids to evaluate the tube formation ability of HUVECs using tube formation assay. The results demonstrated that HMGA2 silencing inhibited GBC cell proliferation, migration, invasion and EMT, as evidenced by the downregulated expression of Ki67, proliferating cell nuclear antigen, MMP2, MMP9, N-cadherin, snail family transcriptional repressor 2 and zinc finger E-box-binding homeobox 1, and attenuated cell migration and invasion. However, the opposite results were obtained following HMGA2 overexpression. Moreover, HMGA2 knockdown and overexpression downregulated and upregulated VEGFA expression, respectively. In addition, the tube formation ability of HUVECs and the expression levels of CD31, VEGFR1 and VEGFR2 were downregulated following HMGA2 silencing. However, these effects were partially rescued by simultaneous VEGFA overexpression. In conclusion, the findings of the present study revealed that HMGA2 may promote GBC cell migration, invasion, EMT and angiogenesis. Therefore, inhibiting HMGA2 expression could be considered as a possible therapeutic approach for GBC.
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Affiliation(s)
- Jun Yan
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
| | - Peng Dai
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
| | - Xueliang Qin
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
| | - Yanping He
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
| | - Yu Zhang
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
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Gundlach JP, Hauser C, Schlegel FM, Willms A, Halske C, Röder C, Krüger S, Röcken C, Becker T, Kalthoff H, Trauzold A. Prognostic significance of high mobility group A2 (HMGA2) in pancreatic ductal adenocarcinoma: malignant functions of cytoplasmic HMGA2 expression. J Cancer Res Clin Oncol 2021; 147:3313-3324. [PMID: 34302528 PMCID: PMC8484217 DOI: 10.1007/s00432-021-03745-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 07/16/2021] [Indexed: 01/26/2023]
Abstract
PURPOSE HMGA2 has frequently been found in benign as well as malignant tumors and a significant association between HMGA2 overexpression and poor survival in different malignancies was described. In pancreatic ductal adenocarcinoma (PDAC), nuclear HMGA2 expression is associated with tumor dedifferentiation and presence of lymph node metastasis. Nevertheless, the impact of HMGA2 occurrence in other cell compartments is unknown. METHODS Intracellular distribution of HMGA2 was analyzed in PDAC (n = 106) and peritumoral, non-malignant ducts (n = 28) by immunohistochemistry. Findings were correlated with clinico-pathological data. Additionally, intracellular HMGA2 presence was studied by Western blotting of cytoplasmic and nuclear fractions of cultured cells. RESULTS HMGA2 was found in the cytoplasm and in the nucleus of cultured cells. In human tumor tissue, HMGA2 was also frequently found in the cytoplasm and the nucleus of tumor cells, however, nuclear staining was generally stronger. Direct comparison from tumor tissue with corresponding non-neoplastic peritumoral tissue revealed significantly stronger expression in tumors (p = 0.003). Of note, the nuclear staining was significantly stronger in lymph node metastatic cell nuclei compared to primary tumor cell nuclei (p = 0.049). Interestingly, cytoplasmic staining positively correlated with lymph vessel (p = 0.004) and venous invasion (p = 0.046). CONCLUSION HMGA2 is a prognostic marker in PDAC. Firstly, we found a positive correlation for cytoplasmic HMGA2 expression with lympho-vascular invasion and, secondly, we found a significantly stronger nuclear expression of HMGA2 in cancer-positive lymph node nuclei compared to primary tumor cell nuclei. So far, the role of cytoplasmic HMGA2 is nearly unknown, however, our data lend support to the hypothesis that cytoplasmic HMGA2 expression is involved in nodal spread.
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Affiliation(s)
- Jan-Paul Gundlach
- Department of General Surgery, Visceral-, Thoracic-, Transplantation- and Pediatric-Surgery, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105, Kiel, Germany.,Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany
| | - Charlotte Hauser
- Department of General Surgery, Visceral-, Thoracic-, Transplantation- and Pediatric-Surgery, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105, Kiel, Germany.,Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany
| | - Franka Maria Schlegel
- Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany
| | - Anna Willms
- Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany
| | - Christine Halske
- Department of Pathology, UKSH, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105, Kiel, Germany
| | - Christian Röder
- Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany
| | - Sandra Krüger
- Department of Pathology, UKSH, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105, Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, UKSH, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105, Kiel, Germany
| | - Thomas Becker
- Department of General Surgery, Visceral-, Thoracic-, Transplantation- and Pediatric-Surgery, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105, Kiel, Germany
| | - Holger Kalthoff
- Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany
| | - Anna Trauzold
- Department of General Surgery, Visceral-, Thoracic-, Transplantation- and Pediatric-Surgery, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105, Kiel, Germany. .,Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany.
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Wang C, Zhang T, Wang K, Zhang S, Sun Q, Yang X. ER-α36 Promotes the Malignant Progression of Cervical Cancer Mediated by Estrogen via HMGA2. Front Oncol 2021; 11:712849. [PMID: 34336701 PMCID: PMC8317436 DOI: 10.3389/fonc.2021.712849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 06/28/2021] [Indexed: 01/12/2023] Open
Abstract
Objectives Estrogen is proven to promote the malignant behaviors of many cancers via its receptors. Estrogen receptor alfa 36 (ER-α36) is a newly identified isoform of estrogen receptor alfa (ER-α), the role of ER-α36 in regulating the effects of estrogen and its potential impact on human cervical cancer is poorly understood. Methods Immunohistochemistry staining was used to evaluate the expression of ER-α36, estrogen receptor alfa 66 (ER-α66) and their prognostic values in cervical cancer. The effects of ER-α36 and ER-α66 on the proliferation and metastasis of cervical cancer were measured in vitro. A xenograft tumor assay was used to study the tumorigenesis role of ER-α36 in vivo. Furthermore, the functional gene at the downstream of ER-α36 was obtained via next-generation sequencing, and the biological functions of high mobility group A2 (HMGA2) in cervical cancer cells were investigated in vitro. Results ER-α36 was over-expressed in cervical cancer tissues and elevated ER-α36 expression was associated with poor prognosis in cervical cancer patients. High expression of ER-α36 promoted the proliferation, invasion and metastasis of cervical cancer cells mediated by estrogen, while silencing ER-α36 had the opposite effects. Further research showed that HMGA2 was a downstream target of ER-α36 in cervical cancer cells. The oncogenic effect of ER-α36 was attenuated after HMGA2 knockdown. Conclusions High expression of ER-α36 was correlated with a poor prognosis in cervical cancer by regulating HMGA2. ER-α36 could be a prognostic biomarker and a target for cervical cancer treatment.
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Affiliation(s)
- Chunyan Wang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China
| | - Tianli Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China
| | - Kun Wang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China
| | - Shuo Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China
| | - Qing Sun
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xingsheng Yang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China
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12
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Hasanin AH, Habib EK, El Gayar N, Matboli M. Promotive action of 2-acetylaminofluorene on hepatic precancerous lesions initiated by diethylnitrosamine in rats: Molecular study. World J Hepatol 2021; 13:328-342. [PMID: 33815676 PMCID: PMC8006078 DOI: 10.4254/wjh.v13.i3.328] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/14/2020] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diethylnitrosamine (DEN) induces hepatic neoplastic lesions over a prolonged period. AIM To investigate the promotive action of 2-acetylaminofluorene (2-AAF) when combined with DEN in order to develop a rat model for induction of precancerous lesion and investigate the molecular mechanism underlying the activity of 2-AAF. METHODS The pre-precancerous lesions were initiated by intraperitoneal injection of DEN for three weeks consecutively, followed by one intraperitoneal injection of 2-AAF at three different doses (100, 200 and 300 mg/kg). Rats were separated into naïve, DEN, DEN + 100 mg 2-AAF, DEN + 200 mg 2-AAF, and DEN + 300 mg 2-AAF groups. Rats were sacrificed after 10 wk and 16 wk. Liver functions, level of alpha-fetoprotein, glutathione S-transferase-P and proliferating cell nuclear antigen staining of liver tissues were performed. The mRNA level of RAB11A, BAX, p53, and Cyclin E and epigenetic regulation by long-noncoding RNA (lncRNA) RP11-513I15.6, miR-1262 (microRNA), and miR-1298 were assessed in the sera and liver tissues of the rats. RESULTS 2-AAF administration significantly increased the percent area of the precancerous foci and cell proliferation along with a significant decrease in RAB11A, BAX, and p53 mRNA, and the increase in Cyclin E mRNA was associated with a marked decrease in lncRNA RP11-513I15.6 expression with a significant increase in both miR-1262 and miR-1298. CONCLUSION 2-AFF promoted hepatic precancerous lesions initiated through DEN by decreasing autophagy, apoptosis, and tumor suppression genes, along with increased cell proliferation, in a time- and dose-dependent manner. These actions were mediated under the epigenetic regulation of lncRNA RP11-513I15.6/miR-1262/miR-1298.
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Affiliation(s)
- Amany Helmy Hasanin
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo 11318, Egypt
| | - Eman K Habib
- Anatomy and Embryology Department, Faculty of Medicine, Ain Shams University, Cairo 11318, Egypt
| | - Nesreen El Gayar
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo 11318, Egypt
| | - Marwa Matboli
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo 11381, Egypt.
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13
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HMGA2 as a Critical Regulator in Cancer Development. Genes (Basel) 2021; 12:genes12020269. [PMID: 33668453 PMCID: PMC7917704 DOI: 10.3390/genes12020269] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/01/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023] Open
Abstract
The high mobility group protein 2 (HMGA2) regulates gene expression by binding to AT-rich regions of DNA. Akin to other DNA architectural proteins, HMGA2 is highly expressed in embryonic stem cells during embryogenesis, while its expression is more limited at later stages of development and in adulthood. Importantly, HMGA2 is re-expressed in nearly all human malignancies, where it promotes tumorigenesis by multiple mechanisms. HMGA2 increases cancer cell proliferation by promoting cell cycle entry and inhibition of apoptosis. In addition, HMGA2 influences different DNA repair mechanisms and promotes epithelial-to-mesenchymal transition by activating signaling via the MAPK/ERK, TGFβ/Smad, PI3K/AKT/mTOR, NFkB, and STAT3 pathways. Moreover, HMGA2 supports a cancer stem cell phenotype and renders cancer cells resistant to chemotherapeutic agents. In this review, we discuss these oncogenic roles of HMGA2 in different types of cancers and propose that HMGA2 may be used for cancer diagnostic, prognostic, and therapeutic purposes.
