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Šafanda A, Kendall Bártů M, Michálková R, Švajdler M, Shatokhina T, Laco J, Matěj R, Méhes G, Drozenová J, Hausnerová J, Špůrková Z, Škarda J, Hácová M, Náležinská M, Dundr P, Němejcová K. The role of stathmin expression in the differential diagnosis, prognosis, and potential treatment of ovarian sex cord-stromal tumors. Diagn Pathol 2024; 19:118. [PMID: 39215355 PMCID: PMC11363365 DOI: 10.1186/s13000-024-01541-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Stathmin, a cytosolic microtubule-destabilizing phosphoprotein involved in the regulation of mitosis, is widely expressed in various malignancies and acts as an adverse prognostic factor. Our research analyzed its immunohistochemical expression on a large cohort of ovarian sex cord-stromal tumors, evaluating its potential utility in differential diagnosis, prognosis, and therapeutic application. METHODS We examined 390 cases of ovarian sex cord-stromal tumors including 281 adult granulosa cell tumors (AGCT), 5 juvenile granulosa cell tumors (JGCT), 33 Sertoli-Leydig cell tumors (SLCT), 50 fibromas/thecomas (F/T), 11 Leydig cell tumors/steroid cell tumors (LCT/SterCT), 5 sex-cord stromal tumors NOS (SCST-NOS), 3 Sertoli cell tumors (SCT), and 2 sclerosing stromal tumors (ScST). Immunohistochemical analysis was performed using TMAs. RESULTS Strong expression (> 50%) was observed in all cases of AGCT, JGCT, SLCT, SCST-NOS, SCT and 1 ScST. The other case of ScST exhibited mild expression (5-10%). The negative cases included exclusively F/T and LCT/SterCT, with F/T showing 24% of negative cases and LCT/SterCT comprising 64% of negative cases. CONCLUSION The results of our study indicate that stathmin is neither a prognostic marker nor suitable for the differential diagnosis of challenging cases of ovarian sex cord-stromal tumors. However, its predictive value may be theoretically significant, as a decrease in stathmin expression potentialy influences response to chemotherapy treatment.
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Affiliation(s)
- Adam Šafanda
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, Prague 2, 12800, Czech Republic
| | - Michaela Kendall Bártů
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, Prague 2, 12800, Czech Republic
| | - Romana Michálková
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, Prague 2, 12800, Czech Republic
| | - Marián Švajdler
- Šikl's Department of Pathology, The Faculty of Medicine, Faculty Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Tetiana Shatokhina
- Department of Oncological Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Jan Laco
- The Fingerland Department of Pathology, Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Radoslav Matěj
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, Prague 2, 12800, Czech Republic
- Department of Pathology, Charles University 3rd Faculty of Medicine, University Hospital Královské Vinohrady, Prague, 10034, Czech Republic
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University, Thomayer University Hospital, Prague, Czech Republic
| | - Gábor Méhes
- Department of Pathology, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Jana Drozenová
- Department of Pathology, Charles University 3rd Faculty of Medicine, University Hospital Královské Vinohrady, Prague, 10034, Czech Republic
| | - Jitka Hausnerová
- Department of Pathology, University Hospital Brno and Medical Faculty, Masaryk University, Brno, Czech Republic
| | - Zuzana Špůrková
- Department of Pathology, Bulovka University Hospital, Prague, Czech Republic
| | - Jozef Škarda
- Department of Pathology, University Hospital Ostrava and Faculty of Medicine University of Ostrava, Ostrava, Czech Republic
| | - Mária Hácová
- Department of Pathology, The Regional Hospital Pardubice, Pardubice, Czech Republic
| | - Monika Náležinská
- Division of Gynecologic Oncology, Department of Surgical Oncology, Masaryk Memorial Cancer Institute and Medical Faculty of Masaryk University, Brno, Czech Republic
| | - Pavel Dundr
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, Prague 2, 12800, Czech Republic
| | - Kristýna Němejcová
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, Prague 2, 12800, Czech Republic.
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Lombardo C, Broggi G, Vitale E, Ledda C, Loreto C, Matera S, Hagnas M, Caltabiano R, Filetti V. Expression of stathmin in asbestos-like fibers-induced mesothelioma: A preliminary report. Histol Histopathol 2023; 38:1249-1256. [PMID: 37466108 DOI: 10.14670/hh-18-649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
BACKGROUND Mesothelioma is strongly associated with exposure to asbestos fibers, however, recent studies have also linked exposure to "naturally occurring asbestos" fibers with this disease. Fluoro-edenite, a silicate mineral found in the southeast of Biancavilla (Sicily, Italy), has been identified as a potential risk factor for mesothelioma. Unfortunately, this cancer often has a poor prognosis, and current diagnostic and prognostic biomarkers are inadequate. Histological subtype, gender, and age at diagnosis are the most significant parameters for mesothelioma. Stathmin, a cytosolic protein that regulates cell growth and migration and is overexpressed in many human malignancies, has not yet been linked to mesothelioma survival or clinical-pathological variables. AIM The aim of this study was to investigate the immunohistochemical expression of stathmin in ten mesothelioma tissue samples with available clinical and follow-up data. MATERIAL AND METHODS Paraffin-embedded tissue samples from ten mesothelioma patients were processed for immunohistochemical analyses to evaluate stathmin expression. RESULTS Our findings suggest that stathmin overexpression is associated with shorter overall survival in patients with mesothelioma. Furthermore, stathmin expression was significantly correlated with the survival time of mesothelioma patients. CONCLUSION Our results suggest that stathmin expression may serve as a potential prognostic biomarker for mesothelioma. This biomarker could be used to promptly identify patients with poor prognosis and to guide clinicians in the selection of treatment options.
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Affiliation(s)
- Claudia Lombardo
- Department of Biomedical and Biotechnology Sciences, Section of Human Anatomy, Histology and Sciences of Movement, University of Catania, Catania, Italy
| | - Giuseppe Broggi
- Department of Medical and Surgical Sciences and Advanced Technologies, "G.F. Ingrassia", Anatomic Pathology, University of Catania, Catania, Italy
| | - Ermanno Vitale
- Department of Clinical and Experimental Medicine, Section of Occupational Medicine, University of Catania, Catania, Italy.
| | - Caterina Ledda
- Department of Clinical and Experimental Medicine, Section of Occupational Medicine, University of Catania, Catania, Italy
| | - Carla Loreto
- Department of Biomedical and Biotechnology Sciences, Section of Human Anatomy, Histology and Sciences of Movement, University of Catania, Catania, Italy
| | - Serena Matera
- Department of Clinical and Experimental Medicine, Section of Occupational Medicine, University of Catania, Catania, Italy
| | - Maria Hagnas
- Rovaniemi Health Center, Rovaniemi, Finland
- Center for Life Course Health Research, University of Oulu, Oulu, Finland
| | - Rosario Caltabiano
- Department of Medical and Surgical Sciences and Advanced Technologies, "G.F. Ingrassia", Anatomic Pathology, University of Catania, Catania, Italy
| | - Veronica Filetti
- Department of Biomedical and Biotechnology Sciences, Section of Human Anatomy, Histology and Sciences of Movement, University of Catania, Catania, Italy
- Department of Clinical and Experimental Medicine, Section of Occupational Medicine, University of Catania, Catania, Italy
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Ogushi K, Yokobori T, Nobusawa S, Shirakura T, Hirato J, Erkhem-Ochir B, Okami H, Dorjkhorloo G, Nishi A, Suzuki M, Otake S, Saeki H, Shirabe K. High Tumoral STMN1 Expression Is Associated with Malignant Potential and Poor Prognosis in Patients with Neuroblastoma. Cancers (Basel) 2023; 15:4482. [PMID: 37760452 PMCID: PMC10526320 DOI: 10.3390/cancers15184482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Stathmin 1 (STMN1), a marker for immature neurons and tumors, controls microtubule dynamics by destabilizing tubulin. It plays an essential role in cancer progression and indicates poor prognosis in several cancers. This potential protein has not been clarified in clinical patients with neuroblastoma. Therefore, this study aimed to assess the clinical significance and STMN1 function in neuroblastoma with and without MYCN amplification. METHODS Using immunohistochemical staining, STMN1 expression was examined in 81 neuroblastoma samples. Functional analysis revealed the association among STMN1 suppression, cellular viability, and endogenous or exogenous MYCN expression in neuroblastoma cell lines. RESULT High levels of STMN1 expression were associated with malignant potential, proliferation potency, and poor prognosis in neuroblastoma. STMN1 expression was an independent prognostic factor in patients with neuroblastoma. Furthermore, STMN1 knockdown inhibited neuroblastoma cell growth regardless of endogenous and exogenous MYCN overexpression. CONCLUSION Our data suggest that assessing STMN1 expression in neuroblastoma could be a powerful indicator of prognosis and that STMN1 might be a promising therapeutic candidate against refractory neuroblastoma with and without MYCN amplification.
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Affiliation(s)
- Kenjiro Ogushi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan; (K.O.); (H.O.); (G.D.); (M.S.); (S.O.); (H.S.); (K.S.)
| | - Takehiko Yokobori
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan; (K.O.); (H.O.); (G.D.); (M.S.); (S.O.); (H.S.); (K.S.)
- Division of Integrated Oncology Research, Initiative for Advanced Research (GIAR), Gunma University, Maebashi 371-8511, Japan;
| | - Sumihito Nobusawa
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (S.N.); (T.S.)
| | - Takahiro Shirakura
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (S.N.); (T.S.)
| | - Junko Hirato
- Department of Pathology, Public Tomioka General Hospital, Tomioka 370-2393, Japan;
| | - Bilguun Erkhem-Ochir
- Division of Integrated Oncology Research, Initiative for Advanced Research (GIAR), Gunma University, Maebashi 371-8511, Japan;
| | - Haruka Okami
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan; (K.O.); (H.O.); (G.D.); (M.S.); (S.O.); (H.S.); (K.S.)
| | - Gendensuren Dorjkhorloo
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan; (K.O.); (H.O.); (G.D.); (M.S.); (S.O.); (H.S.); (K.S.)
| | - Akira Nishi
- Department of Surgery, Gunma Children’s Medical Center, Shibukawa 377-8577, Japan;
| | - Makoto Suzuki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan; (K.O.); (H.O.); (G.D.); (M.S.); (S.O.); (H.S.); (K.S.)
- Department of Surgery, Iwate Medical University School of Medicine, Morioka 028-3695, Japan
| | - Sayaka Otake
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan; (K.O.); (H.O.); (G.D.); (M.S.); (S.O.); (H.S.); (K.S.)
| | - Hiroshi Saeki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan; (K.O.); (H.O.); (G.D.); (M.S.); (S.O.); (H.S.); (K.S.)
| | - Ken Shirabe
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan; (K.O.); (H.O.); (G.D.); (M.S.); (S.O.); (H.S.); (K.S.)
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Liu R, Liang X, Guo H, Li S, Yao W, Dong C, Wu J, Lu Y, Tang J, Zhang H. STNM1 in human cancers: role, function and potential therapy sensitizer. Cell Signal 2023:110775. [PMID: 37331415 DOI: 10.1016/j.cellsig.2023.110775] [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: 04/19/2023] [Revised: 05/23/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023]
Abstract
STMN1 belongs to the stathmin gene family, it encodes a cytoplasmic phosphorylated protein, stathmin1, which is commonly observed in vertebrate cells. STMN1 is a structural microtubule-associated protein (MAP) that binds to microtubule protein dimers rather than microtubules, with each STMN1 binding two microtubule protein dimers and preventing their aggregation, leading to microtubule instability. STMN1 expression is elevated in a number of malignancies, and inhibition of its expression can interfere with tumor cell division. Its expression can change the division of tumor cells, thereby arresting cell growth in the G2/M phase. Moreover, STMN1 expression affects tumor cell sensitivity to anti-microtubule drug analogs, including vincristine and paclitaxel. The research on MAPs is limited, and new insights on the mechanism of STMN1 in different cancers are emerging. The effective application of STMN1 in cancer prognosis and treatment requires further understanding of this protein. Here, we summarize the general characteristics of STMN1 and outline how STMN1 plays a role in cancer development, targeting multiple signaling networks and acting as a downstream target for multiple microRNAs, circRNAs, and lincRNAs. We also summarize recent findings on the function role of STMN1 in tumor resistance and as a therapeutic target for cancer.
