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Wang X, Ma M, Shao S, Xu X, Qin C, Gao R, Zhang Z. TWIST1 regulates HK2 ubiquitination degradation to promote pancreatic cancer invasion and metastasis. Cancer Cell Int 2025; 25:37. [PMID: 39920765 PMCID: PMC11806722 DOI: 10.1186/s12935-024-03583-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 11/22/2024] [Indexed: 02/09/2025] Open
Abstract
OBJECTIVE TWIST1 is known to promote glycolysis and contribute to pancreatic cancer development; however, its underlying mechanisms remain poorly understood. This study aims to elucidate the molecular mechanisms by which TWIST1 influences aerobic glycolysis in pancreatic ductal adenocarcinoma (PDAC). METHODS The expression levels of TWIST1, MMP9, MT1-MMP, and FDX1 in clinical tissues and cancer cell lines were assessed using quantitative reverse transcription PCR (QRT-PCR). Cell treatments with Elesclomol-Cu and 2-deoxyglucose (2DG) were conducted. Immunofluorescence staining and immunoprecipitation analyses were performed to investigate the binding relationship between TWIST1 and HK2. Colony formation and Transwell assays were utilized to evaluate the effects of TWIST1 on cell proliferation, migration, and invasion. Western blotting was employed to detect proteins related to cuproptosis and apoptosis, while ubiquitination assays assessed TWIST1's regulation of HK2 ubiquitination. RESULTS TWIST1 expression was significantly elevated in PDAC tissues, and over-expression of TWIST1 in PDAC cells enhanced colony formation and cell proliferation. Notably, HK2 levels were markedly higher in pancreatic cancer tissues compared to adjacent normal tissues. TWIST1 was found to directly bind and interact with HK2, showing co-localization in the cytoplasm of PDAC cells. Furthermore, TWIST1 was shown to stabilize HK2 by inhibiting its ubiquitin-mediated degradation. Knockdown of TWIST1 or HK2 enhanced the inhibitory effects of 2DG on cell migration and invasion. Treatment with Elesclomol-Cu and 2DG significantly reduced the expression of the cuproptosis-related factor FDX1 with no impact on other cell death factors. CONCLUSION This study demonstrates that TWIST1 regulates the ubiquitination and degradation of HK2, thereby promoting glycolysis-induced cuproptosis and facilitating pancreatic cancer invasion and metastasis. Understanding the underlying mechanisms of PDAC, including the regulation of key proteins such as HK2 by TWIST1, is crucial for developing more effective treatment strategies. Findings highlight the importance of targeting these molecular pathways, which could lead to improved diagnostic and therapeutic approaches, ultimately enhancing patient outcomes and prognosis.
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Affiliation(s)
- Xinxing Wang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Mingze Ma
- Departments of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Shuai Shao
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Xianwen Xu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Chuan Qin
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China
| | - Ruxin Gao
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Zhenhai Zhang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
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Joo DC, Kim GH, I H, Park SJ, Lee MW, Lee BE. Clinical Implications of Circulating Tumor Cells in Patients with Esophageal Squamous Cell Carcinoma: Cancer-Draining Blood Versus Peripheral Blood. Cancers (Basel) 2024; 16:2921. [PMID: 39199691 PMCID: PMC11352898 DOI: 10.3390/cancers16162921] [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: 07/25/2024] [Revised: 08/17/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024] Open
Abstract
Circulating tumor cells (CTCs) in cancer-draining veins have diagnostic and prognostic value. However, studies on esophageal squamous cell carcinoma (ESCC) are limited. This study aimed to compare CTCs obtained from different sampling sites (peripheral vein vs. cancer-draining azygos vein) and to investigate their association with the clinicopathological characteristics of ESCC patients. Blood samples were collected preoperatively from both veins in 40 ESCC patients at Pusan National University Hospital from June 2020 to April 2022. CTCs were detected using a centrifugal microfluidic method with fluid-assisted separation. CTCs and TWIST (+) CTCs were detected more frequently in the azygos vein blood than in the peripheral vein blood; however, the difference was not statistically significant (85.0% [34/40] vs. 77.5% [31/40], p = 0.250 and 82.5% [33/40] vs. 75.0% [30/40], p = 0.586, respectively). CTC and TWIST (+) CTC counts were significantly higher in the azygos vein blood than in the peripheral vein blood (7 vs. 3, p < 0.001, and 6 vs. 2, p < 0.001, respectively). CTCs and TWIST (+) CTCs from peripheral and azygos veins showed no association with clinicopathological characteristics. Further large-scale studies are needed to clarify their role as predictive biomarkers for prognosis and chemotherapy responses in ESCC patients.
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Affiliation(s)
- Dong Chan Joo
- Department of Internal Medicine, Pusan National University School of Medicine, Busan 49241, Republic of Korea; (D.C.J.); (M.W.L.); (B.E.L.)
- Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea;
| | - Gwang Ha Kim
- Department of Internal Medicine, Pusan National University School of Medicine, Busan 49241, Republic of Korea; (D.C.J.); (M.W.L.); (B.E.L.)
- Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea;
| | - Hoseok I
- Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea;
- Department of Thoracic and Cardiovascular Surgery, Pusan National University School of Medicine, Busan 49241, Republic of Korea
| | - Su Jin Park
- Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea;
| | - Moon Won Lee
- Department of Internal Medicine, Pusan National University School of Medicine, Busan 49241, Republic of Korea; (D.C.J.); (M.W.L.); (B.E.L.)
- Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea;
| | - Bong Eun Lee
- Department of Internal Medicine, Pusan National University School of Medicine, Busan 49241, Republic of Korea; (D.C.J.); (M.W.L.); (B.E.L.)
- Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea;
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Song WP, Wang SY, Zhou SC, Wu DS, Xie JY, Liu TT, Wu XZ, Che GW. Prognostic and clinicopathological value of Twist expression in esophageal cancer: A meta-analysis. World J Gastrointest Oncol 2022; 14:1874-1886. [PMID: 36187399 PMCID: PMC9516646 DOI: 10.4251/wjgo.v14.i9.1874] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/30/2022] [Accepted: 07/31/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Twist is a repressor of E-cadherin transcription that induces epithelial-mesenchymal transition and cancer metastasis. However, the prognostic value of Twist expression in patients with esophageal cancer remains controversial. AIM To investigate the prognostic and clinicopathological value of Twist expression in esophageal cancer. METHODS Published literature in databases such as EMBASE, Web of Science, PubMed, China National Knowledge Infrastructure, Wanfang, and VIP databases was searched for eligible articles. Participants with esophageal cancer whose tumor tissues underwent immunohistochemistry to detect the expression of Twist were considered. Our meta-analysis was conducted using Stata version 12.0. The hazard ratio (HR) and relative ratio (RR) with their 95%CI were pooled. Heterogeneity was estimated by I 2 statistics. RESULTS Eleven articles published between 2009 and 2021 fulfilled the selection criteria. The pooled HR for overall survival was 1.88 (95%CI: 1.32-2.69, I 2 = 68.6%), and the pooled HR for disease-free survival/relapse-free survival/progression-free survival was 1.84 (95%CI: 1.12-3.02, I 2 = 67.1%), suggesting that high Twist expression is associated with poor prognosis in esophageal cancer patients. In addition, overexpression of Twist was correlated with T stage (T3 + T4 vs T1 + T2, RR = 1.38, 95%CI: 1.14-1.67), lymph node metastasis (yes vs no, RR = 1.34, 95%CI: 1.11-1.60), distant metastasis (yes vs no, RR = 1.18, 95%CI: 1.02-1.35), tumor, node and metastasis (TNM) stage (III + IV vs I + II, RR = 1.35, 95%CI: 1.14-1.60), and clinical stage (III + IV vs I + II, RR = 1.58, 95%CI: 1.34-1.87). However, no correlation between Twist expression and age, gender, tumor location, differentiation, or venous invasion was observed. CONCLUSION High expression of Twist is associated with poor esophageal cancer prognosis. Moreover, Twist overexpression is correlated with T stage, lymph node metastasis, distant metastasis, TNM stage, and clinical stage, which indicates that Twist might accelerate esophageal cancer progression and metastasis.
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Affiliation(s)
- Wen-Peng Song
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Su-Yan Wang
- Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Si-Cheng Zhou
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Dong-Sheng Wu
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Yu Xie
- Laboratory Experiments in Microbiology, Shuang Liu Center for Disease Control and Prevention, Chengdu 610041, Sichuan Province, China
| | - Tong-Tong Liu
- West China School of Public Health & West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiu-Zhu Wu
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Guo-Wei Che
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Fardi Golyan F, Forghanifard MM. A new gene panel as a marker for ESCC poor prognosis; INPP5A, TWIST1, MMP2, and EGFR. Adv Med Sci 2021; 66:231-236. [PMID: 33798953 DOI: 10.1016/j.advms.2021.03.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/29/2021] [Accepted: 03/12/2021] [Indexed: 01/09/2023]
Abstract
PURPOSE Esophageal squamous cell carcinoma (ESCC) is categorized among ten common aggressive malignancies, with a higher incidence and mortality rates in the developing than in developed countries. The inositol polyphosphate 5-phosphatase (INPP5A), as an intracellular-calcium mobilizer and modifier enzyme, facilitates cell responses to various stimuli. Epithelial-mesenchymal transition (EMT), a transformation procedure, has a vital role in cancer progression and metastasis when epithelial cells lose their traits in favor of obtaining mesenchymal features. In this study, we analyzed the correlation between the expression of INPP5A and the involved genes in EMT pathway through the progression and development of the ESCCs. MATERIALS AND METHODS The gene expression analyses of INPP5A, TWIST1, MMP-2, and EGFR were performed using relative comparative real-time PCR in 58 ESCCs patients compared to corresponding margin-normal esophageal tissues. RESULTS A significant inverse correlation between INPP5A and EGFR/MMP-2 mRNA expression was observed in tumor samples. Underexpression of INPP5A was significantly correlated with overexpression of TWIST1, MMP-2, and EGFR in different invasiveness and aggressiveness pathological features of the ESCCs (P < 0.05). CONCLUSIONS The results propose a tumor suppressor role for INPP5A and oncogenic function for concomitant expression of the other genes in ESCC invasion and metastasis. The current study is the first report elucidating the correlation between the downregulation of INPP5A and upregulation of TWIST1, MMP-2, and EGFR in ESCC and introduces this panel of the genes as a marker for poor prognosis of the disease.
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Affiliation(s)
- Fatemeh Fardi Golyan
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Lee HJ, Kim GH, Park SJ, Kwon CH, Lee MW, Lee BE, Baek DH, I H. Clinical Significance of TWIST-Positive Circulating Tumor Cells in Patients with Esophageal Squamous Cell Carcinoma. Gut Liver 2021; 15:553-561. [PMID: 33293482 PMCID: PMC8283289 DOI: 10.5009/gnl20194] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 08/25/2020] [Accepted: 09/02/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND/AIMS Unlike other gastrointestinal tract cancers, there are relatively few reports on the clinical significance of circulating tumor cells (CTCs) and TWIST, a marker of epithelial-mesenchymal transition, in patients with esophageal squamous cell carcinoma (ESCC). This study aimed to evaluate the clinical significance of TWIST expression in CTCs in patients with ESCC. METHODS Peripheral blood samples for CTC analyses were prospectively obtained from 52 patients with ESCC prior to treatment between September 2017 and September 2019. CTCs were detected using a centrifugal microfluidic system based on a fluid-assisted separation technique, and CTCs positive for TWIST on immunostaining were defined as TWIST (+) CTCs. RESULTS Of the 52 patients with ESCC, CTCs and TWIST (+) CTCs were detected in 44 patients (84.6%) and 39 patients (75.0%), respectively. The CTC and TWIST (+) CTC counts were significantly higher in patients aged >65 years and those who had a large tumor (>3 cm) than in those aged ≤65 years and those who had a small tumor (≤3 cm), respectively. There were no differences in CTC and TWIST (+) CTC counts according to tumor location, histologic grade, or TNM stage. TWIST (+) CTCs were significantly associated with histologic grade; a proportion of TWIST (+) CTCs ≥0.5 was significantly associated with advanced histologic grade. Other clinicopathologic characteristics such as sex, age, tumor location, tumor size, and TNM stages were not significantly associated with TWIST (+) CTCs. CONCLUSIONS Our study showed that TWIST (+) CTCs were frequently detected in patients with ESCC, and a high proportion of TWIST (+) CTCs was associated with poor differentiation.