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14
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Wang X, Wang J, Wu J. Emerging roles for HMGA2 in colorectal cancer. Transl Oncol 2020; 14:100894. [PMID: 33069103 PMCID: PMC7563012 DOI: 10.1016/j.tranon.2020.100894] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 09/08/2020] [Accepted: 09/21/2020] [Indexed: 02/08/2023] Open
Abstract
HMGA2 (High Mobility Group AT-hook 2) has been reported to promote colorectal cancer (CRC) development by regulating the transcription of target genes. It participates in nearly all aspects of cellular processes, including cell transformation, proliferation, apoptosis, senescence, metastasis, epithelial-to-mesenchymal transition (EMT), DNA repair and stem cell self-renewal. In the past decades, a group of downstream targets and binding partners have been identified in a wide range of cancers. Our findings of HMGA2 as a key factor in the MDM2/p53, IL11/STAT3 and Wnt/β-catenin signaling pathways prompt us to summarize current advances in the functional and molecular basis of HMGA2 in CRC. In this review, we address the roles of HMGA2 in the oncogenic networks of CRC based on recent advances. We review its aberrant expression, explore underlying mechanisms, discuss its pro-tumorigenic effects, and highlight promising small-molecule inhibitors based on targeting HMGA2 here. However, the understanding of HMGA2 in CRC progression is still elusive, thus we also discuss the future perspectives in this review. Collectively, this review provides novel insights into the oncogenic properties of HMGA2, which has potential implications in the diagnosis and treatment of CRC.
HMGA2 promotes colorectal cancer (CRC) development by regulating the transcriptions of target genes. Circulating cell-free HMGA2 mRNA has been identified as a potential screening marker in CRC. HMGA2 appears to be a key factor in the networks of MDM2/p53, IL11/STAT3 and Wnt/β-catenin signaling pathways in CRC. Many agents and siRNAs serve as potential therapeutic approaches by targeting HMGA2 for the treatment of CRC. Deciphering HMGA2-mediated machinery helps to conceive effective therapy strategies and develop novel inhibitors in CRC.
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Affiliation(s)
- Xin Wang
- Department of Pathology & Pathophysiology, Department of Colorectal Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jian Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Jingjing Wu
- Department of Pathology & Pathophysiology, Department of Colorectal Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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15
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Ha W, Hinde A, Xie L, Trager MH, Liu L. Biomarker function of HMGA2 in ultraviolet-induced skin cancer development. Exp Dermatol 2020; 29:1021-1026. [PMID: 32780494 DOI: 10.1111/exd.14174] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 06/22/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022]
Abstract
The high mobility group AT-hook 2 (HMGA2) gene encodes a transcription factor that is expressed during embryonic development but down-regulated in adult tissues. Its re-expression in adult tissues is often associated with tumorigenesis. In this study, we found that HMGA2 is highly expressed in human cutaneous squamous cell carcinoma (SCC) cell lines and primary SCC tumors, but not in adjacent normal skin. In non-ultraviolet (UV)-irradiated mouse skin, baseline Hmga2 expression was detected in the epidermis but not in hair follicles. Following chronic UV exposure, we found activation of Hmga2 in hair follicles. UV-induced mouse skin SCC tumors displayed a ubiquitous increase in Hmga2 expression compared to non-tumor-bearing adjacent skin. In human SCC cells, decreased HMGA2 expression was linked with reduced cell proliferation following depletion of FOXM1 and TRIP13, two UV master regulator genes. Taken together, these findings highlight an important biomarker function of HMGA2 expression in UV-induced skin tumorigenesis and cell proliferation.
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Affiliation(s)
- Wootae Ha
- The Hormel Institute, University of Minnesota, Austin, MN, USA
| | - Amanda Hinde
- The Hormel Institute, University of Minnesota, Austin, MN, USA
| | - Lillian Xie
- The Hormel Institute, University of Minnesota, Austin, MN, USA
| | - Megan H Trager
- Department of Dermatology, Columbia University, New York, NY, USA
| | - Liang Liu
- The Hormel Institute, University of Minnesota, Austin, MN, USA.,Department of Dermatology, Columbia University, New York, NY, USA
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16
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Hodgson A, Swanson D, Tang S, Dickson BC, Turashvili G. Gene fusions characterize a subset of uterine cellular leiomyomas. Genes Chromosomes Cancer 2020; 59:688-696. [PMID: 32677742 DOI: 10.1002/gcc.22888] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/03/2020] [Accepted: 07/14/2020] [Indexed: 01/12/2023] Open
Abstract
Uterine leiomyomas are the most common benign tumor of the female genital tract. Previous studies have shown that conventional leiomyomas often harbor-specific alterations including rearrangements involving HMGA2. Cellular leiomyomas are a variant of uterine leiomyoma that are less well-studied from a genomic point of view. Morphologically and immunohistochemically, cellular leiomyomas may be confused with low-grade endometrial stromal neoplasms, a group of tumors which frequently harbor a number of recurrent gene fusions. Ancillary molecular testing may be used to investigate tumors where low-grade endometrial stromal neoplasms enter into the differential diagnosis. At our institution, we identified a uterine cellular leiomyoma harboring a HMGA2-TRAF3IP2 fusion. After a retrospective review 11 additional tumors were identified. All included cases were reviewed and evaluated for immunohistochemical expression of smooth muscle actin, desmin, h-caldesmon, CD10, estrogen receptor, and progesterone receptor. RNA sequencing using the TruSight RNA Fusion Panel was performed on formalin-fixed paraffin-embedded tissue samples. In addition to the index case, two other cases harbored fusions: HMGA2-NAA11 and TPCN2-YAP1, of which the latter is novel and was confirmed with reverse transcriptase-polymerase chain reaction. In conclusion, a subset of cellular leiomyomas harbor rearrangements involving HMGA2, suggesting molecular kinship with conventional uterine leiomyomas. In addition, the prevalence of the novel TPCN2-YAP1 gene fusion in cellular leiomyomas requires further study. The fusions reported here, when identified, may be useful when the diagnosis of cellular leiomyoma is in question.
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Affiliation(s)
- Anjelica Hodgson
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada
| | - David Swanson
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada
| | - Shangguo Tang
- Department of Pathology, McMaster University Medical Centre, Hamilton, Ontario, Canada
| | - Brendan C Dickson
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada
| | - Gulisa Turashvili
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada
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17
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De Martino M, Fusco A, Esposito F. HMGA and Cancer: A Review on Patent Literatures. Recent Pat Anticancer Drug Discov 2020; 14:258-267. [PMID: 31538905 DOI: 10.2174/1574892814666190919152001] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/04/2019] [Accepted: 09/11/2019] [Indexed: 01/02/2023]
Abstract
BACKGROUND The high mobility group A proteins modulate the transcription of numerous genes by interacting with transcription factors and/or altering the structure of chromatin. These proteins are involved in both benign and malignant neoplasias as a result of several pathways. A large amount of benign human mesenchymal tumors has rearrangements of HMGA genes. On the contrary, malignant tumors show unarranged HMGA overexpression that is frequently and causally related to neoplastic cell transformation. Here, we review the function of the HMGA proteins in human neoplastic disorders, the pathways by which they contribute to carcinogenesis and the new patents focused on targeting HMGA proteins. OBJECTIVE Current review was conducted to check the involvement of HMGA as a druggable target in cancer treatment. METHODS We reviewed the most recent patents focused on targeting HMGA in cancer treatment analyzing patent literature published during the last years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents. RESULTS HMGA proteins are intriguing targets for cancer therapy and are objects of different patents based on the use of DNA aptamers, inhibitors, oncolytic viruses, antisense molecules able to block their oncogenic functions. CONCLUSION Powerful strategies able to selectively interfere with HMGA expression and function could represent a helpful approach in the development of new anti-cancer therapies.
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Affiliation(s)
- Marco De Martino
- Istituto di Endocrinologia e Oncologia Sperimentale-CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli "Federico II", via Pansini 5, Naples 80131, Italy.,Department of Psychology, University of Campania, Caserta 81100, Italy
| | - Alfredo Fusco
- Istituto di Endocrinologia e Oncologia Sperimentale-CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli "Federico II", via Pansini 5, Naples 80131, Italy
| | - Francesco Esposito
- Istituto di Endocrinologia e Oncologia Sperimentale-CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli "Federico II", via Pansini 5, Naples 80131, Italy
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18
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Integrative genomics approach identifies molecular features associated with early-stage ovarian carcinoma histotypes. Sci Rep 2020; 10:7946. [PMID: 32409713 PMCID: PMC7224294 DOI: 10.1038/s41598-020-64794-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 04/22/2020] [Indexed: 12/27/2022] Open
Abstract
Ovarian cancer comprises multiple subtypes (clear-cell (CCC), endometrioid (EC), high-grade serous (HGSC), low-grade serous (LGSC), and mucinous carcinomas (MC)) with differing molecular and clinical behavior. However, robust histotype-specific biomarkers for clinical use have yet to be identified. Here, we utilized a multi-omics approach to identify novel histotype-specific genetic markers associated with ovarian carcinoma histotypes (CCC, EC, HGSC, and MC) using DNA methylation, DNA copy number alteration and RNA sequencing data for 96 primary invasive early-stage (stage I and II) ovarian carcinomas. More specifically, the DNA methylation analysis revealed hypermethylation for CCC in comparison with the other histotypes. Moreover, copy number imbalances and novel chromothripsis-like rearrangements (n = 64) were identified in ovarian carcinoma, with the highest number of chromothripsis-like patterns in HGSC. For the 1000 most variable transcripts, underexpression was most prominent for all histotypes in comparison with normal ovarian samples. Overall, the integrative approach identified 46 putative oncogenes (overexpressed, hypomethylated and DNA gain) and three putative tumor suppressor genes (underexpressed, hypermethylated and DNA loss) when comparing the different histotypes. In conclusion, the current study provides novel insights into molecular features associated with early-stage ovarian carcinoma that may improve patient stratification and subclassification of the histotypes.