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Affiliation(s)
- Ruiqi Liu
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China; Graduate Department, Bengbu Medical College, Bengbu, Anhui, China
| | - Xiaodong Liang
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China; Graduate Department, Bengbu Medical College, Bengbu, Anhui, China
| | - Haiwei Guo
- Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Shuang Li
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Weiping Yao
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China; Graduate Department, Bengbu Medical College, Bengbu, Anhui, China
| | - Chenfang Dong
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China; Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiajun Wu
- Graduate Department, Bengbu Medical College, Bengbu, Anhui, China; Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Yanwei Lu
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jianming Tang
- Department of Radiation Oncology, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Haibo Zhang
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou Medical College, Hangzhou, Zhejiang, China.
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Zhou X, Yang C, Li Y, Chen D, Wang T, Liu T, Yan W, Su Z, Peng B, Ren X. Cordycepin reprogramming lipid metabolism to block metastasis and EMT via ERO1A/mTOR/SREBP1 axis in cholangiocarcinoma. Life Sci 2023:121698. [PMID: 37080351 DOI: 10.1016/j.lfs.2023.121698] [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: 12/19/2022] [Revised: 03/30/2023] [Accepted: 04/10/2023] [Indexed: 04/22/2023]
Abstract
Cholangiocarcinoma (CCA) with a high malignancy is usually diagnosed as advanced and is prone to metastasis and leads to a poor prognosis. It is reported that cordycepin has anti-tumor effect. However, the molecular targets and mechanisms of cordycepin in inhibiting CCA metastasis remains unclear. In order to evaluate the therapeutic effect of cordycepin on CCA metastasis, experiments were conducted in vivo and in vitro. The results showed that cordycepin inhibited the migration and EMT progression of HuCCT1 and QBC939 cells. Cordycepin has a strong hypolipidemic effects, therefore, we examined its effect on lipid metabolism in CCA. Cordycepin inhibits SREBP1 mediated fatty acid synthesis through the AKT/mTOR signaling pathway. Meanwhile, cordycepin can reduce ERO1A expression in HuCCT1 and QBC939 cells. ERO1A plays a role in malignant tumors. ERO1A promotes migration and lipid metabolism of CCA cells through AKT/mTOR signaling pathway. In addition, cordycepin significantly inhibited the tumor metastasis and the serum levels of TG and T-CHO in mice. Taken together, we demonstrate that cordycepin mediated ERO1A/mTOR/SREBP1 axis inhibits lipid metabolism and metastasis in CCA cells in vitro and in vivo. These data suggest that cordycepin can be used as a novel drug for the clinical treatment of CCA and to improve the prognosis.
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Affiliation(s)
- Xuebing Zhou
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji, China
| | - Chunyu Yang
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji, China
| | - Yuan Li
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji, China
| | - Dan Chen
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji, China
| | - Tong Wang
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji, China
| | - Tesi Liu
- Otorhinolaryngology Institute at Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Wendi Yan
- Department of Pathology of Jilin Cancer Hospital, Jilin, china
| | - Zhaoxia Su
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji, China
| | - Bosen Peng
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji, China
| | - Xiangshan Ren
- Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji, China; Key Laboratory of Pathobiology, Yanbian University, State Ethnic Affairs Commission, Yanji, China.
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Němejcová K, Šafanda A, Bártů MK, Michálková R, Drozenová J, Fabian P, Hausnerová J, Laco J, Matěj R, Méhes G, Škapa P, Stružinská I, Dundr P. A comprehensive immunohistochemical analysis of 26 markers in 250 cases of serous ovarian tumors. Diagn Pathol 2023; 18:32. [PMID: 36855066 PMCID: PMC9972686 DOI: 10.1186/s13000-023-01317-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 02/18/2023] [Indexed: 03/02/2023] Open
Abstract
BACKGROUND We examined a large cohort of serous tubo-ovarian tumors with 26 immunohistochemical markers, with the aim to assess their value for differential diagnosis and prognosis. METHODS Immunohistochemical analyses with 26 immunomarkers were performed on 250 primary tubo-ovarian tumors including 114 high grade serous carcinomas (HGSC), 97 low grade serous carcinomas (LGSC), and 39 serous borderline tumors (micropapillary variant, mSBT). The associations of overall positivity with clinicopathological characteristics were evaluated using the chi-squared test or Fisher's Exact test. RESULTS We found significantly different expression of p53, p16, ER, PR, PTEN, PAX2, Mammaglobin, RB1, Cyclin E1, stathmin, LMP2, L1CAM, CD44, and Ki67 in HGSCs compared to LGSCs. No significant differences were found between LGSC and mSBT. None of the other included markers (PAX8, ARID1A, HNF1B, Napsin A, CDX2, SATB2, MUC4, BRG1, AMACR, TTF1, BCOR, NTRK) showed any differences between the investigated serous tumors. Regarding the prognosis, only PR and stathmin showed a statistically significant prognostic meaning in LGSCs, with better overall survival (OS) and recurrence-free survival (RFS) in cases positive for PR, and worse outcome (RFS) for stathmin. None of the study markers showed prognostic significance in HGSCs. CONCLUSION We provided an extensive immunohistochemical analysis of serous ovarian/tubo-ovarian tumors. Although we found some differences in the expression of some markers in HGSCs compared to LGSCs, only p53, p16, and Ki67 seem to be useful in real diagnostic practice. We also suggested the best discriminative cut-off for Ki67 (10% of positive tumor cells) for distinguishing HGSC from LGSC. We found prognostic significance of PR and stathmin in LGSCs. Moreover, the high expression of stathmin could also be of predictive value in ovarian carcinomas as target-specific anti-stathmin effectors are potential therapeutic targets.
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Affiliation(s)
- Kristýna Němejcová
- Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12800, Prague, Czech Republic.
| | - Adam Šafanda
- grid.411798.20000 0000 9100 9940Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12800 Prague, Czech Republic
| | - Michaela Kendall Bártů
- grid.411798.20000 0000 9100 9940Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12800 Prague, Czech Republic
| | - Romana Michálková
- grid.411798.20000 0000 9100 9940Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12800 Prague, Czech Republic
| | - Jana Drozenová
- grid.4491.80000 0004 1937 116XDepartment of Pathology, Charles University, 3rd Faculty of Medicine, University Hospital Královské Vinohrady, 10034 Prague, Czech Republic
| | - Pavel Fabian
- grid.419466.8Department of Oncological Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Jitka Hausnerová
- grid.10267.320000 0001 2194 0956Department of Pathology, University Hospital Brno and Medical Faculty, Masaryk University, Brno, Czech Republic
| | - Jan Laco
- grid.4491.80000 0004 1937 116XThe Fingerland Department of Pathology, Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Radoslav Matěj
- grid.411798.20000 0000 9100 9940Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12800 Prague, Czech Republic ,grid.4491.80000 0004 1937 116XDepartment of Pathology, Charles University, 3rd Faculty of Medicine, University Hospital Královské Vinohrady, 10034 Prague, Czech Republic ,grid.4491.80000 0004 1937 116XDepartment of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University, Thomayer University Hospital, Prague, Czech Republic
| | - Gábor Méhes
- grid.7122.60000 0001 1088 8582Department of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Petr Škapa
- grid.412826.b0000 0004 0611 0905Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Ivana Stružinská
- grid.411798.20000 0000 9100 9940Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12800 Prague, Czech Republic
| | - Pavel Dundr
- grid.411798.20000 0000 9100 9940Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12800 Prague, Czech Republic
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Gao X, Zhang W, Jia Y, Xu H, Zhu Y, Pei X. Identification of a prognosis-related ceRNA network in cholangiocarcinoma and potentially therapeutic molecules using a bioinformatic approach and molecular docking. Sci Rep 2022; 12:16247. [PMID: 36171401 PMCID: PMC9519560 DOI: 10.1038/s41598-022-20362-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 09/12/2022] [Indexed: 11/20/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a highly malignant disease with a poor prognosis, and mechanisms of initiation and development are not well characterized. It is long noncoding RNAs (lncRNAs) acting as miRNA decoys to regulate cancer-related RNAs in competing endogenous RNA (ceRNA) networks that suggest a possible molecular mechanism in CCA. The current study aims to find potential prognosis biomarkers and small molecule therapeutic targets based on the construction of a CCA prognosis-related ceRNA network. A transcriptome dataset for CCA was downloaded from the TCGA database. Differentially expressed lncRNAs (DElncRNAs), DEmiRNAs and DEmRNAs were identified based on the differential expression and a DEceRNA network was constructed using predicted miRNA-lncRNA and miRNA-mRNA interactions. Heat maps, PCA analysis, and Pathway enrichment analysis and GO enrichment analysis were conducted. The prognostic risk model and molecular docking were constructed based on identified key ceRNA networks. A DElncRNA-miRNA-mRNAs network consisting of 434 lncRNA-miRNA pairs and 284 miRNA-mRNA pairs with 200 lncRNAs, 21 miRNAs, and 245 mRNAs was constructed. There were three lncRNAs (AC090772.1, LINC00519, and THAP7-AS1) and their downstream mRNAs (MECOM, MBNL3, RCN2) screened out as prognostic factors in CAA. Three key networks (LINC00519/ hsa-mir-22/ MECOM, THAP7-AS1/hsa-mir-155/MBNL3, and THAP7-AS1/hsa-mir-155/RCN2) were identified based on binding sites prediction and survival analysis. A prognostic risk model was established with a good predictive ability (AUC = 0.66–0.83). Four anticancer small molecules, MECOM and 17-alpha-estradiol (−7.1 kcal/mol), RCN2 and emodin (−8.3 kcal/mol), RCN2 and alpha-tocopherol (−5.6 kcal/mol), and MBNL3 and 17-beta-estradiol (−7.1 kcal/mol) were identified. Based on the DEceRNA network and Kaplan–Meier survival analysis, we identified three important ceRNA networks associated with the poor prognosis of CCA. Four anti-cancer small molecules were screened out by computer-assisted drug screening as potential small molecules for the treatment of CCA. This study provides theoretical support for the development of ceRNA network-based drugs to improve the prognosis of CCA.
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Affiliation(s)
- Xiaoling Gao
- The Medical Laboratory Center, Hainan General Hospital, Haikou, 570311, China.
| | - Wenhao Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Yanjuan Jia
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, 730000, China.,The Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, 730000, China.,Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Hui Xu
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, 730000, China.,The Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, 730000, China
| | - Yuchen Zhu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Xiong Pei
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
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Overexpression of Stathmin 1 Predicts Poor Prognosis and Promotes Cancer Cell Proliferation and Migration in Ovarian Cancer. DISEASE MARKERS 2022; 2022:3554100. [PMID: 35186166 PMCID: PMC8849943 DOI: 10.1155/2022/3554100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 01/25/2022] [Accepted: 01/28/2022] [Indexed: 12/12/2022]
Abstract
Purpose The aim of this study was to investigate the expression of stathmin 1 (STMN1) in ovarian cancer and its effect on prognosis. The effect and mechanism of STMN1 on the proliferation and migration of ovarian cancer cells were also investigated. Methods Expression of STMN1 was measured by immunohistochemical staining in ovarian cancer tissues. The effects of STMN1 on the proliferation and migration capacity of ovarian cancer were evaluated using Cell Counting Kit-8 (CCK-8) assays, colony formation assays, immunofluorescence staining, wound healing assays, and Transwell assays. Transcription factors were predicted by bioinformatic analysis of TCGA database. Results STMN1 was upregulated in ovarian cancer tissues as compared to paracancerous tissues and associated with shorter overall survival. STMN1 expression significantly correlated with FIGO staging and tumor differentiation (P < 0.05). Furthermore, STMN1 promoted proliferation and migration in ovarian cancer cell lines. Bioinformatic analysis revealed that STMN1 was potentially regulated by E2F transcription factors. Then, we found that E2F1 regulated the expression of STMN1 and affected proliferation. Conclusion STMN1 is overexpressed in ovarian cancer, and its high expression suggests a poor prognosis. STMN1 promotes the proliferation and migration of ovarian cancer and is regulated by E2F1. Thus, STMN1 may serve as a negative prognostic factor and possible target for the treatment of ovarian cancer patients.