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Affiliation(s)
- Hyun Jung Lee
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
| | - Gwang Ha Kim
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Su Jin Park
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Chae Hwa Kwon
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Moon Won Lee
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
| | - Bong Eun Lee
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
| | - Dong Hoon Baek
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
| | - Hoseok I
- Department of Thoracic Surgery, Pusan National University College of Medicine, Busan, Korea
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Børretzen A, Gravdal K, Haukaas SA, Mannelqvist M, Beisland C, Akslen LA, Halvorsen OJ. The epithelial-mesenchymal transition regulators Twist, Slug, and Snail are associated with aggressive tumour features and poor outcome in prostate cancer patients. J Pathol Clin Res 2021; 7:253-270. [PMID: 33605548 PMCID: PMC8073012 DOI: 10.1002/cjp2.202] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 12/22/2020] [Accepted: 01/08/2021] [Indexed: 12/17/2022]
Abstract
The prognostic importance of transcription factors promoting epithelial-mesenchymal transition (EMT) and angiogenesis has not been well explored in prostate cancer patients with long follow-up, nor the interplay between these factors. The objective of this study was to assess the individual protein expression and co-expression of Twist, Slug (Snai2), Snail (Snai1), and hypoxia-inducible factor-1 alpha (Hif-1α) in prostate cancer in relation to EMT, angiogenesis, hypoxia, tumour features, disease recurrence, and patient survival. Immunohistochemical staining was performed on tissue microarray sections from 338 radical prostatectomies with long follow-up. In addition, 41 cases of prostatic hyperplasia, 33 non-skeletal metastases, 13 skeletal metastases, and 33 castration-resistant prostate carcinomas were included. Our findings were validated in external gene expression data sets. Twist was overexpressed in primary prostate cancer and markedly reduced in distant metastases (p < 0.0005). Strong expression of Twist and Slug was associated with Hif-1α in localised prostate cancer (p ≤ 0.001), and strong Twist was associated with Hif-1α in castration-resistant carcinomas (p = 0.044). Twist, Slug, and increased Snail at the tumour stromal border were associated with vascular factors (p ≤ 0.045). Each of the three EMT-regulating transcription factors were associated with aggressive tumour features and shorter time to recurrence and cancer-specific death. Notably, the co-expression of factors demonstrated an enhanced influence on outcome. In the subgroup of E-cadherinlow carcinomas, strong Slug was associated with shorter time to all end points and was an independent predictor of time to multiple end points, including cancer-specific death (hazard ratio 3.0, p = 0.041). To conclude, we demonstrate an important relation between EMT, hypoxia, and angiogenesis and a strong link between the investigated EMT regulators and aggressive tumour features and poor patient outcome in prostate cancer. Despite the retrospective nature of this long-term study, our findings could have a significant impact on the future treatment of prostate cancer, where tailored therapies might be directed simultaneously against epithelial-mesenchymal phenotypes, angiogenesis, and tumour hypoxia.
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Affiliation(s)
- Astrid Børretzen
- Centre for Cancer Biomarkers CCBIO, Gade Laboratory for Pathology, Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of PathologyHaukeland University HospitalBergenNorway
| | - Karsten Gravdal
- Department of PathologyHaukeland University HospitalBergenNorway
| | - Svein A Haukaas
- Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of UrologyHaukeland University HospitalBergenNorway
| | - Monica Mannelqvist
- Centre for Cancer Biomarkers CCBIO, Gade Laboratory for Pathology, Department of Clinical MedicineUniversity of BergenBergenNorway
| | - Christian Beisland
- Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of UrologyHaukeland University HospitalBergenNorway
| | - Lars A Akslen
- Centre for Cancer Biomarkers CCBIO, Gade Laboratory for Pathology, Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of PathologyHaukeland University HospitalBergenNorway
| | - Ole J Halvorsen
- Centre for Cancer Biomarkers CCBIO, Gade Laboratory for Pathology, Department of Clinical MedicineUniversity of BergenBergenNorway
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Dai SL, Wei SS, Zhang C, Li XY, Liu YP, Ma M, Lv HL, Zhang Z, Zhao LM, Shan BE. MTA2 promotes the metastasis of esophageal squamous cell carcinoma via EIF4E-Twist feedback loop. Cancer Sci 2021; 112:1060-1074. [PMID: 33340431 PMCID: PMC7935808 DOI: 10.1111/cas.14778] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 12/08/2020] [Accepted: 12/14/2020] [Indexed: 12/13/2022] Open
Abstract
Metastasis‐associated protein 2 (MTA2) is frequently amplified in many types of cancers; however, the role and underlying molecular mechanism of MTA2 in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we reported that MTA2 is highly expressed in ESCC tissue and cells, and is closely related to the malignant characteristics and poor prognosis of patients with ESCC. Through in vitro and in vivo experiments, we demonstrated that MTA2 significantly promoted ESCC growth, metastasis, and epithelial‐mesenchymal transition (EMT) progression. This integrative analysis combined with expression microarray showed that MTA2 could interact with eukaryotic initiation factor 4E (EIF4E), which positively regulates the expression of Twist, known as a master regulator of EMT. Moreover, the results of chromatin immunoprecipitation revealed that MTA2 was recruited to the E‐cadherin promoter by Twist, which reduced the acetylation level of the promoter region and thus inhibited expression of E‐cadherin, and subsequently promoted the aggressive progression of ESCC. Collectively, our study provided novel evidence that MTA2 plays an aggressive role in ESCC metastasis by a novel EIF4E‐Twist positive feedback loop, which may provide a potential therapeutic target for the management of ESCC.