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19
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Han X, Huang T, Han J. Long noncoding RNA VPS9D1-AS1 augments the malignant phenotype of non-small cell lung cancer by sponging microRNA-532-3p and thereby enhancing HMGA2 expression. Aging (Albany NY) 2020; 12:370-386. [PMID: 31902794 PMCID: PMC6977701 DOI: 10.18632/aging.102628] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 12/18/2019] [Indexed: 12/24/2022]
Abstract
We investigated the influence of the long noncoding RNA VPS9D1 antisense RNA 1 (VPS9D1-AS1) on the malignant phenotype of non-small cell lung cancer (NSCLC) cells in vitro and in vivo. We also explored the mechanisms by which VPS9D1-AS1 exerts its oncogenic action during NSCLC progression. VPS9D1-AS1 expression was upregulated in NSCLC; the extent of its upregulation significantly correlated with patients’ adverse clinicopathological characteristics and shorter overall survival. When VPS9D1-AS1 was knocked down in NSCLC cells, their proliferation, colony-forming capacity, migration, and invasiveness were lower, whereas their apoptosis rate was higher, compared to the control. VPS9D1-AS1 knockdown attenuated tumor growth of NSCLC cells in vivo. Mechanistically, VPS9D1-AS1 directly interacted with microRNA-532-3p (miR-532-3p) in NSCLC cells; the impact of VPS9D1-AS1 knockdown on NSCLC cells was attenuated by miR-532-3p inhibition. Furthermore, VPS9D1-AS1 knockdown decreased the expression of high mobility group AT-hook 2 (HMGA2) in NSCLC cells via miR-532-3p sponging. Recovery of HMGA2 expression partially reversed the inhibitory effects of VPS9D1-AS1 knockdown on NSCLC cells. Thus, VPS9D1-AS1 functions as a competing endogenous RNA that positively regulates HMGA2 expression by sponging miR-532-3p in NSCLC cells, suggesting that the VPS9D1-AS1–miR-532-3p–HMGA2 pathway can be a potential diagnostic and/or therapeutic target in NSCLC.
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Affiliation(s)
- Xiao Han
- Guangxi Medical University, Cancer Hospital, Nanning 530021, China
| | - Tianren Huang
- Guangxi Medical University, Cancer Hospital, Nanning 530021, China
| | - Junqing Han
- Cancer Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
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20
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Li K, Yang J, Chen J, Shi Y, Zhang Z, Chen W. High mobility group AT-hook 2 and c-MYC as potential prognostic factors in pancreatic ductal adenocarcinoma. Oncol Lett 2019; 19:1584-1592. [PMID: 31966084 DOI: 10.3892/ol.2019.11205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 11/08/2019] [Indexed: 12/13/2022] Open
Abstract
The present study investigated if c-MYC and high mobility group AT-hook 2 (HMGA2) expression was associated with prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). A total of 102 patients undergoing surgery for PDAC were retrospectively reviewed. Immunohistochemistry was used to detect c-MYC and HMGA2 protein expression in PDAC and peritumoral tissue samples. Expression of c-MYC and HMGA2 was associated with clinicopathological characteristics and prognoses of patients with PDAC using multivariate analysis. HMGA2 and c-MYC protein expression was significantly higher in PDAC tissues compared with peritumoral tissue (P<0.001). HMGA2 and c-MYC expression was also significantly higher in patients with PDAC who had lymph node metastasis, invasion of regional tissues and tumor node metastasis (TNM) stage III or IV disease compared with those who had no lymph node metastasis, no invasion of regional tissues and TNM stage I or II disease (P<0.001). Multivariate logistic regression analysis was used to identify TNM stage (P=0.007) and invasion (P=0.003) as significant independent predictors of c-MYC expression (model AUC=0.8201), and lymph node metastasis (P=0.002) and invasion (P=0.003) as significant independent predictors of HMGA2 expression (model AUC=0.7638). Cox multivariate analysis showed that expression of c-MYC (P=0.019) and HMGA2 (P<0.001), TNM stage (P=0.014) and lymph node metastasis (P=0.032) were associated with reduced overall survival time. HMGA2 and c-MYC may be important biological markers and potential therapeutic targets involved in the tumorigenesis, metastasis, invasion and prognosis of PDAC.
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Affiliation(s)
- Ke Li
- Department of Radiology, First Affiliated Hospital, Army Medical University, Chongqing 400038, P.R. China
| | - Jiali Yang
- Institute of Hepatopancreatobiliary Surgery, First Affiliated Hospital, Army Medical University, Chongqing 400038, P.R. China
| | - Jiafei Chen
- Department of Radiology, First Affiliated Hospital, Army Medical University, Chongqing 400038, P.R. China
| | - Yanshu Shi
- Department of Radiology, First Affiliated Hospital, Army Medical University, Chongqing 400038, P.R. China
| | - Zhuoli Zhang
- Northwestern Quantitative Imaging Core Lab, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Wei Chen
- Department of Radiology, First Affiliated Hospital, Army Medical University, Chongqing 400038, P.R. China
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21
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Ahmed SM, Dröge P. Oncofetal HMGA2 attenuates genotoxic damage induced by topoisomerase II target compounds through the regulation of local DNA topology. Mol Oncol 2019; 13:2062-2078. [PMID: 31271486 PMCID: PMC6763970 DOI: 10.1002/1878-0261.12541] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 06/26/2019] [Accepted: 07/03/2019] [Indexed: 12/26/2022] Open
Abstract
Rapidly dividing cells maintain chromatin supercoiling homeostasis via two specialized classes of enzymes, DNA topoisomerase type 1 and 2 (TOP1/2). Several important anticancer drugs perturb this homeostasis by targeting TOP1/2, thereby generating genotoxic DNA damage. Our recent studies indicated that the oncofetal chromatin structuring high‐mobility group AT‐hook 2 (HMGA2) protein plays an important role as a DNA replication fork chaperone in coping with DNA topological ramifications that occur during replication stress, both genomewide and at fragile sites such as subtelomeres. Intriguingly, a recent large‐scale clinical study identified HMGA2 expression as a sole predicting marker for relapse and poor clinical outcomes in 350 acute myeloid leukemia (AML) patients receiving combinatorial treatments that targeted TOP2 and replicative DNA synthesis. Here, we demonstrate that HMGA2 significantly enhanced the DNA supercoil relaxation activity of the drug target TOP2A and that this activator function is mechanistically linked to HMGA2's known ability to constrain DNA supercoils within highly compacted ternary complexes. Furthermore, we show that HMGA2 significantly reduced genotoxic DNA damage in each tested cancer cell model during treatment with the TOP2A poison etoposide or the catalytic TOP2A inhibitor merbarone. Taken together with the recent clinical data obtained with AML patients targeted with TOP2 poisons, our study suggests a novel mechanism of cancer chemoresistance toward combination therapies administering TOP2 poisons or inhibitors. We therefore strongly argue for the future implementation of trials of HMGA2 expression profiling to stratify patients before finalizing clinical treatment regimes.
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Affiliation(s)
- Syed Moiz Ahmed
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | - Peter Dröge
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
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22
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Lee MY, da Silva B, Ramirez DC, Maki RG. Novel HMGA2-YAP1 fusion gene in aggressive angiomyxoma. BMJ Case Rep 2019; 12:12/5/e227475. [PMID: 31142482 DOI: 10.1136/bcr-2018-227475] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
We describe a case of a 44-year-old woman with locally advanced aggressive angiomyxoma with a novel translocation high-mobility group AT-hook 2-yes-associated protein 1 (HMGA2-YAP1) fusion, implying a t(11;12)(q22.1;q14.3) translocation. She was started on gonadotropin-releasing hormone agonist injection and an aromatase inhibitor for persistent disease, which responded to treatment; she was subsequently treated with radiation before a more definitive operation was conducted. This case report indicates that HGMA2-YAP1-translocated aggressive angiomyxoma is responsive to oestrogen antagonism and hopefully will allow for the development of diagnostics useful for this rare but often morbid neoplasm. This case also highlights the importance of appropriate workup of a soft tissue mass.
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Affiliation(s)
- Mee-Young Lee
- Cancer Institute, Northwell Health, Lake Success, New York, USA
| | - Brandon da Silva
- Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Daniel C Ramirez
- Pathology, Northwell Health, Lake Success, New York, USA.,Pathology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Robert G Maki
- Cancer Institute, Northwell Health, Lake Success, New York, USA.,Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
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23
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Jiang Y, Zhu C, He D, Gao Q, Tian X, Ma X, Wu J, Das BC, Severinov K, Hitzeroth II, Debata PR, Liu R, Zou L, Shi L, Xu H, Wang K, Bao Y, Ka-Kit LR, You Z, Cui Z, Hu Z. Cytological Immunostaining of HMGA2, LRP1B, and TP63 as Potential Biomarkers for Triaging Human Papillomavirus-Positive Women. Transl Oncol 2019; 12:959-967. [PMID: 31102921 PMCID: PMC6525307 DOI: 10.1016/j.tranon.2019.04.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 04/16/2019] [Accepted: 04/16/2019] [Indexed: 01/17/2023] Open
Abstract
Background: Since human papillomavirus (HPV) DNA testing has been promoted as primary screening strategy, the triage method has also evolved from morphological testing to a molecular biomarker detection to improve screening efficiency. In this study, we investigated the performance of three HPV integration hot-spots, HMGA2, LRP1B, and TP63, as potential triage markers in HPV screening tests. Materials and Methods: This cross-sectional study was conducted from November 2016 to December 2017 in the First Affiliated Hospital of Sun Yat-sen University. Immunocytochemistry was carried out using residual cervical cell samples from 121 HPV-positive cases (23 normal, 24 cervical intraepithelial neoplasia (CIN) 1, and 74 CIN2+). Results: Of the 121 cases, 77 showed completely paired for the three biomarkers. In these 77 cases, receiver operating characteristic (ROC) analysis of HMGA2 showed the best potential for detecting CIN2+ among HPV+ cases (sensitivity 70%; specificity 91.89%; AUC 0.839). TP63 was second most effective biomarker (AUC 0.838; sensitivity 80%; specificity 81.08%). In contrast, LRP1B had the smallest AUC (0.801) among the three biomarkers but had the highest sensitivity (90%) and specificity (56.76%). To test the triage value of combining the three biomarkers, logistic regression was conducted followed by ROC comparison analysis. Promisingly, the combination of the three biomarkers gave the largest AUC of 0.951 with 92.5% sensitivity and 89.1% specificity (P < .0001 compared to liquid-based cytology test by Z-test). Conclusions: A combination of HMGA2, LRP1B, and TP63 as potential biomarkers may be useful for screening during triage of HPV-positive patients, particularly for detecting CIN2 + .