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Liou S, Nilforoushan N, Kang Y, Moatamed NA. p16 is superior to Stathmin-1 and HSP27 in identifying cervical dysplasia. Diagn Pathol 2021; 16:85. [PMID: 34544445 PMCID: PMC8451080 DOI: 10.1186/s13000-021-01144-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 08/26/2021] [Indexed: 11/12/2022] Open
Abstract
Background The aim of this study was to determine how Stathmin-1 and Heat Shock Protein 27 (HSP27) can be used as adjunctive biomarkers to differentiate high-grade dysplasia from benign/reactive lesions in cervical tissues. In addition, we aimed to see if any of these markers can differentiate endometrial from endocervical adenocarcinomas. Methods Fifty cases including benign cervical tissue, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), adenocarcinoma in situ of the endocervix, invasive endocervical adenocarcinoma, and endometrial adenocarcinoma were selected. Stathmin-1 and HSP27 immunohistochemistry (IHC) were performed for each case and the results were compared to the previously available p16 IHC stains. Results p16 stained positively in 100% of HSIL, endocervical adenocarcinoma in situ, and invasive endocervical cases. Stathmin-1 stained positively in 43% of HSIL and 90% of endocervical adenocarcinoma in situ and all invasive endocervical cases. Stathmin-1 and p16 were negative in all benign cervical samples. Stathmin-1, HSP27, and p16 stained 100% of LSIL cases. HSP27 stained indiscriminately, including 100% of benign cervical tissue. 87% of the endometrial adenocarcinomas stained positively for p16, Stathmin-1, and HSP27. Conclusion p16 remains superior to both Stathmin-1 and HSP27 in differentiating dysplasia from benign, reactive changes of the cervix. Supplementary Information The online version contains supplementary material available at 10.1186/s13000-021-01144-w.
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Affiliation(s)
- Sofia Liou
- Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, BOX 951732, 13-145 CHS, Los Angeles, CA, 90095-1732, USA
| | - Neshat Nilforoushan
- Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, BOX 951732, 13-145 CHS, Los Angeles, CA, 90095-1732, USA
| | - Yuna Kang
- Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, BOX 951732, 13-145 CHS, Los Angeles, CA, 90095-1732, USA
| | - Neda A Moatamed
- Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, BOX 951732, 13-145 CHS, Los Angeles, CA, 90095-1732, USA.
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Shi D, Zhang Z, Kong C. CARMA3 Transcriptional Regulation of STMN1 by NF-κB Promotes Renal Cell Carcinoma Proliferation and Invasion. Technol Cancer Res Treat 2021; 20:15330338211027915. [PMID: 34190011 PMCID: PMC8256254 DOI: 10.1177/15330338211027915] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
CARD-containing MAGUK protein 3 (CARMA3) is associated with tumor occurrence and progression. However, the signaling pathways involved in CARMA3 function remain unclear. We aimed to analyze the association between CARMA3 and stathmin (STMN1) through the NF-κB pathway, which is associated with cell proliferation and invasion, in clear cell renal cell carcinoma (ccRCC). We evaluated the effects of CARMA3 and STMN1 expression on cell migration, proliferation, and invasion in various cell lines, and their expression in tissue samples from patients with ccRCC. CARMA3 was highly expressed in ccRCC tissues and cell lines. Moreover, CARMA3 promoted the proliferation and invasion of RCC cells by activating the NF-κB pathway to transcribe STMN1. Stathmin exhibited a consistent profile with CARMA3 in ccRCC tissue, and could be an effector for CARMA3-activated cell proliferation and invasion of ccRCC cells. In summary, CARMA3 may serve as a promising target for ccRCC treatment.
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Affiliation(s)
- Du Shi
- Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhe Zhang
- Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chuize Kong
- Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Thongchot S, Vidoni C, Ferraresi A, Loilome W, Khuntikeo N, Sangkhamanon S, Titapun A, Isidoro C, Namwat N. Cancer-Associated Fibroblast-Derived IL-6 Determines Unfavorable Prognosis in Cholangiocarcinoma by Affecting Autophagy-Associated Chemoresponse. Cancers (Basel) 2021; 13:cancers13092134. [PMID: 33925189 PMCID: PMC8124468 DOI: 10.3390/cancers13092134] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary We aimed to validate with clinical and molecular data the hypothesis that CAF infiltration and release of IL-6 predict poor prognosis in CCA patients following dysregulation of autophagy in cancer cells. Stromal IL-6 and cancer-cell-associated autophagy proteins were assayed by Tissue MicroArray immunohistochemistry and their expression correlated with overall survival (OS) in a cohort of 70 CCA patients. We found that patients bearing a CCA with low stromal IL-6 and active autophagy flux in the cancer cells have the best prognosis and this correlates with a more effective response to post-operative chemotherapy. A similar trend was observed in CCA patients from the TCGA database. In vitro experiments with primary CAFs isolated from human CCA showed that IL-6 impairs the autophagy-associated apoptotic response to 5-FU in human CCA cells. Stromal IL-6 inhibition of autophagy in cancer cells was confirmed in an animal model of CCA. Our data support a therapeutic strategy that includes drugs limiting the stromal inflammation and enhancing autophagy to improve the survival of CCA patients. Abstract Background: Interleukin-6 (IL-6) released by cancer-associated fibroblasts (CAFs) has been shown to associate with the malignant behavior of cholangiocarcinoma (CCA). Here, we aimed to validate with clinical and molecular data the hypothesis that CAF infiltration and release of IL-6 predict poor prognosis in CCA patients following dysregulation of autophagy in cancer cells. Methods: Stromal IL-6 and cancer-cell-associated autophagy proteins LC3 and p62 were assayed by Tissue MicroArray immunohistochemistry and their expression correlated with overall survival (OS) in a cohort of 70 CCA patients. The 5-FU cytotoxicity and autophagy were determined in CCA cells cultured with CAF-conditioned medium. Results: We show that patients bearing a CCA with low production of stromal IL-6 and active autophagy flux in the cancer cells have the best prognosis and this correlates with a more effective response to post-operative chemotherapy. A similar trend was observed in CCA patients from the TCGA database. In vitro genetic manipulation of IL-6 production by primary CAFs isolated from human CCA showed that IL-6 impairs the autophagy-associated apoptotic response to 5-FU in human CCA cells. Stromal IL-6 inhibition of autophagy in cancer cells was confirmed in an animal model of CCA. Conclusion: Our data support a therapeutic strategy that includes autophagy-enhancing drugs along with adjuvants limiting the stromal inflammation (i.e., the secretion of IL-6) to improve the survival of CCA patients.
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Affiliation(s)
- Suyanee Thongchot
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (S.T.); (W.L.)
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, Italy; (C.V.); (A.F.)
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Chiara Vidoni
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, Italy; (C.V.); (A.F.)
| | - Alessandra Ferraresi
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, Italy; (C.V.); (A.F.)
| | - Watcharin Loilome
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (S.T.); (W.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (N.K.); (S.S.); (A.T.)
| | - Narong Khuntikeo
- Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (N.K.); (S.S.); (A.T.)
- Department of Surgery, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand
| | - Sakkarn Sangkhamanon
- Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (N.K.); (S.S.); (A.T.)
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand
| | - Attapol Titapun
- Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (N.K.); (S.S.); (A.T.)
- Department of Surgery, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand
| | - Ciro Isidoro
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, Italy; (C.V.); (A.F.)
- Correspondence: (C.I.); (N.N.); Tel.: +39-(0321)-660507 (C.I.); +66-6-3635-2491 (N.N.)
| | - Nisana Namwat
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (S.T.); (W.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (N.K.); (S.S.); (A.T.)
- Correspondence: (C.I.); (N.N.); Tel.: +39-(0321)-660507 (C.I.); +66-6-3635-2491 (N.N.)
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Wang J, Ni X, Shen S, Zhang D, Ni X, Suo T, Lu P, Fan K, Liu H, Liu H. Phosphorylation at Ser10 triggered p27 degradation and promoted gallbladder carcinoma cell migration and invasion by regulating stathmin1 under glucose deficiency. Cell Signal 2021; 80:109923. [PMID: 33444777 DOI: 10.1016/j.cellsig.2021.109923] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/07/2021] [Accepted: 01/08/2021] [Indexed: 10/22/2022]
Abstract
Gallbladder carcinoma (GBC) is a considerable challenge because of its high metastatic potential. The tumor microenvironment is characterized by nutrient starvation, which promotes tumor metastasis. Stathmin1, an important microtubuleregulating protein, is overexpressed and promotes metastasis in GBC. It remains unclear how the harsh tumor microenvironment regulates stathmin1 expression to affect GBC metastasis. We employed glucose deficiency to mimic nutrient starvation and found that glucose deficiency upregulated stathmin1 transcription. However, glucose deficiency also promoted p27 degradation. There was a significant negative correlation between stathmin1 and p27 protein levels under glucose deficiency. Further study revealed that, under glucose deficiency, human kinase interacting with stathmin (hKIS) induced phosphorylation at Ser10 of p27 and its translocation to the cytoplasm for degradation, which upregulated the transcription factor E2F1 to promote stathmin1 transcription. hKIS knockdown significantly inhibited p27 cytoplasmic translocation and its consequent degradation. Stathmin1 knockdown significantly inhibited GBC cell migration and invasion in vitro. Our study revealed the role of the hKIS/p27/E2F1 axis in upregulating stathmin1 transcription to promote GBC cell migration and invasion under glucose deficiency conditions.
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Affiliation(s)
- Jiwen Wang
- Department of General Surgery, Zhongshan Hospital, General Surgery Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, ZhongShan Hospital, Fudan University, Shanghai 200032, China
| | - Xiaojian Ni
- Department of General Surgery, Zhongshan Hospital, General Surgery Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, ZhongShan Hospital, Fudan University, Shanghai 200032, China
| | - Sheng Shen
- Department of General Surgery, Zhongshan Hospital, General Surgery Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, ZhongShan Hospital, Fudan University, Shanghai 200032, China
| | - Dexiang Zhang
- General Surgery Department, Zhongshan-Xuhui Hospital Affiliated to Fudan University, Shanghai 200031, China
| | - Xiaoling Ni
- Department of General Surgery, Zhongshan Hospital, General Surgery Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, ZhongShan Hospital, Fudan University, Shanghai 200032, China
| | - Tao Suo
- Department of General Surgery, Zhongshan Hospital, General Surgery Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, ZhongShan Hospital, Fudan University, Shanghai 200032, China
| | - Pinxiang Lu
- General Surgery Department, Zhongshan-Xuhui Hospital Affiliated to Fudan University, Shanghai 200031, China
| | - Kun Fan
- Department of General Surgery, Zhongshan Hospital, General Surgery Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, ZhongShan Hospital, Fudan University, Shanghai 200032, China; General Surgery Department, Zhongshan-Xuhui Hospital Affiliated to Fudan University, Shanghai 200031, China.
| | - Han Liu
- Department of General Surgery, Zhongshan Hospital, General Surgery Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, ZhongShan Hospital, Fudan University, Shanghai 200032, China.
| | - Houbao Liu
- Department of General Surgery, Zhongshan Hospital, General Surgery Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, ZhongShan Hospital, Fudan University, Shanghai 200032, China.
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Zhang J, Li A, Sun H, Xiong X, Qin S, Wang P, Dai L, Zhang Z, Li X, Liu Z. Amentoflavone triggers cell cycle G2/M arrest by interfering with microtubule dynamics and inducing DNA damage in SKOV3 cells. Oncol Lett 2020; 20:168. [PMID: 32934735 PMCID: PMC7471765 DOI: 10.3892/ol.2020.12031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 07/14/2020] [Indexed: 12/19/2022] Open
Abstract
Ovarian cancer is the seventh most common cancer and the second most common cause of cancer-associated mortality among gynecological malignancies worldwide. The combination of antimitotic agents, such as taxanes, and the DNA-damaging agents, such as platinum compounds, is the standard treatment for ovarian cancer. However, due to chemoresistance, development of novel therapeutic strategies for the treatment of ovarian cancer remains critical. Amentoflavone (AMF) is a biflavonoid derived from the extracts of Selaginella tamariscina, which has been used as a Chinese herb for thousands of years. A previous study demonstrated that AMF inhibits angiogenesis of endothelial cells and induces apoptosis in hypertrophic scar fibroblasts. In order to check the influence of AMF on cell proliferation, the effects of AMF on cell cycle and DNA damage were measured by cell viability, flow cytometry, immunofluorescence and western blotting assays in SKOV3 cells, an ovarian cell line. In the present study, treatment with AMF inhibited ovarian cell proliferation, increased P21 expression, decreased CDK1/2 expression, interrupted the balance of microtubule dynamics and arrested cells at the G2 phase. Furthermore, treatment with AMF increased the expression levels of phospho-Histone H2AX (γ-H2AX; a variant of histone 2A, that belongs to the histone 2A family member X) and the DNA repair protein RAD51 homolog 1 (Rad51), indicating the occurrence of DNA damage since γ-H2AX and Rad51 are both key markers of DNA damage. Consistent with previous findings, the results of the present study suggest that AMF is a potential therapeutic agent for the treatment of ovarian cancer. In addition, the effects of AMF on cell cycle arrest and DNA damage induction may be the molecular mechanisms by which AMF might exert its potential therapeutic benefits in ovarian cancer.