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Affiliation(s)
- Su-Li Dai
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Si-Si Wei
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Cong Zhang
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiao-Ya Li
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yue-Ping Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ming Ma
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hui-Lai Lv
- Department of Fifth Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhenzhen Zhang
- Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Lian-Mei Zhao
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Bao-En Shan
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Kamarajah SK, Marson EJ, Zhou D, Wyn-Griffiths F, Lin A, Evans RPT, Bundred JR, Singh P, Griffiths EA. Meta-analysis of prognostic factors of overall survival in patients undergoing oesophagectomy for oesophageal cancer. Dis Esophagus 2020; 33:5843554. [PMID: 32448903 DOI: 10.1093/dote/doaa038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 03/25/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Currently, the American Joint Commission on Cancer (AJCC) staging system is used for prognostication for oesophageal cancer. However, several prognostically important factors have been reported but not incorporated. This meta-analysis aimed to characterize the impact of preoperative, operative, and oncological factors on the prognosis of patients undergoing curative resection for oesophageal cancer. METHODS This systematic review was performed according to PRISMA guidelines and eligible studies were identified through a search of PubMed, Scopus, and Cochrane CENTRAL databases up to 31 December 2018. A meta-analysis was conducted with the use of random-effects modeling to determine pooled univariable hazard ratios (HRs). The study was prospectively registered with the PROSPERO database (Registration: CRD42018157966). RESULTS One-hundred and seventy-one articles including 73,629 patients were assessed quantitatively. Of the 122 factors associated with survival, 39 were significant on pooled analysis. Of these. the strongly associated prognostic factors were 'pathological' T stage (HR: 2.07, CI95%: 1.77-2.43, P < 0.001), 'pathological' N stage (HR: 2.24, CI95%: 1.95-2.59, P < 0.001), perineural invasion (HR: 1.54, CI95%: 1.36-1.74, P < 0.001), circumferential resection margin (HR: 2.17, CI95%: 1.82-2.59, P < 0.001), poor tumor grade (HR: 1.53, CI95%: 1.34-1.74, P < 0.001), and high neutrophil:lymphocyte ratio (HR: 1.47, CI95%: 1.30-1.66, P < 0.001). CONCLUSION Several tumor biological variables not included in the AJCC 8th edition classification can impact on overall survival. Incorporation and validation of these factors into prognostic models and next edition of the AJCC system will enable personalized approach to prognostication and treatment.
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Affiliation(s)
- Sivesh K Kamarajah
- Northern Oesophagogastric Cancer Unit, Newcastle University NHS Foundation Trust Hospitals, Newcastle upon Tyne, UK.,Institute of Cellular Medicine, University of Newcastle, Newcastle upon Tyne, UK
| | - Ella J Marson
- College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Dengyi Zhou
- College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | | | - Aaron Lin
- College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Richard P T Evans
- Department of Upper Gastrointestinal Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.,Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - James R Bundred
- College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Pritam Singh
- Department of Upper Gastrointestinal Surgery, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK
| | - Ewen A Griffiths
- Department of Upper Gastrointestinal Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.,Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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Li C, Chen Y, Zhang Q, Guo C, Chen F, Xi S, Zeng J, Ke C, Sharma HS, Chen Z. Expression of Twist associated to microcirculation patterns of human glioma correlated with progression and survival of the patient. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 151:201-217. [PMID: 32448608 DOI: 10.1016/bs.irn.2020.03.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Twist is a transcription factor involved in the process of epithelial to mesenchymal transition (EMT) of carcinoma cells, and the promotion of invasion of gliomas through the mesenchymal adjusting process. However, its clinical significance in human glioma has not yet to be understood. To delineate the clinical-pathological significance and prognostic value of Twist, the expression of Twist was evaluated by Immunohistochemistry for 187 glioma samples. We found that Twist demonstrated frequent nuclear expression in the glioma samples and its expression levels were associated with tumor grade (P<0.001). Furthermore, high Twist expression was correlated with a poor outcome in patients with glioma (P=0.001), particularly with high grade glioma (P=0.026). Interestingly, Twist expression showed positive correlation with microvascular density (MVD) (r=0.145, P=0.048) as well as vasculogenic mimicry (VM) (r=0.273, P<0.001) in the tumors. These results suggest that Twist could be a predictor for poor prognosis in glioma patients. Additionally, Twist expression was associated with two major microcirculation patterns: endothelial-dependent vessels and VM in glioma, indicating that Twist could be a potential molecular target for anti-glioma therapy.
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Affiliation(s)
- Cong Li
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yinsheng Chen
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Qingping Zhang
- Department of Neurosurgery, Shenzhen Nanshan People's Hospital (Shenzhen University Sixth Affiliated Hospital), Shenzhen, China
| | - Chengcheng Guo
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Furong Chen
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shaoyan Xi
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jing Zeng
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chao Ke
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, University Hospital, Uppsala University, S-75185 Uppsala, Sweden.
| | - Zhongping Chen
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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Forghanifard MM, Azaraz S, Ardalan Khales S, Morshedi Rad D, Abbaszadegan MR. MAML1 promotes ESCC aggressiveness through upregulation of EMT marker TWIST1. Mol Biol Rep 2020; 47:2659-2668. [PMID: 32180088 DOI: 10.1007/s11033-020-05356-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/27/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Mastermind-like 1 (MAML1) is the main transcriptional co-activator of Notch signaling pathway. It plays essential roles in several pathways including MEF2C, p53, Nf-кB and Wnt/β-catenin. TWIST1 is known as a regulator of epithelial mesenchymal transition (EMT), which is considered as a primary step in promotion of tumor cell metastasis. Since concomitant expression of these genes was observed in tumors, our aim in this study was to elucidate the linkage between MAML1 and TWIST1 co-overexpression in esophageal squamous cell carcinoma (ESCC). RESULTS While MAML1 silencing significantly down-regulated TWIST1, its ectopic expression up-regulated TWIST1 expression in both mRNA and protein levels in KYSE-30 cells. Expression of mesenchymal markers was increased significantly after MAML1 and TWIST1 ectopic expression, while epithelial markers expression was significantly decreased after silencing of both genes. Concomitant protein expression of MAML1 and TWIST1 was significantly observed in ESCC patients. Enforced expression of TWIST1 had no impact on MAML1 gene expression in KYSE-30 cells. CONCLUSION The results clearly suggest transcriptional regulation of TWIST1 by MAML1 transcription factor in ESCC cells KYSE-30. Since TWIST1 is known as an EMT inducing marker, our results may revealed the mastermind behind TWIST1 function and introduced MAML1 as an upstream master regulator of TWIST1 and EMT in KYSE-30 cells.