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Affiliation(s)
- Yunhui Jiang
- Department of Pathology, Jingmen No.2 People's Hospital/Institute for Cancer Prevention and Treatment，Jingchu University of Technology, Jingmen, Hubei Province, 448000, China.
| | - Chengyi Zhu
- Department of Obstetrics & Gynecology, Dongfeng Hospital, Hubei University of Medicine, Shiyan, Hubei Province, 442008, China.
| | - Dan He
- Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2(nd) Road, Yuexiu, Guangzhou, Guangdong Province, 510080, China.
| | - Qinglei Gao
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China.
| | - Xun Tian
- Central Hospital of Wuhan City, Huazhong University of Science and Technology, PR China.
| | - Xin Ma
- Department of Urology, The General Hospital of the People's Liberation Army, Beijing, China.
| | - Jun Wu
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
| | - Bhudev C Das
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University Uttar Pradesh, Sector-125, Noida, India.
| | - Konstantin Severinov
- Skolkovo Institute of Science and Technology, 100 Novaya str., Skolkovo, Moscow Region, Russia.
| | - Inga Isabel Hitzeroth
- E. Rybicki's Biopharming Research Unit. 11 Clifford Avenue, Vredehoek, 8001, Cape Town, South Africa.
| | | | - Rong Liu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China.
| | - Liang Zou
- Jingmen No.2 People's Hospital, Jingmen, Hubei Province, China..
| | - Long Shi
- Jingmen No.2 People's Hospital, Jingmen, Hubei Province, China..
| | - Hua Xu
- Jingmen No.2 People's Hospital, Jingmen, Hubei Province, China..
| | - Kaixiu Wang
- Jingmen No.2 People's Hospital, Jingmen, Hubei Province, China..
| | | | - Leung Ross Ka-Kit
- School of Public Health, The University of Hong Kong, Hong Kong, SAR, Dongguan Maternal and Child Hospital.
| | - Zeshan You
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Road, Yuexiu, Guangzhou, Guangdong Province, 510080, China.
| | - Zifeng Cui
- Department of Obstetrics and Gynecology, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Road, Yuexiu, Guangzhou, Guangdong Province, 510080, China.
| | - Zheng Hu
- Department of Obstetrics and Gynecology, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Road, Yuexiu, Guangzhou, Guangdong Province, 510080, China; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China.
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24
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Xing F, Song Z, He Y. MiR-219-5p inhibits growth and metastasis of ovarian cancer cells by targeting HMGA2. Biol Res 2018; 51:50. [PMID: 30474570 PMCID: PMC6260846 DOI: 10.1186/s40659-018-0199-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 11/18/2018] [Indexed: 12/31/2022] Open
Abstract
Background Accumulating studies have demonstrated that high-mobility group A2 (HMGA2), an oncofetal protein, plays a role in tumor development and progression. However, the molecular role of HMGA2 in ovarian carcinoma is yet to be established. MicroRNAs (miRNAs), a group of small noncoding RNAs, negatively regulate gene expression and their dysregulation has been implicated in tumorigenesis. The aim of this study was to investigate the potential involvement of a specific miRNA, miR-219-5p, in HMGA2-induced ovarian cancer. Methods The ovarian cancer cell line, SKOV3, was employed, and miR-219-5p and HMGA2 overexpression vectors constructed. The CCK-8 kit was used to determine cell proliferation and the Transwell® assay used to measure cell invasion and migration. RT-PCR and western blot analyses were applied to analyze the expression of miR-219-5p and HMGA2, and the luciferase reporter assay used to examine the interactions between miR-219-5p and HMGA2. Nude mice were employed to characterize in vivo tumor growth regulation. Results Expression of miR-219-5p led to suppression of proliferation, invasion and migration of the ovarian cancer cell line, SKOV3, by targeting HMGA2. The inhibitory effects of miR-219-5p were reversed upon overexpression of HMGA2. Data from the luciferase reporter assay showed that miR-219-5p downregulates HMGA2 via direct integration with its 3′-UTR. Consistent with in vitro findings, expression of miR-219-5p led to significant inhibition of tumor growth in vivo. Conclusion Our results collectively suggest that miR-219-5p inhibits tumor growth and metastasis by targeting HMGA2.
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Affiliation(s)
- Feng Xing
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Tongji University School of Medicine, No 301 Middle Yan Chang Road, Shanghai, 200072, China
| | - Zhijiao Song
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Tongji University School of Medicine, No 301 Middle Yan Chang Road, Shanghai, 200072, China
| | - Yuanying He
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Tongji University School of Medicine, No 301 Middle Yan Chang Road, Shanghai, 200072, China.
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25
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Wang Y, Hu L, Wang J, Li X, Sahengbieke S, Wu J, Lai M. HMGA2 promotes intestinal tumorigenesis by facilitating MDM2-mediated ubiquitination and degradation of p53. J Pathol 2018; 246:508-518. [DOI: 10.1002/path.5164] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 07/30/2018] [Accepted: 08/28/2018] [Indexed: 12/22/2022]
Affiliation(s)
- Yuhong Wang
- Department of Pathology; Zhejiang University School of Medicine; Hangzhou Zhejiang PR China
- Key Laboratory of Disease Proteomics of Zhejiang Province; Hangzhou Zhejiang China
| | - Lin Hu
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences; Soochow University; Suzhou Jiangsu PR China
| | - Jian Wang
- Department of Surgical Oncology; Second Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou Zhejiang PR China
| | - Xiangwei Li
- Department of Pathology; Zhejiang University School of Medicine; Hangzhou Zhejiang PR China
- Key Laboratory of Disease Proteomics of Zhejiang Province; Hangzhou Zhejiang China
| | - Sana Sahengbieke
- Department of Pathology; Zhejiang University School of Medicine; Hangzhou Zhejiang PR China
- Key Laboratory of Disease Proteomics of Zhejiang Province; Hangzhou Zhejiang China
| | - Jingjing Wu
- Department of Pathology; Zhejiang University School of Medicine; Hangzhou Zhejiang PR China
- Key Laboratory of Disease Proteomics of Zhejiang Province; Hangzhou Zhejiang China
| | - Maode Lai
- Department of Pathology; Zhejiang University School of Medicine; Hangzhou Zhejiang PR China
- Key Laboratory of Disease Proteomics of Zhejiang Province; Hangzhou Zhejiang China
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26
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Xie J, Ubango J, Ban Y, Chakravarti D, Kim JJ, Wei JJ. Comparative analysis of AKT and the related biomarkers in uterine leiomyomas with MED12, HMGA2, and FH mutations. Genes Chromosomes Cancer 2018; 57:485-494. [PMID: 29790226 DOI: 10.1002/gcc.22643] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 05/15/2018] [Accepted: 05/16/2018] [Indexed: 11/07/2022] Open
Abstract
Uterine leiomyomas (ULM) are histologically and molecularly heterogeneous and clinically they grow at vastly different rates. Several driver gene mutations have been identified in ULM, including MED12 mutations, HMGA2 overexpression, and biallelic FH inactivation. ULM with different driver mutant genes may use different molecular pathways, but currently no clear correlation between gene mutations and growth related pathways has been established. To better define this relationship, we collected ULM with MED12 (n = 25), HMGA2 (n = 15), and FH (n = 27) mutations and examined the sex steroid hormone, cell cycle, and AKT pathway genes by immunohistochemistry. While ER and PR were highly expressed in all types of ULM, FH ULM showed lower ER expression and higher PR expression. HMGA2 tumors had significantly higher levels of AKT signaling and mitogenic activity than other ULM types. HMGA2 activated AKT signaling through upregulation of IGF2BP2. Silencing HMGA2 in ULM cells resulted in downregulation of AKT and upregulation of p16 and p21, which eventually led to cell senescence. HMGA2 overexpression in ULM is not only related to tumor development but also plays a role in controlling cellular proliferation through the AKT pathway.
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Affiliation(s)
- Jia Xie
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Julianne Ubango
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Yanli Ban
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Debabrata Chakravarti
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - J Julie Kim
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Jian-Jun Wei
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.,Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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27
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Abd El Gwad A, Matboli M, El-Tawdi A, Habib EK, Shehata H, Ibrahim D, Tash F. Role of exosomal competing endogenous RNA in patients with hepatocellular carcinoma. J Cell Biochem 2018; 119:8600-8610. [PMID: 30015383 DOI: 10.1002/jcb.27109] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 05/04/2018] [Indexed: 12/14/2022]
Abstract
Recent research has tried to use exosomal RNAs (coding and noncoding) as potential diagnostic markers for hepatocellular carcinoma (HCC). Initially, by using bioinformatics, we selected an HCC-exosomal RNA-based biomarker panel. The choice of this panel depends on the integration of Ras-related in brain (RAB11A) gene expression and its competing endogenous network. This network includes long noncoding RNA RP11-513I15.6 (lncRNA-RP11-513I15.6) and microRNA-1262 (miR-1262). Secondly, we tried to validate the expression of this network in the sera of 60 patients with HCC in comparison with 42 chronic hepatitis C virus-infected patients and 18 healthy controls. Then we assessed the diagnostic efficiency of this panel using a receiver operating characteristic curve analysis. The panel of 3 exosomal RNA-based biomarkers (lncRNA-RP11-513I15.6, miR-1262, and RAB11A) showed excellent sensitivity and specificity in discriminating patients with HCC from patients with chronic hepatitis C virus and healthy controls. Among these 3 RNAs, serum RAB11A mRNA was the most independent prognostic factor. The selected circulatory exosomal RNA-based biomarker panel showed its ability to be used as a diagnostic and prognostic biomarker tool for HCC. Moreover, these biomarkers could be therapeutic targets.
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Affiliation(s)
- Asmaa Abd El Gwad
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Marwa Matboli
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed El-Tawdi
- General Surgery Department, Military Medical Academy, Egypt
| | - Eman K Habib
- Anatomy & Embryology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hanan Shehata
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Doaa Ibrahim
- Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Fathy Tash
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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28
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Popadić D, Heßelbach K, Richter-Brockmann S, Kim GJ, Flemming S, Schmidt-Heck W, Häupl T, Bonin M, Dornhof R, Achten C, Günther S, Humar M, Merfort I. Gene expression profiling of human bronchial epithelial cells exposed to fine particulate matter (PM 2.5) from biomass combustion. Toxicol Appl Pharmacol 2018; 347:10-22. [PMID: 29596927 DOI: 10.1016/j.taap.2018.03.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 03/08/2018] [Accepted: 03/21/2018] [Indexed: 02/08/2023]
Affiliation(s)
- Désirée Popadić
- Institute of Pharmaceutical Sciences, Department of Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Katharina Heßelbach
- Institute of Pharmaceutical Sciences, Department of Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Sigrid Richter-Brockmann
- Institute of Geology and Palaeontology - Applied Geology, University of Muenster, Muenster, Germany
| | - Gwang-Jin Kim
- Institute of Pharmaceutical Sciences, Department of Pharmaceutical Bioinformatics, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Stephan Flemming
- Institute of Pharmaceutical Sciences, Department of Pharmaceutical Bioinformatics, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Wolfgang Schmidt-Heck
- Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute (HKI), Jena, Germany
| | - Thomas Häupl
- Department of Rheumatology and Clinical Immunology, Charité University Hospital Berlin, Berlin, Germany
| | - Marc Bonin
- Department of Rheumatology and Clinical Immunology, Charité University Hospital Berlin, Berlin, Germany
| | - Regina Dornhof
- Institute of Pharmaceutical Sciences, Department of Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Christine Achten
- Institute of Geology and Palaeontology - Applied Geology, University of Muenster, Muenster, Germany
| | - Stefan Günther
- Institute of Pharmaceutical Sciences, Department of Pharmaceutical Bioinformatics, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Matjaz Humar
- Institute of Pharmaceutical Sciences, Department of Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
| | - Irmgard Merfort
- Institute of Pharmaceutical Sciences, Department of Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-University Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs University Freiburg, Freiburg, Germany.