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Affiliation(s)
- Jinli Zhang
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Aiguo Li
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Hanjing Sun
- Department of Traditional Chinese Medicine, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Xifeng Xiong
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Shengnan Qin
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Pengzhen Wang
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Libing Dai
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Zhi Zhang
- Department of Burn and Plastic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Xiaojian Li
- Department of Burn and Plastic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Zhihe Liu
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong 510220, P.R. China
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Molecular Evolution and Characterization of Fish Stathmin Genes. Animals (Basel) 2020; 10:ani10081328. [PMID: 32752168 PMCID: PMC7460142 DOI: 10.3390/ani10081328] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/21/2020] [Accepted: 07/29/2020] [Indexed: 11/25/2022] Open
Abstract
Simple Summary Stathmin is a highly conserved microtubule remodeling protein. Here, 175 putative stathmin genes were identified in 27 species of fish. Gene organization, motif distribution, divergence of duplicated genes, functional divergence, synteny relationship, and protein-protein interaction were performed to investigate their evolutionary history. In addition, expression profiles of some stathmins were examined under dimethoate treatment. The results will provide useful references for further functional analyses. Abstract Stathmin is a highly conserved microtubule remodeling protein, involved in many biological processes such as signal transduction, cell proliferation, neurogenesis and so on. However, little evolutional information has been reported about this gene family in fish. In this study, 175 stathmin genes were identified in 27 species of fish. Conserved exon-intron structure and motif distributions were found in each group. Divergence of duplicated genes implied the species’ adaptation to the environment. Functional divergence suggested that the evolution of stathmin is mainly influenced by purifying selection, and some residues may undergo positive selection. Moreover, synteny relationship near the stathmin locus was relatively conserved in some fish. Network analyses also exhibited 74 interactions, implying functional diversity. The expression pattern of some stathmin genes was also investigated under pesticide stress. These will provide useful references for their functional research in the future.
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Alabiad MA, Harb OA, Abdelfattah MT, El-Shafaay BS, El-Taher AK, El-Hendawy EI. The values of Transgelin, Stathmin, BCOR and Cyclin-D1 expression in differentiation between Uterine Leiomyosarcoma (ULMS) and Endometrial Stromal Sarcoma (ESS); diagnostic and prognostic implications. SURGICAL AND EXPERIMENTAL PATHOLOGY 2020. [DOI: 10.1186/s42047-020-00065-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Morphologic distinction between uterine leiomyosarcoma (ULMS) and endometrial stromal sarcoma (ESS) alone is not straightforward and has been shown to be challenging especially with poor differentiation, so immunohistochemistry (IHC) is often employed as an adjunct to morphology in uterine sarcoma.
Aim
We aimed to assess the diagnostic utility of Transgelin, Stathmin, BCOR and Cyclin-D1 separately and in-combinations in distinguishing ULMS from ESS, and to evaluate their prognostic value in patients with such sarcoma subtypes.
Material and Methods
We included 44 patients with uterine sarcoma. The diagnostic performances of Transgelin, Stathmin, BCOR and Cyclin-D1 were assessed in samples from all patients using immunohistochemistry.
Results
The combination of Stathmin and Transgelin expression has high sensitivity and specificity for diagnosis of LMS and differentiating it from ESS; 95.5% and associated with poor prognosis in LMS patients.
The combination of BCOR and Cyclin-D1 expression has high sensitivity and specificity for diagnosis of ESS and differentiating it from LMS; 90.9% and 95.5% respectively and associated with poor prognosis in ESS patients. The combination of Stathmin and Transgelin, BCOR and CyclinD1 expression has high sensitivity and specificity for diagnosis of LMS and differentiating it from ESS; 100%.
Conclusion
Combination of Stathmin, Transgelin, BCOR and Cycline-D1 raised the accuracy of differentiation between ULMS and ESS to 100% and has prognostic roles in such sarcomas.
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Hypoxia destroys the microstructure of microtubules and causes dysfunction of endothelial cells via the PI3K/Stathmin1 pathway. Cell Biosci 2019; 9:20. [PMID: 30820314 PMCID: PMC6380067 DOI: 10.1186/s13578-019-0283-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 02/13/2019] [Indexed: 11/30/2022] Open
Abstract
Background Endothelial cells (EC) are sensitive to changes in the microenvironment, including hypoxia and ischemia. Disruption of the microtubular network has been reported in cases of ischemia. However, the signaling pathways involved in hypoxia-induced microtubular disruption are unknown. The purpose of this study was to investigate the molecular mechanisms involved in hypoxia-induced microtubular disassembly in human umbilical vein endothelial cells (HUVECs). Results HUVECs were cultured under normoxic or hypoxic conditions and pretreated with or without colchicine or paclitaxel. The MTT assay, Transwell assay, trans-endothelial permeability assay, and 5-bromo-2′-deoxy-uridine staining were used to test the survival rate, migration, permeability, and proliferation of cells, respectively. Transmission electron microscopy and phalloidin staining were used to observe the microstructure and polymerization of microtubules. The results show that the functions of HUVECs and the microtubular structure were destroyed by hypoxia, but were protected by paclitaxel and a reactive oxygen species (ROS) inhibitor. We further used western blot, a luciferase assay, and co-immunoprecipitation to describe a non-transcription-independent mechanism for PI3K activation-inhibited microtubular stability mediated by Stathmin1, a PI3K interactor that functions in microtubule depolymerization. Finally, we determined that hypoxia and ROS blocked the interaction between PI3K and Stathmin1 to activate disassembly of microtubules. Conclusion Thus, our data demonstrate that hypoxia induced the production of ROS and damaged EC function by destroying the microtubular structure through the PI3K/stathmin1 pathway.
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Zhong Y, Zhang Y, Ma D, Ren X, Xu C, Wan D. Inhibition of HOXB7 suppresses p27-mediated acute lymphoblastic leukemia by regulating basic fibroblast growth factor and ERK1/2. Life Sci 2019; 218:1-7. [DOI: 10.1016/j.lfs.2018.12.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Revised: 12/07/2018] [Accepted: 12/07/2018] [Indexed: 01/30/2023]
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Stathmin is a potential therapeutic target but not a prognostic marker in melanoma: an immunohistochemical study of 323 melanocytic lesions. Melanoma Res 2018; 29:157-162. [PMID: 30422880 DOI: 10.1097/cmr.0000000000000550] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
In several solid tumors, an increased stathmin expression is associated with both poor prognosis and resistance to certain chemotherapy types. However, the data regarding melanocytic lesions are very limited. The goals of our study are as follows: the assessment of stathmin expression in benign and malignant melanocytic lesions, and the significance of its expression for the differential diagnostics between benign and malignant lesions; the analysis of the prognostic significance of stathmin expression in melanoma; and the evaluation of stathmin expression in melanoma and melanoma metastases with respect to possible therapeutic targeting. Immunohistochemical analysis of stathmin expression was done in 323 melanocytic lesions, including 205 primary cutaneous melanomas, 60 melanoma metastases, and 58 melanocytic nevi. Stathmin expression was found in all analyzed groups of melanocytic lesions. Using the H-scoring system, the observed intensity of expression was as follows: melanocytic nevi: 146.1 (mean) and 150 (median); melanomas: 116.7 (mean) and 110 (median); and melanoma metastases: 136.8 (mean) and 140 (median). The stathmin expression was significantly lower in the cohort of primary melanomas when compared with metastases and nevi (P=0.001). The stathmin expression showed no prognostic significance. The high stathmin expression in melanoma suggests that stathmin might be a promising marker for therapeutic targeting in ongoing clinical trials. Compared with several other solid tumors, stathmin expression in melanoma showed no prognostic significance. The potential use of stathmin expression in differential diagnostics is limited by its common expression, and despite the statistically significant differences between nevi and melanoma, it may not be used in this setting.
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Pellizzari I, Fabris L, Berton S, Segatto I, Citron F, D'Andrea S, Cusan M, Benevol S, Perin T, Massarut S, Canzonieri V, Schiappacassi M, Belletti B, Baldassarre G. p27kip1 expression limits H-Ras-driven transformation and tumorigenesis by both canonical and non-canonical mechanisms. Oncotarget 2018; 7:64560-64574. [PMID: 27579539 PMCID: PMC5323099 DOI: 10.18632/oncotarget.11656] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 07/19/2016] [Indexed: 12/15/2022] Open
Abstract
The tumor suppressor protein p27Kip1 plays a pivotal role in the control of cell growth and metastasis formation.Several studies pointed to different roles for p27Kip1 in the control of Ras induced transformation, although no explanation has been provided to elucidate these differences. We recently demonstrated that p27kip1 regulates H-Ras activity via its interaction with stathmin.Here, using in vitro and in vivo models, we show that p27kip1 is an important regulator of Ras induced transformation. In H-RasV12 transformed cells, p27kip1 suppressed cell proliferation and tumor growth via two distinct mechanisms: 1) inhibition of CDK activity and 2) impairment of MT-destabilizing activity of stathmin. Conversely, in K-Ras4BV12 transformed cells, p27kip1 acted mainly in a CDK-dependent but stathmin-independent manner.Using human cancer-derived cell lines and primary breast and sarcoma samples, we confirmed in human models what we observed in mice.Overall, we highlight a pathway, conserved from mouse to human, important in the regulation of H-Ras oncogenic activity that could have therapeutic and diagnostic implication in patients that may benefit from anti-H-Ras therapies.
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Affiliation(s)
- Ilenia Pellizzari
- Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy
| | - Linda Fabris
- Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.,Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX, USA
| | - Stefania Berton
- Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy
| | - Ilenia Segatto
- Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy
| | - Francesca Citron
- Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy
| | - Sara D'Andrea
- Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy
| | - Martina Cusan
- Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy
| | - Sara Benevol
- Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy
| | - Tiziana Perin
- Pathology Unit, CRO Aviano, National Cancer Institute, Aviano, Italy
| | - Samuele Massarut
- Breast Surgery Unit, CRO Aviano, National Cancer Institute, Aviano, Italy
| | | | - Monica Schiappacassi
- Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy
| | - Barbara Belletti
- Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy
| | - Gustavo Baldassarre
- Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy
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Aronova A, Min IM, Crowley MJP, Panjwani SJ, Finnerty BM, Scognamiglio T, Liu YF, Whitsett TG, Garg S, Demeure MJ, Elemento O, Zarnegar R, Fahey TJ. STMN1 is Overexpressed in Adrenocortical Carcinoma and Promotes a More Aggressive Phenotype In Vitro. Ann Surg Oncol 2017; 25:792-800. [PMID: 29214451 DOI: 10.1245/s10434-017-6296-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and few therapeutic options. Stathmin1 (STMN1) is a cytosolic protein involved in microtubule dynamics through inhibition of tubulin polymerization and promotion of microtubule depolymerization, which has been implicated in carcinogenesis and aggressive behavior in multiple epithelial malignancies. We aimed to evaluate expression of STMN1 in ACC and to elucidate how this may contribute to its malignant phenotype. METHODS STMN1 was identified by RNA sequencing as a highly differentially expressed gene in human ACC samples compared with benign adrenal tumors. Expression was confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical (IHC) staining of a tissue microarray (TMA) from two independent cohorts. The biologic relevance of STMN1 was investigated in NCI-H295R cells by lentivirus-mediated silencing. RESULTS Differential gene expression demonstrated an eightfold increase in STMN1 messenger RNA (mRNA) in malignant compared with benign adrenal tissue. IHC showed significantly higher expression of STMN1 protein in ACC compared with normal and benign tissues. STMN1 knockdown in an ACC cell line resulted in decreased cell viability, cell-cycle arrest at G0/G1, and increased apoptosis in serum-starved conditions compared with scramble short hairpin RNA (shRNA) controls. STMN1 knockdown also decreased migration, invasion, and anchorage-independent growth compared with controls. CONCLUSIONS STMN1 is overexpressed in human ACC samples, and knockdown of this target in vitro resulted in a less aggressive phenotype of ACC, particularly under serum-starved conditions. Further study is needed to investigate the feasibility of interfering with STMN1 as a potential therapeutic target.