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Affiliation(s)
| | - Shirin Azaraz
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sima Ardalan Khales
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Dorsa Morshedi Rad
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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11
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Shen Q, Shang B, Jiang B, Wang Y, Wang Z, Chen G. Overexpression of JAB1 promotes malignant behavior and predicts poor prognosis in esophageal squamous cell carcinoma. Thorac Cancer 2020; 11:973-982. [PMID: 32064781 PMCID: PMC7113044 DOI: 10.1111/1759-7714.13350] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/14/2020] [Accepted: 01/21/2020] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND This study investigated the expression and biological function of JAB1 in esophageal squamous cell carcinoma (ESCC). METHODS The expression of JAB1 in ESCC tissues and cells was measured using reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and western blot analysis. Kaplan-Meier survival analysis was performed to explore the effect of JAB1 expression on the prognosis of ESCC patients. Furthermore, experiments were conducted in vivo and in vitro to determine the effect of JAB1 expression on the malignant behavior of ESCC cells. RESULTS Compared with adjacent tissues, JAB1 was highly overexpressed in cancer tissues (P = 0.01). Univariate and multivariate analyses of clinical data indicated that patients with JAB1 overexpression had a worse prognosis (P = 0.001 and P = 0.049, respectively). Cell function experiments and tumorigenesis experiments in nude mice showed that the upregulation of JAB1 might promote malignant behavior, and vice versa. CONCLUSIONS Overexpression of JAB1 promoted the proliferation, migration, and invasion of ESCC cells, and was significantly associated with poor prognosis of ESCC patients. Therefore, JAB1 could be considered as a promising prognostic factor and a possible target for the specific therapy of ESCC. KEY POINTS In this study, we found that JAB1 was highly overexpressed in cancer tissues, which could influence the malignant behavior of ESCC cells, and was significantly associated with poor prognosis of ESCC patients.
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Affiliation(s)
- Qi Shen
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Bin Shang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Bin Jiang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Yu Wang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Zhou Wang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Gang Chen
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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12
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Zhu Y, Zhang W, Wang P. Smoking and gender modify the effect of TWIST on patient survival in head and neck squamous carcinoma. Oncotarget 2017; 8:85816-85827. [PMID: 29156759 PMCID: PMC5689649 DOI: 10.18632/oncotarget.20682] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 07/26/2017] [Indexed: 12/20/2022] Open
Abstract
PURPOSE TWIST is a critical factor for predicting prognosis in several human cancers. Here, we study the prognostic significance of TWIST1 and TWIST2 in Head and Neck squamous cell carcinoma (HNSCC) as well as interactions of TWISTs with both gender and smoking in patient survival. METHODS upper quartile normalized RNA-seq V2 RSEM values of TWIST1 and TWIST2 expressions were retrieved from a TCGA HNSCC dataset. Kaplan-Meier survival curves were used to assess the associations of TWIST1 and TWIST2 with patient survival, and multivariate Cox proportional hazards regression models were used to estimate the hazards ratios (HRs) and their 95% confidence intervals (CIs). RESULTS Survival analyses showed that high TWIST1 expression was associated with a poor overall survival at a borderline significance level, while a superior but not statistically significant overall survival was observed in high TWIST2 expression. The multivariate Cox proportional hazards regression model showed a significantly elevated risk of death (HR=1.37, p = 0.038) in patients with high TWIST1 compared to low TWIST1, and a borderline significantly decreased risk of death (HR = 0.74, p = 0.055) in patients with high TWIST2 compared to low TWIST2. Further stratification analyses showed that increased risks of death were found significantly in male and borderline significantly in smoker patients with high TWIST1 compared to low one, and a significantly decreased risk of death in non-smoker patients with high TWIST2 compared to low one. CONCLUSIONS TWIST1 and TWIST2 are differentially associated with HNSCC patient survival. Gender and smoking could modify the effect of TWISTs on the risk of death in HNSCC patients.
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Affiliation(s)
- Yun Zhu
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wenjuan Zhang
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Ping Wang
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Cancer Genetic Laboratory, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77025, USA
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13
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Zhao Z, Rahman MA, Chen ZG, Shin DM. Multiple biological functions of Twist1 in various cancers. Oncotarget 2017; 8:20380-20393. [PMID: 28099910 PMCID: PMC5386770 DOI: 10.18632/oncotarget.14608] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 01/01/2017] [Indexed: 01/05/2023] Open
Abstract
Twist1 is a well-known regulator of transcription during embryonic organogenesis in many species. In humans, Twist1 malfunction was first linked to Saethre-Chotzen syndrome and later identified to play an essential role in tumor initiation, stemness, angiogenesis, invasion, metastasis, and chemo-resistance in a variety of carcinomas, sarcomas, and hematological malignances. In this review, we will first focus on systematically elaborating the diverse pathological functions of Twist1 in various cancers, then delineating the intricate underlying network of molecular mechanisms, based on which we will summarize current therapeutic strategies in cancer treatment that target and modulate Twist1-involved signaling pathways. Most importantly, we will put special emphasis on revealing the independence and interdependency of these multiple biological functions of Twist1, piecing together the whole delicate picture of Twist1's diversified pathological roles in different cancers and providing new perspectives to guide future research.