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29
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Abstract
microRNAs (miRs) are targets for genomic aberrations and emerging treatments against cancer. It has been demonstrated that targeting miR-569 may potentially benefit patients with ovarian or breast cancer. However, the exact roles of miR-569 remain unclear in human lung cancer cells. Using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR), it was demonstrated that miR-569 expression was consistently decreased in lung cancer cells. As well as cell proliferation and migration inhibition, apoptosis and cell arrest at the G1 phase were induced following reversion of miR-569 expression in lung cancer cells. The present study demonstrated that miR-569 was able to downregulate FOS and high mobility group A2 mRNA and protein expression using RT-qPCR and western blot analysis. The observed role of miRNA-569 in lung cancer cells in the present study suggested that it may be a novel and promising therapeutic target, and a novel biomarker for detecting lung cancer.
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Affiliation(s)
- Yi Ping Zheng
- Department of Geriatrics, The First Affiliated Hospital of Dalian Medical College, Dalian, Liaoning 116000, P.R. China
| | - Linxia Wu
- Department of Geriatrics, The First Affiliated Hospital of Dalian Medical College, Dalian, Liaoning 116000, P.R. China
| | - Jie Gao
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical College, Dalian, Liaoning 116000, P.R. China
| | - Yanfu Wang
- Department of Geriatrics, The First Affiliated Hospital of Dalian Medical College, Dalian, Liaoning 116000, P.R. China
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30
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Nanoscale Assembly of High-Mobility Group AT-Hook 2 Protein with DNA Replication Fork. Biophys J 2018; 113:2609-2620. [PMID: 29262356 DOI: 10.1016/j.bpj.2017.10.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 08/24/2017] [Accepted: 10/12/2017] [Indexed: 01/31/2023] Open
Abstract
High mobility group AT-hook 2 (HMGA2) protein is composed of three AT-hook domains. HMGA2 expresses at high levels in both embryonic stem cells and cancer cells, where it interacts with and stabilizes replication forks (RFs), resulting in elevated cell proliferation rates. In this study, we demonstrated that HMGA2 knockdown reduces cell proliferation. To understand the features required for interaction between HMGA2 and RFs, we studied the solution structure of HMGA2, free and in complex with RFs, using an integrated host of biophysical techniques. Circular dichroism and NMR experiments confirmed the disordered state of unbound HMGA2. Dynamic light scattering and sedimentation velocity experiments demonstrated that HMGA2 and RF are monodisperse in solution, and form an equimolar complex. Small-angle x-ray scattering studies revealed that HMGA2 binds in a side-by-side orientation to RF where 3 AT-hooks act as a clamp to wrap around a distorted RF. Thus, our data provide insights into how HMGA2 interacts with stalled RFs and the function of the process.
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31
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Weidle UH, Birzele F, Kollmorgen G, Nopora A. Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis. Cancer Genomics Proteomics 2018; 15:1-15. [PMID: 29275359 PMCID: PMC5822180 DOI: 10.21873/cgp.20061] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 10/09/2017] [Accepted: 10/17/2017] [Indexed: 02/06/2023] Open
Abstract
Treatment of disseminated epithelial ovarian cancer (EOC) is an unmet medical need. Therefore, the identification along with preclinical and clinical validation of new targets is an issue of high importance. In this review we focus on microRNAs that mediate metastasis of EOC. We summarize up-regulated metastasis-promoting and down-regulated metastasis-suppressing microRNAs. We focus on preclinical in vitro and in vivo functions as well as their metastasis-related clinical correlations. Finally, we outline modalities for therapeutic intervention and critical issues of microRNA-based therapeutics in the context of metastatic EOC.
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Affiliation(s)
- Ulrich H Weidle
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
| | - Fabian Birzele
- Roche Innovation Center Basel, F. Hofman La Roche, Basel, Switzerland
| | - Gwen Kollmorgen
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
| | - Adam Nopora
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
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32
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Wang J, Papanicolau-Sengos A, Chintala S, Wei L, Liu B, Hu Q, Miles KM, Conroy JM, Glenn ST, Costantini M, Magi-Galluzzi C, Signoretti S, Choueiri T, Gallucci M, Sentinelli S, Fazio VM, Poeta ML, Liu S, Morrison C, Pili R. Collecting duct carcinoma of the kidney is associated with CDKN2A deletion and SLC family gene up-regulation. Oncotarget 2017; 7:29901-15. [PMID: 27144525 PMCID: PMC5058651 DOI: 10.18632/oncotarget.9093] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 04/16/2016] [Indexed: 01/17/2023] Open
Abstract
The genetic landscape and molecular features of collecting duct carcinoma (CDC) of the kidney remain largely unknown. Herein, we performed whole exome sequencing (WES) and transcriptome sequencing (RNASeq) on 7 CDC samples (CDC1 −7). Among the 7 samples, 4 samples with matched non-tumor tissue were used for copy number analysis by SNP array data. No recurrent somatic SNVs were observed except for MLL, which was found to be mutated (p.V297I and p.F407C) in 2 samples. We identified somatic SNVs in 14 other cancer census genes including: ATM, CREBBP, PRDM1, CBFB, FBXW7, IKZF1, KDR, KRAS, NACA, NF2, NUP98, SS18, TP53, and ZNF521. SNP array data identified a CDKN2A homozygous deletion in 3 samples and SNV analysis showed a non-sense mutation of the CDKN2A gene with unknown somatic status. To estimate the recurrent rate of CDKN2A abnormalities, we performed FISH screening of additional samples and confirmed the frequent loss (62.5%) of CDKN2A expression. Since cisplatin based therapy is the common treatment option for CDC, we investigated the expression of solute carrier (SLC) family transporters and found 45% alteration. In addition, SLC7A11 (cystine transporter, xCT), a cisplatin resistance associated gene, was found to be overexpressed in 4 out of 5 (80%) cases of CDC tumors tested, as compared to matched non-tumor tissue. In summary, our study provides a comprehensive genomic analysis of CDC and identifies potential pathways suitable for targeted therapies.
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Affiliation(s)
- Jianmin Wang
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Antonios Papanicolau-Sengos
- Department of Pathology and Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Sreenivasulu Chintala
- Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.,Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA
| | - Lei Wei
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Biao Liu
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Qiang Hu
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Kiersten Marie Miles
- Department of Pathology and Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Jeffrey M Conroy
- Department of Pathology and Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Sean T Glenn
- Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Manuela Costantini
- Department of Urology, Regina Elena National Cancer Institute of Rome, Rome, Italy.,Laboratory of Genetic and Clinical Pathology, University Campus BioMedico of Rome, Rome, Italy.,Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy
| | | | - Sabina Signoretti
- Department of Pathology and Kidney Cancer Program, Dana Farber, Boston, MA, USA
| | - Toni Choueiri
- Department of Pathology and Kidney Cancer Program, Dana Farber, Boston, MA, USA
| | - Michele Gallucci
- Department of Urology, Regina Elena National Cancer Institute of Rome, Rome, Italy
| | - Steno Sentinelli
- Department of Urology, Regina Elena National Cancer Institute of Rome, Rome, Italy
| | - Vito M Fazio
- Laboratory of Genetic and Clinical Pathology, University Campus BioMedico of Rome, Rome, Italy
| | - Maria Luana Poeta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy
| | - Song Liu
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Carl Morrison
- Department of Pathology and Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Roberto Pili
- Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.,Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA
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33
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High mobility group protein A2 overexpression indicates poor prognosis for cancer patients: a meta-analysis. Oncotarget 2017; 9:1237-1247. [PMID: 29416690 PMCID: PMC5787434 DOI: 10.18632/oncotarget.23085] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 11/17/2017] [Indexed: 12/17/2022] Open
Abstract
Overexpression of the high mobility group protein A2 (HMGA2), an architectural transcription factor, has been linked to poor prognosis in many malignancies, although this remains controversial. Herein, we conducted a meta-analysis to investigate whether HMGA2 has prognostic value, and evaluated the association between HMGA2 and clinicopathologic factors in malignancies. A total of 29 studies involving 4114 patients were included in this meta-analysis. The pooled results demonstrated that elevated HMGA2 predicted a poor overall survival (OS) (hazard ratio [HR] = 1.82; 95% confidence interval [CI] = 1.62-2.05; P < 0.001) and disease-free survival/progression-free survival/recurrence-free survival (HR = 1.94; 95% CI = 1.27-2.98; P = 0.002). Subgroup analysis conducted by study region, sample size, detection method, and analysis method indicated that HMGA2 overexpression correlated with poor OS. Furthermore, HMGA2 overexpression was found to be linked to poor OS in various cancers except ovarian cancer (pooled HR = 1.14; 95% CI = 0.62-2.09; P = 0.673). High HMGA2 expression level also correlated with advanced TNM stage (OR = 2.44; 95% CI =1.87-3.2; P < 0.001), lymphovascular invasion (OR = 2.46, 95% CI = 1.67-3.64; P < 0.001), distant metastasis (OR = 2.66; 95% CI =1.51-4.69; P < 0.001), and lymph node metastasis (OR = 1.83; 95% CI =1.27-2.64; P = 0.001). In conclusion, HMGA2 overexpression indicates a worse prognosis and may serve as a prognostic predictor in cancer patients.