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Affiliation(s)
- Anna Aronova
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA.
| | - Irene M Min
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Michael J P Crowley
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Suraj J Panjwani
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Brendan M Finnerty
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Theresa Scognamiglio
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Yi-Fang Liu
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | | | - Shipra Garg
- Translational Genomics Research Institute, Phoenix, AZ, USA
| | | | - Olivier Elemento
- Department of Physiology and Biophysics, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Rasa Zarnegar
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Thomas J Fahey
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
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21
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Kimura A, Ogata K, Altan B, Yokobori T, Mochiki E, Yanai M, Kogure N, Yanoma T, Suzuki M, Bai T, Kuwano H. Nuclear heat shock protein 110 expression is associated with poor prognosis and hyperthermo-chemotherapy resistance in gastric cancer patients with peritoneal metastasis. World J Gastroenterol 2017; 23:7541-7550. [PMID: 29204054 PMCID: PMC5698247 DOI: 10.3748/wjg.v23.i42.7541] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 09/08/2017] [Accepted: 09/19/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the significance of heat shock protein 110 (HSP110) in gastric cancer (GC) patients with peritoneal metastasis undergoing hyperthermo-chemotherapy.
METHODS Primary GC patients (n = 14) with peritoneal metastasis or positive peritoneal lavage cytology who underwent distal or total gastrectomy between April 2000 and December 2011 were enrolled in this study. The patients underwent postoperative intraperitoneal hyperthermo-chemotherapy using a Thermotron RF-8 heating device two weeks after surgery. We analyzed nuclear HSP110 expression in surgically resected tumors using immunohistochemistry. Additionally, the effect of HSP110 suppression on hyptherthermo-chemosensitivity was assessed in vitro in the MKN45 GC cell line using the HSP inhibitor KNK437.
RESULTS HSP110 immnohistochemical staining in 14 GC patients showed that five (35.7%) samples belonged to the low expression group, and nine (64.3%) samples belonged to the high expression group. Progression-free survival was significantly shorter in the HSP110 high-expression group than in the low-expression group (P = 0.0313). However, no significant relationships were identified between HSP110 expression and the clinicopathological characteristics of patients. Furthermore, high HSP110 expression was not an independent prognostic factor in GC patients with peritoneal metastasis (P = 0.0625). HSP110 expression in MKN45 cells was suppressed by KNK437 at the hyperthermic temperature of 43 °C in vitro. Comparison of MKN45 cell proliferation in the presence and absence of KNK437 at 43 °C, revealed that proliferation was significantly decreased when HSP110 was inhibited by KNK437. Additionally, HSP110 suppression via HSP inhibitor treatment increased cellular sensitivity to hyperthermo-chemotherapy in vitro.
CONCLUSION The expression of nuclear HSP110 in GC patients might be a new marker of chemosensitivity and a therapeutic target for patients who are tolerant to existing hyperthermo-chemotherapies.
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Affiliation(s)
- Akiharu Kimura
- and Hiroyuki Kuwano, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Kyoichi Ogata
- and Hiroyuki Kuwano, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Bolag Altan
- and Hiroyuki Kuwano, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
- Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Takehiko Yokobori
- and Hiroyuki Kuwano, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
- Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Erito Mochiki
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama 350-0844, Japan
| | - Mitsuhiro Yanai
- and Hiroyuki Kuwano, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Norimichi Kogure
- and Hiroyuki Kuwano, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Toru Yanoma
- and Hiroyuki Kuwano, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Masaki Suzuki
- and Hiroyuki Kuwano, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Tuya Bai
- and Hiroyuki Kuwano, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
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22
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Ishii N, Araki K, Yokobori T, Gantumur D, Yamanaka T, Altan B, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Hosouchi Y, Kuwano H, Shirabe K. Reduced FBXW7 expression in pancreatic cancer correlates with poor prognosis and chemotherapeutic resistance via accumulation of MCL1. Oncotarget 2017; 8:112636-112646. [PMID: 29348852 PMCID: PMC5762537 DOI: 10.18632/oncotarget.22634] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 10/05/2017] [Indexed: 01/05/2023] Open
Abstract
Pancreatic cancer is a highly malignant tumor type with poor outcomes, and elucidation of the mechanisms involved in cancer progression and therapeutic resistance is critical. FBXW7 is a key regulator of tumor malignant potential, and its substrate MCL1 regulates therapeutic resistance in human malignancies. Therefore, determination of the relevance of FBXW7 expression is critical for improving patient outcomes. In this study, we investigated the function and clinical significance of FBXW7 in pancreatic cancer. FBXW7 expression was evaluated by immunohistochemistry in 122 pancreatic cancer tissues. Reduced FBXW7 expression was significantly associated with advanced venous invasion, high MCL1 expression, enhanced Ki-67 expression, and poor prognosis and was an independent poor prognostic factor. Among patients who underwent gemcitabine treatment after surgery, reduced FBXW7 expression was also significantly associated with poor prognosis. Knockdown of FBXW7 in vitro enhanced cell proliferation, and migration, and invasion abilities and promoted gemcitabine and nab-paclitaxel chemoresistance in pancreatic cancer cells. Moreover, FBXW7-knockdown cells showed accumulation of MCL1, and the enhanced chemoresistance observed in FBXW7-knockdown cells was eliminated by MCL1 suppression. These results suggested that FBXW7 was associated with cancer progression and mediated sensitivity to gemcitabine and nab-paclitaxel via MCL1 accumulation in pancreatic cancer. Thus, the FBXW7/MCL1 axis may be a promising therapeutic tool to overcome refractory pancreatic cancer.
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Affiliation(s)
- Norihiro Ishii
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan.,Department of General Surgical Science, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan
| | - Kenichiro Araki
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan.,Department of General Surgical Science, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan
| | - Takehiko Yokobori
- Research Program for Omics-Based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Maebashi, Japan
| | - Dorgormaa Gantumur
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan
| | - Takahiro Yamanaka
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan.,Department of General Surgical Science, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan
| | - Bolag Altan
- Department of Oncology Clinical Development, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Mariko Tsukagoshi
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan.,Department of General Surgical Science, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan
| | - Takamichi Igarashi
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan.,Department of General Surgical Science, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan
| | - Akira Watanabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan.,Department of General Surgical Science, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan
| | - Norio Kubo
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan.,Department of General Surgical Science, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan
| | - Yasuo Hosouchi
- Department of Surgery and Laparoscopic Surgery, Gunma Prefecture Saiseikai-Maebashi Hospital, Maebashi, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan
| | - Ken Shirabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan
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23
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Bao P, Yokobori T, Altan B, Iijima M, Azuma Y, Onozato R, Yajima T, Watanabe A, Mogi A, Shimizu K, Nagashima T, Ohtaki Y, Obayashi K, Nakazawa S, Bai T, Kawabata-Iwakawa R, Asao T, Kaira K, Nishiyama M, Kuwano H. High STMN1 Expression is Associated with Cancer Progression and Chemo-Resistance in Lung Squamous Cell Carcinoma. Ann Surg Oncol 2017; 24:4017-4024. [PMID: 28933054 DOI: 10.1245/s10434-017-6083-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Indexed: 11/18/2022]
Abstract
BACKGROUND Known as a microtubule-destabilizing protein, STMN1 (gene symbol: STMN1) regulates the dynamics of microtubules, cell cycle progress, and chemo-resistance against taxane agents. It is highly expressed in various human cancers and involved in cancer progression as well as poor prognosis. METHODS Expression of STMN1 was examined by immunohistochemistry using FFPE tissue sections from 186 patients with lung squamous cell carcinoma (LSCC). Analysis of STMN1 suppression was performed for STMN1 small interfering RNA (siRNA)-transfected LSCC cell lines to determine the change in proliferation, invasive and apoptosis abilities, and paclitaxel sensitivity. RESULTS The cytoplasmic STMN1 expression in LSCC was higher than in normal tissues. The high expression was significantly associated with vascular invasion (P = 0.0477) and poor prognosis. In addition, the proliferating and invasive abilities were decreased, and the apoptosis ability and paclitaxel sensitivity were increased in STMN1-suppressed LSCC cells compared with control cells. CONCLUSION The results suggest that STMN1 is a prognostic factor that also is associated with caner progression and chemo-resistance. Therefore, STMN1 could be a predictor for poor prognosis and a potential therapeutic target in LSCC.
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Affiliation(s)
- Pinjie Bao
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Takehiko Yokobori
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan. .,Research Program for Omics-Based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Gunma, Japan.
| | - Bolag Altan
- Department of Oncology Clinical Development, Graduate School of Medicine, Gunma University, Gunma, Japan
| | - Misaki Iijima
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Youko Azuma
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Ryoichi Onozato
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Toshiki Yajima
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Akira Watanabe
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Akira Mogi
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Kimihiro Shimizu
- Department of Thoracic and Visceral Organ Surgery, Graduate School of Medicine, Gunma University, Gunma, Japan
| | - Toshiteru Nagashima
- Department of Thoracic and Visceral Organ Surgery, Graduate School of Medicine, Gunma University, Gunma, Japan
| | - Yoichi Ohtaki
- Department of Thoracic and Visceral Organ Surgery, Graduate School of Medicine, Gunma University, Gunma, Japan
| | - Kai Obayashi
- Department of Thoracic and Visceral Organ Surgery, Graduate School of Medicine, Gunma University, Gunma, Japan
| | - Seshiru Nakazawa
- Department of Thoracic and Visceral Organ Surgery, Graduate School of Medicine, Gunma University, Gunma, Japan
| | - Tuya Bai
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Reika Kawabata-Iwakawa
- Department of Molecular Pharmacology and Oncology, Graduate School of Medicine, Gunma University, Gunma, Japan
| | - Takayuki Asao
- Big Data Center for Integrative Analysis, Gunma University Initiative for Advance Research, Gunma, Japan
| | - Kyoichi Kaira
- Department of Oncology Clinical Development, Graduate School of Medicine, Gunma University, Gunma, Japan
| | - Masahiko Nishiyama
- Department of Molecular Pharmacology and Oncology, Graduate School of Medicine, Gunma University, Gunma, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan
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24
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Han G, Wu Z, Zhao N, Zhou L, Liu F, Niu F, Xu Y, Zhao X. Overexpression of stathmin plays a pivotal role in the metastasis of esophageal squamous cell carcinoma. Oncotarget 2017; 8:61742-61760. [PMID: 28977901 PMCID: PMC5617461 DOI: 10.18632/oncotarget.18687] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 05/23/2017] [Indexed: 12/15/2022] Open
Abstract
Purpose Esophageal squamous cell carcinoma (ESCC) is a serious malignant tumor that affects human health. We analyzed the correlation between serum stathmin level and ESCC and elucidated the molecular mechanisms of stathmin's promotion of ESCC cell invasion and metastasis. Methods Stathmin level in ESCC and healthy control serum were detected by enzyme-linked immunosorbent assay (ELISA), and the clinical parameters were analyzed. We established ESCC cells with stathmin overexpression or knockdown and then evaluated the effects of stathmin on invasion and metastasis in ESCC. Differentially expressed genes were analyzed by Human Transcriptome Array and confirmed by RT-PCR. The expression levels of the integrin family, focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) were detected by immunoblotting. Results Serum levels of stathmin were significantly higher in ESCC than in control serum and associated with lymph node metastasis, tumor stage and size. Furthermore, we found that stathmin promoted migration and invasion of ESCC cells in vitro and in vivo. In addition, we confirmed that the activation of the integrinα5β1/FAK/ERK pathway is increased in stathmin-overexpression cells and accelerates cell motility by enhancing cell adhesion ability. Conclusion Stathmin may predict a potential metastasis biomarker for ESCC.