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Affiliation(s)
- Zhixiang Zhao
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States of America.,Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mohammad Aminur Rahman
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States of America
| | - Zhuo G Chen
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States of America
| | - Dong M Shin
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States of America
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14
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Forghanifard MM, Rad A, Farshchian M, Khaleghizadeh M, Gholamin M, Moghbeli M, Abbaszadegan MR. TWIST1 upregulates the MAGEA4 oncogene. Mol Carcinog 2017; 56:877-885. [DOI: 10.1002/mc.22541] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Overexpression of MAGEA4 oncogene has been demonstrated in different malignancies; however, little is known about its exact mechanism for overexpression. TWIST1, as a bHLH transcription factor, activates a cell migration‐invasion program involved in both embryonic and tumor development. Since MAGEA4 overexpression was statistically correlated to TWIST1, we aimed to elucidate the probable regulatory role of TWIST1 on MAGEA4 expression in KYSE30 cells. Methods: Expression pattern of MAGEA4 and TWIST1 was analyzed in 55 ESCC patients using relative comparative real‐time PCR. In silico analysis of the MAGEA4 gene was performed. Methylation status of MAGEA4 promoter was determined by quantitative methylation specific PCR (qMSP). Using a retroviral system, KYSE30 cells were transduced to ectopically express TWIST1, followed by qRT‐PCR, Western blot analysis, chromatin immunoprecipitation (ChIP), and luciferase assays to elucidate the regulatory role of TWIST1 on MAGEA4 gene expression. Results: Concomitant overexpression of MAGEA4 and TWIST1 was detected in ESCC in significant correlation with each other in different clinicopathological indices of poor prognosis (P < 0.05). The TWIST1‐expressing cells showed significantly higher MAGEA4 expression compared to control cells. ChIP and luciferase assays results confirmed indirect binding of TWIST1 to the E‐boxes of MAGEA4 promoter sequence and revealed a novel regulatory role of TWIST1 in MAGEA4 upregulation. Conclusion: Since MAGEA4 is a highly expressed oncogene in a variety of malignancies in significant correlation with tumor cell invasiveness and aggressiveness, our finding may help understand one regulatory mechanism of increased expression in tumor cells. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
| | - Abolfazl Rad
- Cellular and Molecular Research Center Sabzevar University of Medical Sciences Sabzevar Iran
| | - Moein Farshchian
- Molecular Medicine Research Department ACECR‐Khorasan Razavi Branch Mashhad Iran
| | - Maryam Khaleghizadeh
- Division of Human Genetics Immunology Research Center Avicenna Research Institute Mashhad University of Medical Sciences Mashhad Iran
| | - Mehran Gholamin
- Division of Human Genetics Immunology Research Center Avicenna Research Institute Mashhad University of Medical Sciences Mashhad Iran
| | - Meysam Moghbeli
- Division of Human Genetics Immunology Research Center Avicenna Research Institute Mashhad University of Medical Sciences Mashhad Iran
| | - Mohammad Reza Abbaszadegan
- Division of Human Genetics Immunology Research Center Avicenna Research Institute Mashhad University of Medical Sciences Mashhad Iran
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15
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Aspirin, lysine, mifepristone and doxycycline combined can effectively and safely prevent and treat cancer metastasis: prevent seeds from gemmating on soil. Oncotarget 2016; 6:35157-72. [PMID: 26459390 PMCID: PMC4742096 DOI: 10.18632/oncotarget.6038] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 09/14/2015] [Indexed: 12/11/2022] Open
Abstract
Recent scientific advances have increased our understanding of the cancer metastatic complexities and provided further impetus for new combination therapies to prevent cancer metastasis. Here, we demonstrated that a combination (HAMPT) of aspirin, lysine, mifepristone and doxycycline can effectively and safely prevent cancer metastasis. The pharmaceutically-formulated HAMPT inhibited adhesion of cancer cells to either endothelial cells or extracellular matrix via down-regulating cell adhesion molecules ICAM-1 and α4-integrin. HAMPT inhibited the cloak effect by activated platelets on cancer cells, thereby interfering adhesion and invasion of cancer cells to the underlying stroma. At the effective concentration, HAMPT induced cancer cells into dormancy with minor inhibition on cell viability. Four-day pretreatment followed by 30-day oral administration of HAMPT (33.5-134 mg/kg) to the mice inoculated with cancer cells produced significant inhibition on cancer metastasis dose-dependently without marked side effects. Fifty-day rat toxicity study with HAMPT at doses (335-1340 mg/kg) 20-fold higher than its therapeutic dose produced no significant toxicity. Interestingly, the acute toxic death could not be reached at the maximum administrable dose (5 g/kg). This proof-of-concept study provides the first conceptual evidence that cancer metastasis can be controlled by using affordable old drugs to restrain circulating tumor cells from gemmating on the metastatic soil without the need for cytotoxicity.
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16
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García-Palmero I, Torres S, Bartolomé RA, Peláez-García A, Larriba MJ, Lopez-Lucendo M, Peña C, Escudero-Paniagua B, Muñoz A, Casal JI. Twist1-induced activation of human fibroblasts promotes matrix stiffness by upregulating palladin and collagen α1(VI). Oncogene 2016; 35:5224-5236. [PMID: 26973246 DOI: 10.1038/onc.2016.57] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 01/13/2016] [Accepted: 01/26/2016] [Indexed: 12/17/2022]
Abstract
The transcription factor Twist1 is involved in the epithelial-mesenchymal transition and contributes to cancer metastasis through mostly unknown mechanisms. In colorectal cancer, Twist1 expression is mainly restricted to the tumor stroma. We found that human fibroblast cell lines stably transfected with Twist1 acquired characteristics of activated cancer-associated fibroblasts (CAFs), such as hyperproliferation, an increased ability to migrate and an alignment of the actin cytoskeleton. Further, Twist1-activated fibroblasts promoted increased matrix stiffness. Using quantitative proteomics, we identified palladin and collagen α1(VI) as two major mediators of the Twist1 effects in fibroblast cell lines. Co-immunoprecipitation studies indicated that palladin and Twist1 interact within the nucleus, suggesting that palladin could act as a transcription regulator. Palladin was found to be more relevant for the cellular biomechanical properties, orientation and polarity, and collagen α1(VI) for the migration and invasion capacity, of Twist1-activated fibroblasts. Both palladin and collagen α1(VI) were observed to be overexpressed in colorectal CAFs and to be associated with poor colorectal cancer patient survival and relapse prediction. Our results demonstrate that Twist1-expressing fibroblasts mimic the properties of CAFs present at the tumor invasive front, which likely explains the prometastatic activities of Twist1. Twist1 appears to require both palladin and collagen α1(VI) as downstream effectors for its prometastatic effects, which could be future therapeutic targets in cancer metastasis.