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34
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Abstract
Multiple mechanisms of epigenetic control that include DNA methylation, histone modification, noncoding RNAs, and mitotic gene bookmarking play pivotal roles in stringent gene regulation during lineage commitment and maintenance. Experimental evidence indicates that bivalent chromatin domains, i.e., genome regions that are marked by both H3K4me3 (activating) and H3K27me3 (repressive) histone modifications, are a key property of pluripotent stem cells. Bivalency of developmental genes during the G1 phase of the pluripotent stem cell cycle contributes to cell fate decisions. Recently, some cancer types have been shown to exhibit partial recapitulation of bivalent chromatin modifications that are lost along with pluripotency, suggesting a mechanism by which cancer cells reacquire properties that are characteristic of undifferentiated, multipotent cells. This bivalent epigenetic control of oncofetal gene expression in cancer cells may offer novel insights into the onset and progression of cancer and may provide specific and selective options for diagnosis as well as for therapeutic intervention.
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Kou B, Liu W, Tang X, Kou Q. HMGA2 facilitates epithelial-mesenchymal transition in renal cell carcinoma by regulating the TGF-β/Smad2 signaling pathway. Oncol Rep 2017; 39:101-108. [PMID: 29138866 PMCID: PMC5783590 DOI: 10.3892/or.2017.6091] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Accepted: 11/01/2017] [Indexed: 12/11/2022] Open
Abstract
High-mobility group AT-hook 2 (HMGA2), a member of the high mobility group family, has been reported to correlate with cancer progression. However, there is no report concerning the correlation between HMGA2 and metastasis in renal cell carcinoma. In the present study, we found that HMGA2 was highly expressed in five renal cell carcinoma cell lines compared with that in the normal renal tubular epithelial HK2 cell line. Additionally, HMGA2 facilitated cell migration and invasion of renal cell carcinoma cells, as evidenced by wound healing and Transwell assays. Subsequently, our results revealed that the E-cadherin level was upregulated, while N-cadherin, Twist1 and Twist2 expression were downregulated in HMGA2-depleted ACHN cells. In contrast, overexpression of HMGA2 in 786-O cells enhanced epithelial-mesenchymal transition (EMT). In addition, analysis of the database Cancer Browser further validated the positive correlation between HGMA2 and Twist1 or Twist2 in renal cell carcinoma. Meanwhile, Kaplan-Meier analysis indicated that low HMGA2 expression was closely associated with an increased overall survival in renal cell carcinoma patients. To confirm the underlying mechanism of HMGA2-regulated EMT, our results revealed that silencing of HMGA2 downregulated the mRNA and protein levels of TGF-β and Smad2, while HMGA2 overexpression had the opposite effect. Furthermore, TGF-β overexpression could partially reverse the anti-metastatic effect and mesenchymal-epithelial transition (MET) by HMGA2 loss, while TGF-β deficiency impeded the pro-metastatic phenotype and high expression of EMT markers induced by HMGA2 overexpression. In summary, our results demonstrated that HMGA2 facilitated a metastatic phenotype and the EMT process in renal cell carcinoma cells in vitro through a TGF-β-dependent pathway. In addition, these data strongly suggest that HGMA2 may serve as a potential therapeutic target and prognostic biomarker against renal cell carcinoma in the future.
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Affiliation(s)
- Bo Kou
- Department of Cardiovascular Surgery, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Wei Liu
- Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaoshuang Tang
- Department of Urology, Second Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Qingshan Kou
- Medical Center, First People's Hospital of Xianyang, Xianyang, Shaanxi 712000, P.R. China
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Wang Y, Chen F, Zhao M, Yang Z, Li J, Zhang S, Zhang W, Ye L, Zhang X. The long noncoding RNA HULC promotes liver cancer by increasing the expression of the HMGA2 oncogene via sequestration of the microRNA-186. J Biol Chem 2017; 292:15395-15407. [PMID: 28765279 DOI: 10.1074/jbc.m117.783738] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 07/13/2017] [Indexed: 01/13/2023] Open
Abstract
The long noncoding RNA highly up-regulated in liver cancer (HULC) is aberrantly elevated in hepatocellular carcinoma (HCC), and this up-regulation is crucial for HCC pathogenesis. However, the underlying mechanism in HULC up-regulation is poorly understood. We hypothesized that HULC might modulate the oncogene high mobility group A2 (HMGA2) to promote hepatocarcinogenesis. Quantitative real-time PCR analysis showed that the expression levels of HULC were positively correlated with those of HMGA2 in clinical HCC tissues. Interestingly, we also observed that HULC could up-regulate HMGA2 in HCC cells. Mechanistically, we found that the microRNA-186 inhibited HMGA2 expression by targeting the 3'-untranslated region (3'-UTR) of HMGA2 mRNA. Strikingly, HULC acted as a competing noncoding RNA to sequester miR-186 and thereby relieved miR-186-mediated HMGA2 repression. Functionally, HMGA2 knockdown decreased the HULC-enhanced growth of HCC cells both in vitro and in vivo We conclude that the long noncoding RNA HULC increases HMGA2 expression by sequestering miR-186 post-transcriptionally and thereby promotes liver cancer growth, providing new insights into the mechanism by which HULC enhances hepatocarcinogenesis.
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Affiliation(s)
- Yuan Wang
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China and
| | - Fuquan Chen
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China and
| | - Man Zhao
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China and
| | - Zhe Yang
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China and
| | - Jiong Li
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China and
| | - Shuqin Zhang
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China and
| | - Weiying Zhang
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China and
| | - Lihong Ye
- the State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Xiaodong Zhang
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China and
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The Fragment HMGA2-sh-3p20 from HMGA2 mRNA 3'UTR Promotes the Growth of Hepatoma Cells by Upregulating HMGA2. Sci Rep 2017; 7:2070. [PMID: 28522832 PMCID: PMC5437003 DOI: 10.1038/s41598-017-02311-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 04/10/2017] [Indexed: 01/12/2023] Open
Abstract
High mobility group A2 (HMGA2) plays a crucial role in the development of cancer. However, the mechanism by which HMGA2 promotes the growth of hepatocellular carcinoma (HCC) remains unclear. Here, we explore the hypothesis that HMGA2 may enhance the growth of hepatoma cells through a fragment based on the secondary structure of HMGA2 mRNA 3′-untranslated region (3′UTR). Bioinformatics analysis showed that HMGA2 mRNA displayed a hairpin structure within its 3′UTR, termed HMGA2-sh. Mechanistically, RNA immunoprecipitation assays showed that the microprocessor Drosha or DGCR8 interacted with HMGA2 mRNA in hepatoma cells. Then, Dicer contributes to the generation of the fragment HMGA2-sh-3p20 from the HMGA2-sh. HMGA2-sh-3p20 was screened by PCR analysis. Interestingly, HMGA2-sh-3p20 increased the expression of HMGA2 through antagonizing the tristetraprolin (TTP)-mediated degradation of HMGA2. HMGA2-sh-3p20 inhibited the expression of PTEN by targeting the 3′UTR of PTEN mRNA. In addition, the overexpression of PTEN could downregulate HMGA2 expression. Significantly, we documented the ability of HMGA2-sh-3p20 to promote the growth of hepatoma cells in vitro and in vivo. Thus, we conclude that the fragment HMGA2-sh-3p20 from HMGA2 mRNA 3′UTR promotes the growth of hepatoma cells by upregulating HMGA2. Our finding provides new insights into the mechanism by which HMGA2 enhances hepatocarcinogenesis.
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Palma Flores C, García-Vázquez R, Gallardo Rincón D, Ruiz-García E, Astudillo de la Vega H, Marchat LA, Salinas Vera YM, López-Camarillo C. MicroRNAs driving invasion and metastasis in ovarian cancer: Opportunities for translational medicine (Review). Int J Oncol 2017; 50:1461-1476. [PMID: 28393213 DOI: 10.3892/ijo.2017.3948] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 02/15/2017] [Indexed: 11/06/2022] Open
Abstract
Epithelial ovarian cancer is the fifth most frequent cause of cancer death in women. In spite of the advantages in early detection and treatment options, overall survival rates have improved only slightly in the last decades. Therefore, alternative therapeutic approaches need to overcome resistance and improve the patient survival and outcome. MicroRNAs are evolutionary conserved small non-coding RNAs that function as negative regulators of gene expression by inhibiting translation or inducing degradation of messenger RNAs. In cancer, microRNAs are aberrantly expressed thus representing potential prognostic biomarkers and novel therapeutic targets. The knowledge of novel and unexpected functions of microRNAs is rapidly evolving and the advance in the elucidation of potential clinical applications deserves attention. Recently, a specific set of microRNAs dubbed as metastamiRs have been shown to initiate invasion and metastasis in diverse types of cancer. We reviewed the current status of microRNAs in development and progression of ovarian cancer with a special emphasis on tumor cells invasion and metastasis. Also, we show an update of microRNA functions in oncogenic pathways and discuss the current scenario for potential applications in clinical and translational research in ovarian cancer.
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Affiliation(s)
| | - Raúl García-Vázquez
- Molecular Biomedicine Program and Biotechnology Network, Instituto Politécnico Nacional, Mexico City, Mexico
| | | | - Erika Ruiz-García
- Translational Medicine Laboratory, National Institute of Cancerology, Mexico City, Mexico
| | - Horacio Astudillo de la Vega
- Laboratory of Translational Cancer Research and Cellular Therapy, National Medical Center 'Siglo XXI', Mexico City, Mexico
| | - Laurence A Marchat
- Molecular Biomedicine Program and Biotechnology Network, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Yarely M Salinas Vera
- Autonomous University of Mexico City, Genomics Sciences Program, Mexico City, Mexico
| | - César López-Camarillo
- Autonomous University of Mexico City, Genomics Sciences Program, Mexico City, Mexico
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Role of Nerve Growth Factor (NGF) and miRNAs in Epithelial Ovarian Cancer. Int J Mol Sci 2017; 18:ijms18030507. [PMID: 28245631 PMCID: PMC5372523 DOI: 10.3390/ijms18030507] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 02/12/2017] [Accepted: 02/20/2017] [Indexed: 12/17/2022] Open
Abstract
Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types of cancer, including EOC; both NGF and TRKA levels are elevated in this pathology. EOC presents high angiogenesis and several molecules have been reported to induce this process. NGF increases angiogenesis through its TRKA receptor on endothelial cells, and by indirectly inducing vascular endothelial growth factor expression. Other molecules controlled by NGF include ciclooxigenase-2, disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) and calreticulin (CRT), proteins involved in crucial processes needed for EOC progression. These molecules could be modified through microRNA regulation, which could be regulated by NGF. MicroRNAs are the widest family of non-coding RNAs; they bind to 3'-UTR of mRNAs to inhibit their translation, to deadenilate or to degraded them. In EOC, a deregulation in microRNA expression has been described, including alterations of miR-200 family, cluster-17-92, and miR-23b, among others. Since the NGF-microRNA relationship in pathologies has not been studied, this review proposes that some microRNAs could be associated with NGF/TRKA activation, modifying protein levels needed for EOC progression.