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Affiliation(s)
- Gaijing Han
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zongyong Wu
- Clinical Laboratory, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Nan Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lanping Zhou
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fang Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fangfei Niu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yang Xu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaohang Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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25
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Aksoy A, Artas G, Sevindik OG. Predictive value of stathmin-1 and osteopontin expression for taxan resistance in metastatic castrate-resistant prostate cancer. Pak J Med Sci 2017; 33:560-565. [PMID: 28811771 PMCID: PMC5510103 DOI: 10.12669/pjms.333.12559] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective: Several pathways are known to be activated during metastasis and treatment of cancer. We investigated the role of osteopontin (OPN) and stathmin-1 (STHMN1) in metastatic castrate-resistant (mCRPC). Methods: We included 30 patients who received at least 6 cycles of taxane regimen for metastatic mPC in the present study. For this study retrospective data was taken from Firat University, Faculty of Medicine, Medical Oncology Department between 2009 and 2015. OPN expression and STHMN1 expression were retrospectively evaluated by immunohistochemical staining in biopsy specimens. The relationship between the expression levels of OPN and STMN1 and the response to taxane based regimen and survival was analyzed. Results: There was mild or strong overexpression of OPN and STHMN1 in all the patients. STHMN1 expression was mildly positive (+2) in four of the cases (13.2%) while it was strongly positive (+3) in 25 (83.4%) cases. Similarly, OPN expression was mildly positive (+2) and strongly positive (+3) in five (16.6%) and 25 (87.4%) patients, respectively. There was no significant correlation between the expression levels of STHMN1 and OPN, survival, and response to taxane based regimen (p>0.05); however, OPN overexpression showed a significant correlation with lower Gleason scores (GS) (p:0.032). Conclusions: STHMN1 and OPN may be prognostic markers although they are not predictive markers of response to treatment in mCRPC. The overexpression of OPN may help identifying patients with lower GS.
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Affiliation(s)
- Asude Aksoy
- Asude Aksoy, Department of Medical Oncology, Medical Faculty, Firat University, Elazig, Turkey
| | - Gokhan Artas
- Gokhan Artas, Department of Pathology, Medical Faculty, Firat University, Elazig, Turkey
| | - Omur Gokmen Sevindik
- Omur Gokmen Sevindik, Department of Hematology, Medical Faculty, Firat University, Elazig, Turkey
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26
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High stathmin expression is a marker for poor clinical outcome in endometrial cancer: An NRG oncology group/gynecologic oncology group study. Gynecol Oncol 2017; 146:247-253. [PMID: 28532857 DOI: 10.1016/j.ygyno.2017.05.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 05/09/2017] [Accepted: 05/13/2017] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Gynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin. METHODS We analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer. RESULTS We first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin. CONCLUSIONS Our findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases.
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27
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High STMN1 level is associated with chemo-resistance and poor prognosis in gastric cancer patients. Br J Cancer 2017; 116:1177-1185. [PMID: 28334732 PMCID: PMC5418450 DOI: 10.1038/bjc.2017.76] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Revised: 02/26/2017] [Accepted: 03/01/2017] [Indexed: 02/07/2023] Open
Abstract
Background: Stathmin1 (STMN1) is a cytosolic phosphoprotein that regulates cellular microtubule dynamics and is known to have oncogenic activity. Despite several reports, its roles in gastric cancer (GC) remain unclear owing to a lack of analyses of highly metastatic cases. This study aimed to investigate STMN1 as a prognostic and predictive indicator of response to paclitaxel therapy in patients with GC, including inoperable cases. Methods: Immunohistochemical analysis of STMN1 was performed on both operable (n=95) and inoperable GC (n=61) samples. The roles of STMN1 in cancer cell proliferation and sensitivity to a microtubule-targeting drug, paclitaxel, were confirmed by knockdown experiments using GC cell lines. Results: Multivariate and Kaplan–Meier analyses demonstrated that high STMN1 was predictive of poor prognosis in both the groups. In the operable cohort, STMN1 expression correlated with cancer curability, recurrence, and resistance to adjuvant therapy. A correlation with paclitaxel resistance was observed in inoperable cases. Knockdown of STMN1 in GC cell lines inhibited proliferation and sensitised the cells to paclitaxel by enhancing apoptosis. Conclusions: STMN1 is a possible biomarker for paclitaxel sensitivity and poor prognosis in GC and could be a novel therapeutic target in metastatic GC.
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Wang Y, Gao Z, Zhang D, Bo X, Wang Y, Wang J, Shen S, Liu H, Suo T, Pan H, Ai Z, Liu H. Stathmin decreases cholangiocarcinoma cell line sensitivity to staurosporine-triggered apoptosis via the induction of ERK and Akt signaling. Oncotarget 2017; 8:15775-15788. [PMID: 28178656 PMCID: PMC5362522 DOI: 10.18632/oncotarget.15005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 01/03/2017] [Indexed: 01/03/2023] Open
Abstract
Cholangiocarcinoma is a rare, but highly fatal malignancy. However, the intrinsic mechanism involved in its tumorigenesis remains obscure. An urgent need remains for a promising target for cholangiocarcinoma biological therapies. Based on comparative proteomical technologies, we found 253 and 231 different spots in gallbladder tumor cell lines and cholangiocarcinoma cell lines, respectively, relative to non-malignant cells. Using Mass Spectrometry (MS) and database searching, we chose seven differentially expressed proteins. High Stathmin expression was found in both cholangiocarcinoma and gallbladder carcinoma cells. Stathmin expression was validated using immunohistochemistry and western blot in cholangiocarcinoma tissue samples and peritumoral tissue. It was further revealed that high Stathmin expression was associated with the repression of staurosporine-induced apoptosis in the cholangiocarcinoma cell. Moreover, we found that Stathmin promoted cancer cell proliferation and inhibited its apoptosis through protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) signaling. Integrin, β1 appears to serve as a partner of Stathmin induction of ERK and Akt signaling by inhibiting apoptosis in the cholangiocarcinoma cell. Understanding the regulation of anti-apoptosis effect by Stathmin might provide new insight into how to overcome therapeutic resistance in cholangiocarcinoma.
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Affiliation(s)
- Yueqi Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhihui Gao
- Department of General Surgery, Subei People's Hospital, Yangzhou, Jiangsu Province, China
| | - Dexiang Zhang
- Department of General Surgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Xiaobo Bo
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yaojie Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiwen Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sheng Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Han Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tao Suo
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hongtao Pan
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhilong Ai
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Houbao Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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29
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Watanabe A, Araki K, Yokobori T, Altan B, Ishii N, Tsukagoshi M, Kubo N, Saito F, Suzuki H, Kuwano H. Stathmin 1 promotes the proliferation and malignant transformation of pancreatic intraductal papillary mucinous neoplasms. Oncol Lett 2017; 13:1783-1788. [PMID: 28454324 DOI: 10.3892/ol.2017.5603] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 10/27/2016] [Indexed: 11/06/2022] Open
Abstract
Pancreatic intraductal papillary mucinous neoplasms (IPMNs) are a type of pancreatic tumor, which have been identified following improvements in diagnostic imaging. However, the malignant transformation of IPMN has been difficult to diagnose clinically. To date, the mechanisms driving the progression of IPMN to cancer remain to be fully elucidated. The present study focused on Stathmin 1 (STMN1), a protein that is associated with the development of various types of cancer. The expression of STMN1 was examined immunohistochemically in tissues from cases of IPMN. The correlation between the STMN1 staining and clinical pathological factors was evaluated, and the expression of STMN1, p27 and S-phase kinase-associated protein 2 (SKP2) were compared. High expression levels of STMN1 were significantly correlated with regions of malignancy, and was associated with high expression of SKP2, low expression of nuclear p27 and a high Ki-67 index. High expression levels of STMN1 and SKP2 were significantly correlated with the transformation of IPMN to carcinoma. In addition, within the regions of carcinoma, the expression of STMN1 was weak in regions of adenoma and high in the cancerous regions. It was concluded that the high expression of STMN1 contributed to tumor proliferation and malignant transformation in the patients with IPMN. These results suggested that characterization of the expression of STMN1 may be a promising approach for predicting malignant transformation of pancreatic intraductal papillary mucinous adenoma.
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Affiliation(s)
- Akira Watanabe
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Kenichiro Araki
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Takehiko Yokobori
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Bolag Altan
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Norihiro Ishii
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Mariko Tsukagoshi
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Norio Kubo
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Fumiyoshi Saito
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Hideki Suzuki
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
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30
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Biaoxue R, Hua L, Wenlong G, Shuanying Y. Overexpression of stathmin promotes metastasis and growth of malignant solid tumors: a systemic review and meta-analysis. Oncotarget 2016; 7:78994-79007. [PMID: 27806343 PMCID: PMC5346693 DOI: 10.18632/oncotarget.12982] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 10/22/2016] [Indexed: 01/08/2023] Open
Abstract
Stathmin has been investigated to be involved in development and progress of malignant tumors. This study was to clarify the relationship between expression of stathmin and tumors and assess its clinical significance. We identified 25 studies with a total of 3,571 individuals from the electronic bibliographic databases and strictly evaluated the quality and heterogeneity of included studies. We analysed the relationship between expression of stathmin and clinical characteristics by the fixed-effects and random-effects of meta-analysis and constructed a summary receiver-operator characteristic curve to estimate the test characteristics. The results showed that patients with cancer displayed a higher stathmin expression than those of non-cancer individuals (OR, 0.31), and overexpression of stathmin correlated with tumor cell differentiation (OR, 0.73), lymph node invasion (OR, 0.80) and high TNM stage (OR, 0.67). The pooled sensitivity of stathmin for distinguishing malignant tumors was 0.73 and the specificity was 0.77. The maximum balance joint for sensitivity and specificity (the Q-value) was 0.7566 and the area under the curve (AUC) was 0.8234. In conclusion, these results showed that overexpression of stathmin intimately correlated with malignant behavior of tumors, suggesting it could be a risk factor of malignant tumors. Stathmin had great sensitivity and specificity indicated it should be a significant molecular biomarker for malignant tumors.
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Affiliation(s)
- Rong Biaoxue
- Department of Respiratory Medicine, First Affiliated Hospital, Xi'an Medical University, Xi'an, China
| | - Liu Hua
- Department of Respiratory Medicine, Gansu Provincial Hospital, Lanzhou, China
| | - Gao Wenlong
- Department of Statistics and Epidemiology, Medical College, Lanzhou University, Lanzhou, China
| | - Yang Shuanying
- Department of Respiratory Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
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31
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Wang Z, Jay CM, Evans C, Kumar P, Phalon C, Rao DD, Senzer N, Nemunaitis J. Preclinical Biodistribution and Safety Evaluation of a pbi-shRNA STMN1 Lipoplex after Subcutaneous Delivery. Toxicol Sci 2016; 155:400-408. [PMID: 27815492 DOI: 10.1093/toxsci/kfw223] [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] [Indexed: 11/14/2022] Open
Abstract
Stathmin-1 (STMN1) is a microtubule-destabilizing protein which is overexpressed in cancer. Its overexpression is associated with poor prognosis and also serves as a predictive marker to taxane therapy. We have developed a proprietary bi-functional shRNA (bi-shRNA) platform to execute RNA interference (RNAi)-mediated gene silencing and a liposome-carrier complex to systemically deliver the pbi-shRNA plasmids. In vitro and in vivo testing demonstrated efficacy and specificity of pbi-shRNA plasmid in targeting STMN1 (Phadke, A. P., Jay, C. M., Wang, Z., Chen, S., Liu, S., Haddock, C., Kumar, P., Pappen, B. O., Rao, D. D., Templeton, N. S., et al. (2011). In vivo safety and antitumor efficacy of bifunctional small hairpin RNAs specific for the human Stathmin 1 oncoprotein. DNA Cell Biol. 30, 715-726.). Biodistribution and toxicology studies in bio-relevant Sprague Dawley rats with pbi-shRNA STMN1 lipoplex revealed that the plasmid DNA was delivered to a broad distribution of organs after a single subcutaneous injection. Specifically, plasmid was detected within the first week using QPCR (threshold 50 copies plasmid/1 µg genomic DNA) at the injection site, lung, spleen, blood, skin, ovary (limited), lymph nodes, and liver. It was not detected in the heart, testis or bone marrow. No plasmid was detected from any organ 30 days after injection. Treatment was well tolerated. Minimal inflammation/erythema was observed at the injection site. Circulating cytokine response was also examined by ELISA. The IL-6 levels were induced within 6 h then declined to the vehicle control level 72 h after the injection. TNFα induction was transiently observed 4 days after the DNA lipoplex treatment. In summary, the pbi-shRNA STMN1 lipoplex was well tolerated and displayed broad distribution after a single subcutaneous injection. The pre-clinical data has been filed to FDA and the pbi-shRNA STMN1 lipoplex is being investigated in a phase I clinical study.