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Affiliation(s)
- I García-Palmero
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - S Torres
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - R A Bartolomé
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - A Peláez-García
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - M J Larriba
- Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), IdiPAZ, Madrid, Spain
| | - M Lopez-Lucendo
- Proteomics Core Facility, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - C Peña
- Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
| | - B Escudero-Paniagua
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - A Muñoz
- Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), IdiPAZ, Madrid, Spain
| | - J I Casal
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
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17
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de Paiva Gonçalves V, Ortega AAC, Guimarães MR, Curylofo FA, Junior CR, Ribeiro DA, Spolidorio LC. Chemopreventive Activity of Systemically Administered Curcumin on Oral Cancer in the 4-Nitroquinoline 1-Oxide Model. J Cell Biochem 2015; 116:787-96. [DOI: 10.1002/jcb.25035] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 12/11/2014] [Indexed: 01/05/2023]
Affiliation(s)
- Vinícius de Paiva Gonçalves
- Department of Diagnosis and Surgery; Araraquara School of Dentistry; University of São Paulo State UNESP; Araraquara SP Brazil
| | - Adriana Alicia C. Ortega
- Department of Diagnosis and Surgery; Araraquara School of Dentistry; University of São Paulo State UNESP; Araraquara SP Brazil
| | - Morgana R. Guimarães
- Department of Diagnosis and Surgery; Araraquara School of Dentistry; University of São Paulo State UNESP; Araraquara SP Brazil
| | - Fabiana Almeida Curylofo
- Department of Diagnosis and Surgery; Araraquara School of Dentistry; University of São Paulo State UNESP; Araraquara SP Brazil
| | - Carlos Rossa Junior
- Department of Diagnosis and Surgery; Araraquara School of Dentistry; University of São Paulo State UNESP; Araraquara SP Brazil
| | - Daniel Araki Ribeiro
- Department of Biosciences; Federal University of São Paulo UNIFESP; Santos SP Brazil
| | - Luis C. Spolidorio
- Department of Physiology and Pathology; Araraquara School of Dentistry; University of São Paulo State UNESP; Araraquara SP Brazil
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18
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Zhang P, Hu P, Shen H, Yu J, Liu Q, Du J. Prognostic role of Twist or Snail in various carcinomas: a systematic review and meta-analysis. Eur J Clin Invest 2014; 44:1072-94. [PMID: 25257753 DOI: 10.1111/eci.12343] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 09/21/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Twist and Snail are considered as key transcriptional repressors of E-cadherin tightly related to epithelial-to-mesenchymal transition (EMT) and cancer progression. Numerous studies have investigated the prognostic value of Twist and Snail. However, the published results were controversial or even opposite. Our article aimed to evaluate the prognostic role of Twist and Snail in patients with cancer. DESIGN A comprehensive literature search of PubMed, Embase and Web of Science was conducted. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were assessed to quantify the prognostic role. RESULTS The pooled HR with 38 studies for Twist was 2·18 (95% CI: 1·77-2·68, I(2) = 69·8%, P = 0·000) and for Snail with 40 studies was 1·58 (95% CI: 1·33-1·87, I(2) = 70·0%, P = 0·000), suggesting high Twist/Snail expression predicted poor prognosis related to all clinical outcomes. For Twist, the pooled HR for overall survival (OS) was 2·07 (95% CI: 1·63-2·63, I(2) = 72·6%, P = 0·000) and for progression-free/recurrence-free/metastasis-free/disease-free/cancer-free survival (PFS/RFS/MFS/DFS/CFS) was 2·36 (95% CI: 1·76-3·17, I(2) = 65·0%, P = 0·000). For Snail, the pooled HR for OS was 1·63 (95% CI: 1·33-1·99, I(2) = 70·8%, P = 0·000) and for PFS/RFS/MFS/DFS/CFS was 1·54 (95% CI: 1·17-2·02, I(2) = 59·1%, P = 0·001). All of those results were suggesting that high Twist/Snail expression was associated with poor prognosis. Furthermore, when grouped into different types of cancers, the pooled HRs were also calculated for the subgroups. No publication bias was found except studies evaluating all clinical outcomes of Twist (P = 0·006 for Begg's test and 0·006 for Egger's test). CONCLUSIONS Elevated Twist or Snail expression in tumour tissue indicated poor prognosis for cancer.
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Affiliation(s)
- Ping Zhang
- Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, China
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Nantajit D, Lin D, Li JJ. The network of epithelial-mesenchymal transition: potential new targets for tumor resistance. J Cancer Res Clin Oncol 2014; 141:1697-713. [PMID: 25270087 DOI: 10.1007/s00432-014-1840-y] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 09/20/2014] [Indexed: 12/12/2022]
Abstract
PURPOSE In multiple cell metazoans, the ability of polarized epithelial cells to convert to motile mesenchymal cells in order to relocate to another location is governed by a unique process termed epithelial-mesenchymal transition (EMT). While being an essential process of cellular plasticity for normal tissue and organ developments, EMT is found to be involved in an array of malignant phenotypes of tumor cells including proliferation and invasion, angiogenesis, stemness of cancer cells and resistance to chemo-radiotherapy. Although EMT is being extensively studied and demonstrated to play a key role in tumor metastasis and in sustaining tumor hallmarks, there is a lack of clear picture of the overall EMT signaling network, wavering the potential clinical trials targeting EMT. METHODS In this review, we highlight the potential key therapeutic targets of EMT linked with tumor aggressiveness, hypoxia, angiogenesis and cancer stem cells, emphasizing on an emerging EMT-associated NF-κB/HER2/STAT3 pathway in radioresistance of breast cancer stem cells. RESULTS Further definition of cancer stem cell repopulation due to EMT-controlled tumor microenvironment will help to understand how tumors exploit the EMT mechanisms for their survival and expansion advantages. CONCLUSIONS The knowledge of EMT will offer more effective targets in clinical trials to treat therapy-resistant metastatic lesions.
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Affiliation(s)
- Danupon Nantajit
- Radiation Oncology Unit, Chulabhorn Hospital, Bangkok, 10210, Thailand
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Ng L, Poon RTP, Pang R. Biomarkers for predicting future metastasis of human gastrointestinal tumors. Cell Mol Life Sci 2013; 70:3631-56. [PMID: 23370778 PMCID: PMC11113832 DOI: 10.1007/s00018-013-1266-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Revised: 01/02/2013] [Accepted: 01/10/2013] [Indexed: 12/19/2022]
Abstract
The recent advances in surgery and radiation therapy have significantly improved the prognosis of patients with primary cancer, and the major challenge of cancer treatment now is metastatic disease development. The 5-year survival rate of cancer patients who have distant metastasis at diagnosis is extremely low, suggesting that prediction and early detection of metastasis would definitely improve their prognosis because suitable patient therapeutic management and treatment strategy can be provided. Cancer cells from a primary site give rise to a metastatic tumor via a number of steps which require the involvement and altered expression of many regulators. These regulators may serve as biomarkers for predicting metastasis. Over the past few years, numerous regulators have been found correlating with metastasis. In this review, we summarize the findings of a number of potential biomarkers that are involved in cadherin-catenin interaction, integrin signaling, PI3K/Akt/mTOR signaling and cancer stem cell identification in gastrointestinal cancers. We will also discuss how certain biomarkers are associated with the tumor microenvironment that favors cancer metastasis.