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DNA methylation-regulated microRNA pathways in ovarian serous cystadenocarcinoma: A meta-analysis. Comput Biol Chem 2016; 65:154-164. [DOI: 10.1016/j.compbiolchem.2016.09.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 09/07/2016] [Indexed: 12/31/2022]
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Wang Y, Chen F, Zhao M, Yang Z, Zhang S, Ye L, Gao H, Zhang X. MiR-107 suppresses proliferation of hepatoma cells through targeting HMGA2 mRNA 3'UTR. Biochem Biophys Res Commun 2016; 480:455-460. [PMID: 27773820 DOI: 10.1016/j.bbrc.2016.10.070] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 10/19/2016] [Indexed: 02/02/2023]
Abstract
BACKGROUND AND AIM Aberrant expression of miR-107 is involved in the development of several human cancers. However, the role of miR-107 in hepatocellular carcinoma (HCC) is not well documented. In the present study, we aim to explore the function of miR-107 in hepatocarcinogenesis. METHODS Bioinformatics analysis was applied to predict the target genes of miR-107. Luciferase reporter gene assay was performed to verify the miR-107 binding sites in 3'-untranslated region (3'UTR) of high mobility group A2 (HMGA2) mRNA. The expression levels of mRNA and protein were examined using qRT-PCR and Western blot analysis. Functionally, MTT and EdU assays were carried out for proliferation analysis. Clinically, thirty HCC samples and their corresponding peritumor liver tissues were collected. RESULTS Bioinformatics analysis revealed that miR-107 might target HMGA2 mRNA 3'UTR. Luciferase reporter gene assays verified that the miR-107 binding site was located in the 3'UTR of HMGA2 mRNA. Furthermore, miR-107 could down-regulate HMGA2 at the levels of mRNA and protein in a dose-dependent manner. Interestingly, miR-107 inhibited the proliferation of hepatoma cells, while anti-miR-107 could promote the cell proliferation, which was blocked by the interference of HMGA2. Clinically, miR-107 was lower in HCC samples relative to peritumor liver tissues. The expression levels of miR-107 were negatively correlated with those of HMGA2 mRNA in HCC samples. CONCLUSION MiR-107 suppresses the proliferation of hepatoma cells by targeting HMGA2 mRNA. Our finding provides new insights into the mechanism of hepatocarcinogenesis.
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Affiliation(s)
- Yuan Wang
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Fuquan Chen
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Man Zhao
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Zhe Yang
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Shuqin Zhang
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Lihong Ye
- State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Hongwei Gao
- Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China.
| | - Xiaodong Zhang
- State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China.
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Nymoen DA, Slipicevic A, Holth A, Emilsen E, Hetland Falkenthal TE, Tropé CG, Reich R, Flørenes VA, Davidson B. MiR-29a is a candidate biomarker of better survival in metastatic high-grade serous carcinoma. Hum Pathol 2016; 54:74-81. [DOI: 10.1016/j.humpath.2016.03.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Revised: 03/02/2016] [Accepted: 03/05/2016] [Indexed: 12/27/2022]
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Agostini A, Panagopoulos I, Davidson B, Trope CG, Heim S, Micci F. A novel truncated form of HMGA2 in tumors of the ovaries. Oncol Lett 2016; 12:1559-1563. [PMID: 27446471 DOI: 10.3892/ol.2016.4805] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 05/10/2016] [Indexed: 12/18/2022] Open
Abstract
Neoplasms of the ovary are the second most common tumor of the female reproductive system, and the most lethal of the gynecological malignancies. Ovarian tumors are divided into a copious number of different groups reflecting their different features. The present study analyzed 187 ovarian tumors (39 sex-cord stromal tumors, 22 borderline tumors and 126 carcinomas) for the expression of the high-mobility group AT-hook 2 (HMGA2) gene, for mutations in the isocitrate dehydrogenase (NADP(+)) 1, cytosolic (IDH1), isocitrate dehydrogenase (NADP(+)) 2, mitochondrial (IDH2) and telomerase reverse transcriptase (TERT) genes, and for methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter. Reverse transcription-polymerase chain reaction analysis showed that HMGA2 was expressed in 74.5% of the samples (120/161). A truncated transcript of HMGA2 was identified in 11 cases. A novel truncated form of HMGA2 was found in 4 serous high-grade carcinomas. Only 4 tumors (4/185) showed the TERT C228T mutation. No IDH1 or IDH2 mutations were found. Methylation of the promoter of MGMT was found in 2 borderline tumors (2/185). HMGA2 was expressed, in its truncated and native form, in different ovarian tumors, even the less aggressive types, underscoring the general importance of this gene in ovarian tumorigenesis. Mutations involving TERT, as well as MGMT promoter methylation, are rare events in ovarian tumors.
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Affiliation(s)
- Antonio Agostini
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, 0310 Oslo, Norway
| | - Ioannis Panagopoulos
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, 0310 Oslo, Norway
| | - Ben Davidson
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway; Faculty of Medicine, University of Oslo, 0310 Oslo, Norway
| | - Claes Goran Trope
- Department of Gynecology, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway
| | - Sverre Heim
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, 0310 Oslo, Norway; Faculty of Medicine, University of Oslo, 0310 Oslo, Norway
| | - Francesca Micci
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, 0310 Oslo, Norway
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Galdiero F, Romano A, Pasquinelli R, Pignata S, Greggi S, Vuttariello E, Bello AM, Calise C, Scaffa C, Pisano C, Losito NS, Fusco A, Califano D, Chiappetta G. Detection of high mobility group A2 specific mRNA in the plasma of patients affected by epithelial ovarian cancer. Oncotarget 2016; 6:19328-35. [PMID: 25749380 PMCID: PMC4662494 DOI: 10.18632/oncotarget.2896] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 12/15/2014] [Indexed: 11/25/2022] Open
Abstract
Ovarian cancer is the most lethal gynecological malignancy and the high mortality rate is associated with advanced-stage disease at the time of the diagnosis. In order to find new tools to make diagnosis of Epithelial Ovarian Cancer (EOC) at early stages we have analyzed the presence of specific HMGA2 mRNA in the plasma of patients affected by this neoplasm. HMGA2 overexpression represents a feature of several malignances including ovarian carcinomas. Notably, we detected HMGA2 specific mRNA in the plasma of 40 out 47 patients with EOC, but not in the plasma of healthy donors. All cases found positive for HMGA2 mRNA in the plasma showed HMGA2 protein expression in EOC tissues. Therefore, on the basis of these results, the analysis of circulating HMGA2 specific mRNA might be considered a very promising tool for the early diagnosis of EOC.
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Affiliation(s)
- Francesca Galdiero
- Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
| | - Annunciata Romano
- Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
| | - Rosa Pasquinelli
- Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
| | - Sandro Pignata
- Dipartimento di Oncologia Uroginecologica, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
| | - Stefano Greggi
- Dipartimento di Oncologia Uroginecologica, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
| | - Emilia Vuttariello
- Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
| | - Anna Maria Bello
- Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
| | - Celeste Calise
- Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
| | - Cono Scaffa
- Dipartimento di Oncologia Uroginecologica, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
| | - Carmela Pisano
- Dipartimento di Oncologia Uroginecologica, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
| | - Nunzia Simona Losito
- Anatomia Patologica, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
| | - Alfredo Fusco
- Istituto di Endocrinologia ed Oncologia Sperimentale - CNR Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy
| | - Daniela Califano
- Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
| | - Gennaro Chiappetta
- Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy
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Wang H, Sun Z, Wang Y, Hu Z, Zhou H, Zhang L, Hong B, Zhang S, Cao X. miR-33-5p, a novel mechano-sensitive microRNA promotes osteoblast differentiation by targeting Hmga2. Sci Rep 2016; 6:23170. [PMID: 26980276 PMCID: PMC4793269 DOI: 10.1038/srep23170] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 02/25/2016] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) interfere with the translation of specific target mRNAs and are thought to thereby regulate many cellular processes. However, the role of miRNAs in osteoblast mechanotransduction remains to be defined. In this study, we investigated the ability of a miRNA to respond to different mechanical environments and regulate mechano-induced osteoblast differentiation. First, we demonstrated that miR-33-5p expressed by osteoblasts is sensitive to multiple mechanical environments, microgravity and fluid shear stress. We then confirmed the ability of miR-33-5p to promote osteoblast differentiation. Microgravity or fluid shear stress influences osteoblast differentiation partially via miR-33-5p. Through bioinformatics analysis and a luciferase assay, we subsequently confirmed that Hmga2 is a target gene of miR-33-5p that negatively regulates osteoblast differentiation. Moreover, miR-33-5p regulates osteoblast differentiation partially via Hmga2. In summary, our findings demonstrate that miR-33-5p is a novel mechano-sensitive miRNA that can promote osteoblast differentiation and participate in the regulation of differentiation induced by changes in the mechanical environment, suggesting this miRNA as a potential target for the treatment of pathological bone loss.
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Affiliation(s)
- Han Wang
- The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Zhongyang Sun
- The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, 710032, Xi'an, Shaanxi, China.,Department of orthopedics, No. 454 Hospital of PLA, 210002, Nanjing, Jiangsu, China
| | - Yixuan Wang
- The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Zebing Hu
- The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Hua Zhou
- The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Lianchang Zhang
- The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Bo Hong
- The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Shu Zhang
- The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Xinsheng Cao
- The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
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Wu J, Wang Y, Xu X, Cao H, Sahengbieke S, Sheng H, Huang Q, Lai M. Transcriptional activation of FN1 and IL11 by HMGA2 promotes the malignant behavior of colorectal cancer. Carcinogenesis 2016; 37:511-21. [PMID: 26964871 DOI: 10.1093/carcin/bgw029] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 03/04/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, and metastasis is the principle reason for its poor prognosis. Overexpression of high-mobility gene group A2 (HMGA2) contributes to the aggressiveness of CRC. However, the underlying molecular mechanism of its overexpression is still elusive. In this study, we showed that ectopic expression of HMGA2 significantly enhanced cell migration and invasion in vitro and promoted tumor growth and distant metastasis in vivo In contrast, the silencing of HMGA2 produced the opposite effects in vitro and in vivo Chromatin immunoprecipitation-PCR and luciferase assays revealed that HMGA2 bound directly to the promoters of FN1 and IL11 and significantly induced their transcriptional activities. Moreover, as the direct downstream target of HMGA2, IL11 modulated cell migration and invasion through a pSTAT3-dependent signaling pathway. Furthermore, a strong positive correlation between HMGA2 and IL11 expression was identified in 122 CRC tissues. High IL11 expression was associated with poor differentiation, a large tumor size, lymph node metastasis and low overall survival in CRC patients. Collectively, our data reveal novel insights into the molecular mechanisms underlying HMGA2-mediated CRC metastasis and highlight the possibility of targeting HMGA2 and IL11 for treating CRC patients with metastasis.