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Affiliation(s)
| | | | | | | | | | | | - Neil Senzer
- Strike Bio, Inc, Dallas, Texas.,Gradalis, Inc, Dallas, Texas.,Mary Crowley Cancer Research Centers, Dallas, Texas.,Texas Oncology, P.A, Dallas, Texas
| | - John Nemunaitis
- Strike Bio, Inc, Dallas, Texas .,Gradalis, Inc, Dallas, Texas.,Mary Crowley Cancer Research Centers, Dallas, Texas.,Texas Oncology, P.A, Dallas, Texas
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32
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Adam MG, Matt S, Christian S, Hess-Stumpp H, Haegebarth A, Hofmann TG, Algire C. SIAH ubiquitin ligases regulate breast cancer cell migration and invasion independent of the oxygen status. Cell Cycle 2016; 14:3734-47. [PMID: 26654769 PMCID: PMC4825722 DOI: 10.1080/15384101.2015.1104441] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Seven-in-absentia homolog (SIAH) proteins are evolutionary conserved RING type E3 ubiquitin ligases responsible for the degradation of key molecules regulating DNA damage response, hypoxic adaptation, apoptosis, angiogenesis, and cell proliferation. Many studies suggest a tumorigenic role for SIAH2. In breast cancer patients SIAH2 expression levels correlate with cancer aggressiveness and overall patient survival. In addition, SIAH inhibition reduced metastasis in melanoma. The role of SIAH1 in breast cancer is still ambiguous; both tumorigenic and tumor suppressive functions have been reported. Other studies categorized SIAH ligases as either pro- or antimigratory, while the significance for metastasis is largely unknown. Here, we re-evaluated the effects of SIAH1 and SIAH2 depletion in breast cancer cell lines, focusing on migration and invasion. We successfully knocked down SIAH1 and SIAH2 in several breast cancer cell lines. In luminal type MCF7 cells, this led to stabilization of the SIAH substrate Prolyl Hydroxylase Domain protein 3 (PHD3) and reduced Hypoxia-Inducible Factor 1α (HIF1α) protein levels. Both the knockdown of SIAH1 or SIAH2 led to increased apoptosis and reduced proliferation, with comparable effects. These results point to a tumor promoting role for SIAH1 in breast cancer similar to SIAH2. In addition, depletion of SIAH1 or SIAH2 also led to decreased cell migration and invasion in breast cancer cells. SIAH knockdown also controlled microtubule dynamics by markedly decreasing the protein levels of stathmin, most likely via p27(Kip1). Collectively, these results suggest that both SIAH ligases promote a migratory cancer cell phenotype and could contribute to metastasis in breast cancer.
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Affiliation(s)
- M Gordian Adam
- a Cellular Senescence Group ; German Cancer Research Center DKFZ ; Heidelberg , Germany.,b GTRG Oncology II; GDD; Bayer Pharma AG ; Berlin , Germany
| | - Sonja Matt
- a Cellular Senescence Group ; German Cancer Research Center DKFZ ; Heidelberg , Germany
| | - Sven Christian
- b GTRG Oncology II; GDD; Bayer Pharma AG ; Berlin , Germany
| | | | | | - Thomas G Hofmann
- a Cellular Senescence Group ; German Cancer Research Center DKFZ ; Heidelberg , Germany
| | - Carolyn Algire
- b GTRG Oncology II; GDD; Bayer Pharma AG ; Berlin , Germany
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33
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Sobue S, Mizutani N, Aoyama Y, Kawamoto Y, Suzuki M, Nozawa Y, Ichihara M, Murate T. Mechanism of paclitaxel resistance in a human prostate cancer cell line, PC3-PR, and its sensitization by cabazitaxel. Biochem Biophys Res Commun 2016; 479:808-813. [PMID: 27687545 DOI: 10.1016/j.bbrc.2016.09.128] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 09/25/2016] [Indexed: 12/12/2022]
Abstract
Paclitaxel (PTX) is a microtubule-targeting drug widely used for the treatment of a variety of cancers. However, drug resistance can emerge after a series of treatments, and this can seriously affect the patient's prognosis. Here, we analyzed the mechanism of PTX resistance using a human prostate cancer cell line, PC3, and its PTX-resistant subline, PC3-PR. Compared with PC3, PC3-PR exhibited some unique phenotypes that might be associated with PTX resistance, including decreased expression of acetylated α-tubulin and the cell cycle regulator p21, and increased expression of βIII tubulin, histone deacetylase 6 (HDAC6), and the anti-apoptotic protein Bcl2. The drug exporters MDR1 and MRP1 were not involved in PTX resistance. Although cabazitaxel (CTX), a novel taxoid, has been reported to overcome PTX resistance, its mechanism of action is unknown. We found that treatment of PC3-PR cells with CTX induced expression of acetylated α-tubulin and p21, but not the related regulators p27, p15, and p16 or the Bcl2 family proteins. The pan-HDAC inhibitors trichostatin A and suberanilohydroxamic acid and the HDAC6-specific inhibitor tubacin inhibited PC3-PR proliferation and increased expression of p21 and acetylated α-tubulin in a manner similar to CTX. Our data shed light on the cellular response to PTX and CTX.
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Affiliation(s)
- Sayaka Sobue
- College of Life and Health Sciences, Chubu University, Kasugai, Japan
| | - Naoki Mizutani
- College of Life and Health Sciences, Chubu University, Kasugai, Japan
| | - Yuka Aoyama
- College of Life and Health Sciences, Chubu University, Kasugai, Japan
| | | | - Motoshi Suzuki
- Division of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | | | | | - Takashi Murate
- College of Life and Health Sciences, Chubu University, Kasugai, Japan.
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34
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Biaoxue R, Xiguang C, Hua L, Shuanying Y. Stathmin-dependent molecular targeting therapy for malignant tumor: the latest 5 years' discoveries and developments. J Transl Med 2016; 14:279. [PMID: 27670291 PMCID: PMC5037901 DOI: 10.1186/s12967-016-1000-z] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 08/03/2016] [Indexed: 12/20/2022] Open
Abstract
Knowledge of the molecular mechanisms on malignant tumors is very critical for the development of new treatment strategies like molecularly targeted therapies. In last 5 years, many investigations suggest that stathmin is over-expressed in a variety of human malignant tumors, and potentially promotes the occurrence and development of tumors. Rather, down-regulation of stathmin can reduce cell proliferation, motility and metastasis and induce apoptosis of malignant tumors. Thus, a stathmin antagonist, such as a specific inhibitor (antibody, small molecule compound, peptide, or siRNA), may be a novel strategy of molecular targeted therapy. This review summarizes the research progress of recent 5 years on the role of stathmin in tumorigenesis, the molecular mechanisms and development of anti-stathmin treatment, which suggest that continued investigations into the function of stathmin in the tumorigenesis could lead to more rationally designed therapeutics targeting stathmin for treating human malignant tumors.
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Affiliation(s)
- Rong Biaoxue
- Department of Respiratory Medicine, First Affiliated Hospital, Xi'an Medical University, Xi'an, China.
| | - Cai Xiguang
- Department of Respiratory Medicine, Gansu Provincial Hospital, Lanzhou, China
| | - Liu Hua
- Department of Respiratory Medicine, Gansu Provincial Hospital, Lanzhou, China
| | - Yang Shuanying
- Department of Respiratory Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
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35
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Kuang XY, Chen L, Zhang ZJ, Liu YR, Zheng YZ, Ling H, Qiao F, Li S, Hu X, Shao ZM. Stathmin and phospho-stathmin protein signature is associated with survival outcomes of breast cancer patients. Oncotarget 2016; 6:22227-38. [PMID: 26087399 PMCID: PMC4673159 DOI: 10.18632/oncotarget.4276] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 06/01/2015] [Indexed: 01/07/2023] Open
Abstract
Currently, Stathmin1 (STMN1) and phospho-STMN1 levels in breast cancers and their clinical implications are unknown. We examined the expression of STMN1 and its serine phospho-site (Ser16, Ser25, Ser38, and Ser63) status by immunohistochemistry. Using Cox regression analysis, a STMN1 expression signature and phosphorylation profile plus clinicopathological characteristics (STMN1-E/P/C) was developed in the training set (n = 204) and applied to the validation set (n = 106). This tool enabled us to separate breast cancer patients into high- and low-risk groups with significantly different disease-free survival (DFS) rates (P < 0.001). Importantly, this STMN1-E/P/C model had a greater prognostic value than the traditional TNM classifier, especially in luminal subtype breast cancer (P = 0.002). Further analysis showed that patients in the low-risk group would benefit more from adjuvant paclitaxel-based chemotherapy (P = 0.002). In conclusion, the STMN1-E/P/C signature is a reliable prognostic indicator for luminal subtype breast cancer and may predict the therapeutic response to paclitaxel-based treatments, potentially facilitating individualized management.
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Affiliation(s)
- Xia-Ying Kuang
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Li Chen
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhi-Jie Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Fudan University, Shanghai, China
| | - Yi-Rong Liu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yi-Zi Zheng
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hong Ling
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Feng Qiao
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shan Li
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xin Hu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhi-Ming Shao
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institutes of Biomedical Science, Fudan University, Shanghai, China
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36
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Saito F, Araki K, Yokobori T, Ishii N, Tsukagoshi M, Watanabe A, Kubo N, Altan B, Shirabe K, Kuwano H. High expression of karyopherin-α2 and stathmin 1 is associated with proliferation potency and transformation in the bile duct and gall bladder epithelia in the cases of pancreaticobiliary maljunction. J Surg Oncol 2016; 114:462-8. [DOI: 10.1002/jso.24330] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 06/05/2016] [Indexed: 01/07/2023]
Affiliation(s)
- Fumiyoshi Saito
- Department of General Surgical Science; Graduate School of Medicine; Gunma University; Showamachi, Maebashi Gunma Japan
- Department of Hepatobiliary and Pancreatic Surgery; Graduate School of Medicine; Gunma University; Maebashi Gunma Japan
| | - Kenichiro Araki
- Department of General Surgical Science; Graduate School of Medicine; Gunma University; Showamachi, Maebashi Gunma Japan
- Department of Hepatobiliary and Pancreatic Surgery; Graduate School of Medicine; Gunma University; Maebashi Gunma Japan
| | - Takehiko Yokobori
- Department of Molecular Pharmacology and Oncology; Graduate School of Medicine; Gunma University; Maebashi Gunma Japan
| | - Norihiro Ishii
- Department of General Surgical Science; Graduate School of Medicine; Gunma University; Showamachi, Maebashi Gunma Japan
- Department of Hepatobiliary and Pancreatic Surgery; Graduate School of Medicine; Gunma University; Maebashi Gunma Japan
| | - Mariko Tsukagoshi
- Department of General Surgical Science; Graduate School of Medicine; Gunma University; Showamachi, Maebashi Gunma Japan
- Department of Hepatobiliary and Pancreatic Surgery; Graduate School of Medicine; Gunma University; Maebashi Gunma Japan
| | - Akira Watanabe
- Department of General Surgical Science; Graduate School of Medicine; Gunma University; Showamachi, Maebashi Gunma Japan
- Department of Hepatobiliary and Pancreatic Surgery; Graduate School of Medicine; Gunma University; Maebashi Gunma Japan
| | - Norio Kubo
- Department of General Surgical Science; Graduate School of Medicine; Gunma University; Showamachi, Maebashi Gunma Japan
- Department of Hepatobiliary and Pancreatic Surgery; Graduate School of Medicine; Gunma University; Maebashi Gunma Japan
| | - Bolag Altan
- Department of General Surgical Science; Graduate School of Medicine; Gunma University; Showamachi, Maebashi Gunma Japan
| | - Ken Shirabe
- Department of Hepatobiliary and Pancreatic Surgery; Graduate School of Medicine; Gunma University; Maebashi Gunma Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science; Graduate School of Medicine; Gunma University; Showamachi, Maebashi Gunma Japan
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37
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Wegiel B, Wang Y, Li M, Jernigan F, Sun L. Novel indolyl-chalcones target stathmin to induce cancer cell death. Cell Cycle 2016; 15:1288-94. [PMID: 26986925 DOI: 10.1080/15384101.2016.1160980] [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] [Indexed: 12/20/2022] Open
Abstract
Efficacy of current therapies for advanced and metastatic cancers remains a challenge in clinical practice. We investigated the anti-cancer potency of 3 novel indoly-chalcones (CITs). Our results indicated the lead molecule CIT-026 (Formula = C20H16FNO) induced cell death in prostate and lung cancer cell lines at sub-micromolar concentration. CITs (CIT-026, CIT-214, CIT-223) lead to microtubule destabilization, cell death and low cell proliferation, which in part was dependent on stathmin (STMN1) expression. Knockdown of STMN1 with siRNA against STMN1 in part restored viability of cancer cells in response to CITs. Further, CIT-026 and CIT-223 blocked cancer cell invasion through matrigel-coated chambers. Mechanistically, CITs inhibited phosphorylation of STMN1 leading to STMN1 accumulation and mitotic catastrophe. In summary, we have synthetized novel anti-cancer CIT molecules and defined their mechanism of action in vitro.