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Affiliation(s)
- Jingjing Wu
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Yuhong Wang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Xi Xu
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Hui Cao
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Sana Sahengbieke
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Hongqiang Sheng
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Qiong Huang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Maode Lai
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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Wu J, Lai M, Shao C, Wang J, Wei JJ. STC2 overexpression mediated by HMGA2 is a biomarker for aggressiveness of high-grade serous ovarian cancer. Oncol Rep 2015; 34:1494-502. [PMID: 26165228 DOI: 10.3892/or.2015.4120] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 06/17/2015] [Indexed: 12/14/2022] Open
Abstract
High-grade serous cancer (HGSC) is a lethal form of ovarian cancer due to invasion and early metastasis. Gain of epithelial-mesenchymal transition (EMT) contributes to the aggressiveness of HGSC. High-mobility gene group A2 (HMGA2), an architectural transcription factor, plays a major role in HGSC through the regulation of EMT gene expression. Based on the gene profiling analysis, we found that the potent EMT gene, stanniocalcin 2 (STC2), was highly correlated with HMGA2 expression. In the present study, we demonstrated that STC2 was directly regulated by HMGA2 at the transcriptional level. Overexpressing STC2 in vitro directly enhanced cell migration and invasion. To investigate the correlation of STC2 and HMGA2 expression and the potential biomarker for ovarian cancer, three independent large cohorts of ovarian cancer (cohort 1=278, cohort 2=150 and cohort 3=95 cases) were examined in the present study. The results showed that the expression of HMGA2 and STC2 was positively correlated. Furthermore, STC2 expression was significantly associated with tumor grade and histotype. HGSC had significantly higher levels of STC2 expression and was inversely correlated with patient survival. These findings suggested that STC2 is an important new biomarker that can be used for HGSC.
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Affiliation(s)
- Jingjing Wu
- Department of Pathology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China
| | - Maode Lai
- Department of Pathology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China
| | - Changshun Shao
- Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA
| | - Jian Wang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Jian-Jun Wei
- Department of Pathology, Northwestern University School of Medicine, Chicago, IL 60611, USA
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Xia YY, Yin L, Tian H, Guo WJ, Jiang N, Jiang XS, Wu J, Chen M, Wu JZ, He X. HMGA2 is associated with epithelial-mesenchymal transition and can predict poor prognosis in nasopharyngeal carcinoma. Onco Targets Ther 2015; 8:169-76. [PMID: 25653540 PMCID: PMC4303461 DOI: 10.2147/ott.s74397] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Objective High-mobility group protein 2 (HMGA2) and epithelial–mesenchymal transition (EMT)-associated proteins play key roles in cancer progression and metastasis. However, the clinical significance of HMGA2 and its relationship with EMT markers in nasopharyngeal carcinoma (NPC) is unclear. This study aimed to assess the clinicopathological significance and prognostic value of HMGA2, E-cadherin, and vimentin in NPC. Methods Using immunohistochemistry, HMGA2, E-cadherin, and vimentin expression levels were evaluated in NPC (n=124) and non-tumoral inflammatory nasopharynx (n=20) tissues. The association of HMGA2 and EMT markers with clinicopathological characteristics and relationships between the protein levels and overall survival were analyzed. Results Compared with non-tumorous tissues, HMGA2 and vimentin levels were markedly increased in NPC tissues, whereas decreased E-cadherin levels were observed (P<0.001). Moreover, HMGA2 expression was positively correlated with vimentin levels (r=0.431, P<0.001) and negatively correlated with E-cadherin amounts (r=−0.413, P<0.001) in NPC tissues. The expression of all three proteins correlated significantly with tumor N stage, TNM stage, and 2-year metastasis. Furthermore, significant correlations were found for T stage, N stage, TNM stage, HMGA2, E-cadherin, and vimentin (all P<0.013) with poor prognosis (univariate analysis). However, multivariate analyses showed that only HMGA2 (hazard ratio [HR]: 2.683, 95% confidence interval [CI]: 1.185–6.077, P=0.018) and N stage (HR: 7.892, 95% CI: 2.731–22.807, P<0.001) were independent predictors of poor prognosis. Conclusion These results demonstrated that HMGA2, an independent prognostic factor, may promote NPC progression and metastasis, and is significantly associated with EMT proteins. Therefore, HMGA2 may be considered a potential therapeutic target in NPC.
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Affiliation(s)
- You-You Xia
- The Fourth Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Li Yin
- Department of Radiation Oncology, The Affiliated Jiangsu Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Hao Tian
- The Fourth Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Wen-Jie Guo
- Department of Radiation Oncology, The Affiliated Jiangsu Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Ning Jiang
- Department of Radiation Oncology, The Affiliated Jiangsu Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Xue-Song Jiang
- Department of Radiation Oncology, The Affiliated Jiangsu Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Jing Wu
- The Fourth Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Meng Chen
- The Fourth Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Jian-Zhong Wu
- Research Center of Clinical Oncology, The Affiliated Jiangsu Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Xia He
- Department of Radiation Oncology, The Affiliated Jiangsu Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
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Li L, Zhang J, Weng X, Wen G. Genetic variations in monocyte chemoattractant protein-1 and susceptibility to ovarian cancer. Tumour Biol 2015; 36:233-238. [PMID: 25234717 DOI: 10.1007/s13277-014-2619-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 09/09/2014] [Indexed: 11/27/2022] Open
Abstract
Monocyte chemoattractant protein-1 (MCP-1) is a chemokine which plays critical roles in regulating host immune responses. Researches have shown that MCP-1 may greatly participate in the development of different cancers. In the current study, we investigated the effect of MCP-1 on ovarian cancer by examining the association between MCP-1 genetic polymorphisms and the susceptibility to ovarian cancer. MCP-1 -2158A/G and MCP-1 -362C/G polymorphisms were examined in ovarian cancer patients and healthy controls by using polymerase chain reaction-restriction fragment length polymorphism analysis. Results showed that percentages of MCP-1 -2158GG genotype and G allele were significantly higher in ovarian cancer patients than in controls (odd ratio (OR) = 1.87; 95 % confidence interval (CI), 1.19-2.76; P = 0.012 and OR = 1.47; 95 % CI, 1.11-1.79; P = 0.003; data were adjusted for age and smoking status). The MCP-1 -362GG genotype also revealed increased number in patients. Stratification analyses presented that ovarian cancer cases with serous-papillary type had significantly increased percentage of -362GG genotype than those with other types (13.1 versus 5.0 %, P = 0.032; data were adjusted for age and smoking status). Also, we evaluated the relation between these two polymorphisms and serum level of MCP-1. We identified that the subjects with MCP-1 -2158AG and GG genotypes had clearly increased serum level of MCP-1 than those with AA genotype. These data suggest that MCP-1 may be involved in the pathogenesis of ovarian cancer.
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Affiliation(s)
- Li Li
- Department of Gynaecology, Affiliated Tumor Hospital, Xinjiang Medical University, Urumqi, Xinjiang, 830011, China
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Liu H, Li P, Li B, Sun P, Zhang J, Wang B, Jia B. RKIP inhibits gastric cancer cell survival and invasion by regulating the expression of HMGA2 and OPN. Tumour Biol 2014; 35:11949-58. [PMID: 25172097 DOI: 10.1007/s13277-014-2486-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 08/08/2014] [Indexed: 12/28/2022] Open
Abstract
The objective of this study was to explore the mechanism via which Raf kinase inhibitor protein (RKIP) suppresses the invasion of gastric cancer cells and promote apoptosis, with an attempt to provide evidences for the application of RKIP in treating gastric cancer. The recombinant plasmid pcDNA3.1-RKIP or RKIP-shRNA was transfected into the gastric cancer cell line SGC-7901 using liposome. Then, the messenger RNA (mRNA) and protein expressions of RKIP, HMGA2, and OPN were detected using qPCR and Western blotting. The effects of HMGA2 on the proliferation, apoptosis, and invasion of SGC-7901 cells were detected using flow cytometry and Transwell assay. To further explore the regulatory effect of PKIP on the biological activities of HMGA2, we over-expressed or knock down RKIP and HMGA2 simultaneously and detected its effects on the proliferation, apoptosis, and invasion of SGC-7901 cells. As shown by qPCR and Western blotting, after over-expression of RKIP in SGC-7901 cells, the mRNA and protein expressions of RKIP significantly increased (P < 0.01), whereas the mRNA and protein expressions of HMGA2 and OPN significantly decreased (P < 0.01). In contrast, the transfection of RKIP-shRNA in the SGC-7901 cells resulted in opposite results. After over-expression of HMGA2 in SGC-7901 cells, the protein expression of HMGA2 significantly increased (P < 0.01); however, it significantly decreased after the transfection of HMGA2-shRNA (P < 0.01). As shown by Transwell assay and flow cytometry, After the over-expression of HMGA2 in SGC-7901 cells, the (G2 + S) phase fraction significantly increased (P < 0.01); also, the percentage of the apoptotic cells significantly declined (P < 0.05) and the number of invasive cells significantly increased (P < 0.05). However, the interference of the expression of HMGA2 resulted in opposite results. The simultaneous over-expression of RKIP and HMGA2 in SGC-7901 cells or the simultaneous interference of RKIP and HMGA2 showed no significant difference with the control group in terms of (G2 + S) phase fraction, percentage of apoptotic cells, and number of invasive cells (P > 0.05). In conclusion, RKIP can inhibit the survival and invasion of gastric cancer cells and promote apoptosis, possibly by regulating the expression of HMGA2 or OPN.
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Affiliation(s)
- Hongyi Liu
- Department of Surgical Oncology, General Hospital of Chinese People's Liberation Army, No. 28, Fuxing Rd, Beijing, 100853, People's Republic of China
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