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Affiliation(s)
- Barbara Wegiel
- a Department of Surgery , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA.,b Transplant Institute & Cancer Research Institute, Beth Israel Deaconess Medical Center , Harvard Medical School , Boston , MA , USA
| | - Yiqiang Wang
- a Department of Surgery , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA.,c Center for Drug Discovery and Translational Research , Beth Israel Deaconess Medical Center , Harvard Medical School , Boston , MA , USA
| | - Mailin Li
- a Department of Surgery , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA.,b Transplant Institute & Cancer Research Institute, Beth Israel Deaconess Medical Center , Harvard Medical School , Boston , MA , USA
| | - Finith Jernigan
- a Department of Surgery , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA.,c Center for Drug Discovery and Translational Research , Beth Israel Deaconess Medical Center , Harvard Medical School , Boston , MA , USA
| | - Lijun Sun
- a Department of Surgery , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA.,c Center for Drug Discovery and Translational Research , Beth Israel Deaconess Medical Center , Harvard Medical School , Boston , MA , USA
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38
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Lin X, Liao Y, Chen X, Long D, Yu T, Shen F. Regulation of Oncoprotein 18/Stathmin Signaling by ERK Concerns the Resistance to Taxol in Nonsmall Cell Lung Cancer Cells. Cancer Biother Radiopharm 2016; 31:37-43. [PMID: 26881937 DOI: 10.1089/cbr.2015.1921] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Taxol is a cytotoxic antiepithelioma chemotherapy drug widely used clinically, which results in appearing a broad range of taxol-resistant tumors. Oncoprotein 18 (Op18)/stathmin is a genetically highly conserved small-molecule cytosolic phosphoprotein and highly expressed in tumors. Extracellular signal-regulated kinase (ERK) is a main member of mitogen-activated protein kinases (MAPKs). The study demonstrated that combination of blockage of ERK signal by ERK inhibitor PD98059 and Taxol greatly promoted taxol-induced cellular apoptosis and growth inhibition, decreased the expression of Op18/stathmin and total levels of phosphor-Op18/stathmin, while weakened the cyclin-dependent kinase 2 (cdc2) activity and antiapoptotic protein Bcl-2 expression and inhibited IL-10 autocrine in taxol-resistant NCI-H1299 cells; Taxol-resistant NCI-H1299 cells expressed high levels of ERK and phosphor-ERK in contrast to taxol-sensitive CNE1 cells, and ERK mainly phosphorylated Op18/stathmin at Ser 25 site. These findings suggest that ERK-mediated Op18/stathmin is involved in taxol resistance of tumors; blockage of ERK signal improves the sensitivity of tumor cells to taxol, which provides new clues for treating taxol-resistant carcinomas.
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Affiliation(s)
- Xuechi Lin
- 1 Department of Medical Laboratory, Changsha Medical University , Changsha, China .,2 Department of Clinical Laboratory, Hunan Normal University , Changsha, Hunan
| | - Ying Liao
- 1 Department of Medical Laboratory, Changsha Medical University , Changsha, China .,3 Department of Anatomy, Histology and Embryology, Institute of Neuroscience, Changsha Medical University , Changsha, China
| | - Xian Chen
- 1 Department of Medical Laboratory, Changsha Medical University , Changsha, China
| | - Dan Long
- 1 Department of Medical Laboratory, Changsha Medical University , Changsha, China
| | - Ting Yu
- 1 Department of Medical Laboratory, Changsha Medical University , Changsha, China
| | - Fang Shen
- 1 Department of Medical Laboratory, Changsha Medical University , Changsha, China .,2 Department of Clinical Laboratory, Hunan Normal University , Changsha, Hunan
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Tian FJ, Qin CM, Li XC, Wu F, Liu XR, Xu WM, Lin Y. Decreased stathmin-1 expression inhibits trophoblast proliferation and invasion and is associated with recurrent miscarriage. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:2709-21. [PMID: 26272359 DOI: 10.1016/j.ajpath.2015.06.010] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 06/01/2015] [Accepted: 06/18/2015] [Indexed: 12/20/2022]
Abstract
Fetal trophoblasts invade endometrium and establish a complex interaction with the maternal microenvironment during early pregnancy. However, the molecular mechanisms regulating trophoblast migration and invasion at the maternal-fetal interface remain poorly understood. Immunohistochemistry and immunoblotting have shown that stathmin-1 (STMN1) was down-regulated significantly in placental villi tissue and trophoblasts from patients with recurrent miscarriage. In vitro, overexpression of STMN1 promoted human trophoblast proliferation, migration, and invasion, whereas knockdown of STMN1 inhibited these processes. In addition, knockdown of STMN1 down-regulated N-cadherin and up-regulated E-cadherin in trophoblasts, whereas E-cadherin was up-regulated and N-cadherin was down-regulated in recurrent miscarriage villi tissue. Knockdown of STMN1 attenuated cytoplasmic-nuclear translocation of β-catenin and in turn down-regulated trophoblast matrix metalloproteases. Furthermore, tumor necrosis factor-α (TNF-α) down-regulated STMN1 expression, and serum TNF-α expression correlated inversely with trophoblast STMN1 levels. Interestingly, M1 macrophage-derived TNF-α reduced trophoblast migration and invasion, and an anti-TNF-α antibody reversed this effect. Collectively, this study indicated that STMN1 may play a key role in regulating trophoblast invasion, and that impaired STMN1 expression may lead to abnormal trophoblast invasion and result in recurrent miscarriage.
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Affiliation(s)
- Fu-Ju Tian
- International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuan-Mei Qin
- International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Cui Li
- International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fan Wu
- International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Rui Liu
- International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wang-Ming Xu
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Yi Lin
- International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Embryo-Fetal Original Adult Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Hwang H, Matsuo K, Duncan K, Pakzamir E, Pham HQ, Correa A, Fedenko A, Mhawech-Fauceglia P. Immunohistochemical panel to differentiate endometrial stromal sarcoma, uterine leiomyosarcoma and leiomyoma: something old and something new. J Clin Pathol 2015; 68:710-7. [PMID: 25991737 DOI: 10.1136/jclinpath-2015-202915] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 04/30/2015] [Indexed: 01/12/2023]
Abstract
AIMS To evaluate an immunohistochemical panel differentiating endometrial stromal sarcoma (ESS) from uterine leiomyosarcoma (ULMS) and leiomyoma (LM). METHODS 94 cases (28 ESS, 41 ULMS, 25 LM) were retrieved and arrayed. 10 immunomarkers (estrogen receptor (ER), progesterone receptor (PR), CD10, smooth muscle actin, desmin, h-caldesmon, transgelin, GEM, ASC1, stathmin1) were used. A predictive model was constructed and examined by receiver operating characteristics curve analysis to determine area under the curve (AUC). RESULTS The combination of ER(+)/PR(+)/CD10(+)/GEM(-)/h-caldesmon(-)/transgelin(-) can predict ESS versus ULMS with AUC predictive value of 0.872 (95% CI 0.784 to 0.961, p<0.0001). The combination of ER(+)/PR(+)/CD10(+)/h-caldesmon(-)/transgelin(-) can predict low grade (LG) ESS from 'LG' ULMS with AUC predictive value of 0.914 (95% CI 0.832 to 0.995, p<0.0001). Finally, ULMS and ESS, including the LGs, were more likely to be stathmin1(+) than LM. CONCLUSIONS Due to the different clinical course and management, adding novel antibodies (GEM, transgelin) to the well established immunohistochemistry panel seemed to be useful in distinguishing ESS from ULMS and LG ESS from 'LG' ULMS. Finally, stathmin1 expression could be of value in differentiating LM from uterine sarcomas.
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Affiliation(s)
- Helena Hwang
- Department of Anatomic Pathology, University of Texas at Dallas, Dallas, Texas, USA
| | - Koji Matsuo
- Division of Gynecology Oncology, Departments of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
| | - Kara Duncan
- Department of Surgical Pathology, University of Southern California, Los Angeles, California, USA
| | - Elham Pakzamir
- Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA
| | - Huyen Q Pham
- Division of Gynecology Oncology, Departments of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
| | - Adrian Correa
- Department of Surgical Pathology, University of Southern California, Los Angeles, California, USA
| | - Alexander Fedenko
- Department of Surgical Pathology, University of Southern California, Los Angeles, California, USA
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Niu ZS, Niu XJ, Wang M. Management of hepatocellular carcinoma: Predictive value of immunohistochemical markers for postoperative survival. World J Hepatol 2015; 7:7-27. [PMID: 25624992 PMCID: PMC4295195 DOI: 10.4254/wjh.v7.i1.7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 09/02/2014] [Accepted: 11/07/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for over 90% of all primary liver cancers. With an ever increasing incidence trend year by year, it has become the third most common cause of death from cancer worldwide. Hepatic resection is generally considered to be one of the most effective therapies for HCC patients, however, there is a high risk of recurrence in postoperative HCC. In clinical practice, there exists an urgent need for valid prognostic markers to identify patients with prognosis, hence the importance of studies on prognostic markers in improving the prediction of HCC prognosis. This review focuses on the most promising immunohistochemical prognostic markers in predicting the postoperative survival of HCC patients.
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Affiliation(s)
- Zhao-Shan Niu
- Zhao-Shan Niu, Lab of Micromorphology, Medical College of Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Zhao-Shan Niu, Lab of Micromorphology, Medical College of Qingdao University, Qingdao 266071, Shandong Province, China
| | - Mei Wang
- Zhao-Shan Niu, Lab of Micromorphology, Medical College of Qingdao University, Qingdao 266071, Shandong Province, China
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miR-223 inhibits dengue virus replication by negatively regulating the microtubule-destabilizing protein STMN1 in EAhy926 cells. Microbes Infect 2014; 16:911-22. [PMID: 25181337 PMCID: PMC7110837 DOI: 10.1016/j.micinf.2014.08.011] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 08/15/2014] [Accepted: 08/25/2014] [Indexed: 12/23/2022]
Abstract
The pathogenesis of dengue virus (DENV) infection is not completely understood. Endothelial cells may act as a target of the virus and be involved in disease pathogenesis. Therefore, the identification of host cell components involved in DENV replication would provide useful information for better understanding DENV infection. In this study, a significantly decreased level of miR-223 was found in DENV2-infected EAhy926 cells, a human endothelial-like cell line, whereas miR-223 overexpression inhibited DENV2 replication. Furthermore, we identified that miR-223 directly targeted the 3' untranslated region (3'UTR) of the messenger RNA (mRNA) for microtubule-destabilizing protein stathmin 1 (STMN1), thereby reducing its mRNA and protein levels. The depletion of miR-223 or overexpression of STMN1 enhanced DENV2 replication, whereas the opposite (increased miR-223 or decreased STMN1) suppressed DENV2 replication, indicating that miR-223 down-regulates STMN1 expression by targeting the 3'UTR of the STMN1 gene to inhibit DENV2 replication. Finally, we demonstrated that two transcription factors, C/EBPα and E2F1, are involved in the regulation of miR-223 levels after DENV2 infection in EAhy926 cells. Collectively, our results suggest that miR-223 may act as a novel antiviral factor, which may open an avenue to limit DENV infection.
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Atweh GF, Iancu-Rubin C. p27(Kip1) and STMN1: partners again? Cell Cycle 2014; 13:3163. [PMID: 25485493 PMCID: PMC4613596 DOI: 10.4161/15384101.2014.966580] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Accepted: 09/09/2014] [Indexed: 11/19/2022] Open
Affiliation(s)
- George F Atweh
- Vermont Cancer Center; University of Vermont, Burlington, NY USA
| | - Camelia Iancu-Rubin
- The Tisch Cancer Institute; Icahn School of Medicine at Mount Sinai; New York, NY USA
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