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Affiliation(s)
- Lui Ng
- Department of Surgery, The University of Hong Kong, 102 Pokfulam Road, Hong Kong SAR, China,
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21
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Xu G, Tang S, Yang J, Chen K, Kang J, Zhao G, Feng F, Yang X, Zhao L, Lu Q, Sun L, Hong L, Gong T, Zhang H. BMP7 expression in esophageal squamous cell carcinoma and its potential role in modulating metastasis. Dig Dis Sci 2013; 58:1871-9. [PMID: 23504348 DOI: 10.1007/s10620-013-2611-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Accepted: 02/18/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Our previous study showed that BMP7 revealed significantly higher levels in esophageal squamous cell carcinoma (ESCC) tissues with lymph node metastasis compared with non-lymph node metastasis, using gene expression profiling assays. The roles of BMP7 in ESCC is not fully understood. AIM The aim of this study was to investigate the effect of BMP7 on lymph node metastasis of ESCC and to explore its potential mechanism. METHODS Expression of BMP7 in ESCC tissues was evaluated by immunohistochemistry. BMP7 were down-regulated by RNA interference. The protein and mRNA levels of BMP7 were detected by western blot and RT-PCR, respectively. High content screening and transwell assay were used to identify the metastatic ability of tumor cells. RESULTS Positivity of BMP7 staining was 57.5 % in the tissues of primary carcinoma with lymph node metastasis compared to tissues without lymph node metastasis, and expression of BMP7 was significantly higher in the cell lines with highly metastatic capacity than that in the cell lines without metastatic ability. Suppression of endogenous BMP7 expression by siRNA in the highly metastatic cell lines resulted in significant reduction in ability of cell migration and invasion in both in vitro and in vivo studies. In addition, inhibition of BMP7 by siRNA also leads to up-regulation of E-cadherin and down-regulation of MMP-9 in the highly metastatic cell lines. CONCLUSIONS These findings indicate that BMP7 modulates the expression of E-cadherin and MMP-9, and by which mechanism it may regulate cell migration and metastasis of ESCCs.
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Affiliation(s)
- Guanghui Xu
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 15 Changle Western Road, Xi'an 710032, People's Republic of China
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Hui L, Zhang S, Dong X, Tian D, Cui Z, Qiu X. Prognostic significance of twist and N-cadherin expression in NSCLC. PLoS One 2013; 8:e62171. [PMID: 23626784 PMCID: PMC3633889 DOI: 10.1371/journal.pone.0062171] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2012] [Accepted: 03/18/2013] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Metastasis is the most common cause of disease failure and mortality for non-small cell lung cancer after surgical resection. Twist has been recently identified as a putative oncogene and a key regulator of carcinoma metastasis. N-cadherin is associated with a more aggressive behavior of cell lines and tumors. The aim of this study was to evaluate the clinical relevance of Twist and N-cadherin expression in NSCLC, and the effects of Twist1 knockdown on lung cancer cells. METHODS We examined the expressions of Twist and N-cadherin by immunohistochemistry in 120 cases of non-small cell lung cancer (including 68 cases with follow-up records). We also analyzed Twist1 and N-cadherin mRNA expression in 30 non-small cell lung cancer tissues using quantitative reverse transcription polymerase chain reaction. The functional roles of Twist1 in lung cancer cell lines were evaluated by small interfering RNA-mediated depletion of the protein followed by analyses of cell apoptosis and invasion. RESULTS In lung cancer tissues, the overexpression rate of Twist was 38.3% in lung cancer tissues. Overexpression of N-cadherin was shown in 40.83% of primary tumors. Moreover, Twist1 mRNA expression levels correlated with N-cadherin mRNA levels. Furthermore, overexpression of Twist1 or N-cadherin in primary non-small cell lung cancers was associated with a shorter overall survival (P<0.01, P<0.01, respectively). Depleting Twist expression inhibited cell invasion and increased apoptosis in lung cancer cell lines. CONCLUSIONS The overexpression of Twist and N-cadherin could be considered as useful biomarkers for predicting the prognosis of NSCLC. Twist1 could inhibit apoptosis and promote the invasion of lung cancer cells, and depletion of Twist1 in lung cancer cells led to inhibition of N-cadherin expression.
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Affiliation(s)
- Linping Hui
- Laboratory Center, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
- Center of Laboratory Technology and Experimental Medicine, China Medical University,Shenyang, China
| | - Siyang Zhang
- Center of Laboratory Technology and Experimental Medicine, China Medical University,Shenyang, China
| | - Xinjun Dong
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China
| | - Dali Tian
- Department of Thoracic Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, PR China
| | - Zeshi Cui
- Center of Laboratory Technology and Experimental Medicine, China Medical University,Shenyang, China
| | - Xueshan Qiu
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China
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Low-Marchelli JM, Ardi VC, Vizcarra EA, van Rooijen N, Quigley JP, Yang J. Twist1 induces CCL2 and recruits macrophages to promote angiogenesis. Cancer Res 2013; 73:662-71. [PMID: 23329645 DOI: 10.1158/0008-5472.can-12-0653] [Citation(s) in RCA: 147] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The transcription factor Twist1 induces epithelial-mesenchymal transition and extracellular matrix degradation to promote tumor metastasis. Although Twist1 also plays a role in embryonic vascular development and tumor angiogenesis, the molecular mechanisms that underlie these processes are not as well understood. Here, we report a novel function for Twist1 in modifying the tumor microenvironment to promote progression. We found that expression of Twist1 in human mammary epithelial cells potently promoted angiogenesis. Surprisingly, Twist1 expression did not increase the secretion of the common proangiogenic factors VEGF and basic fibroblast growth factor but rather induced expression of the macrophage chemoattractant CCL2. Attenuation of endogenous Twist1 in vivo blocked macrophage recruitment and angiogenesis, whereas exogenous CCL2 rescued the ability of tumor cells lacking Twist1 to attract macrophages and promote angiogenesis. Macrophage recruitment also was essential for the ability of Twist1-expressing cells to elicit a strong angiogenic response. Together, our findings show that how Twist1 recruits stromal macrophages through CCL2 induction to promote angiogenesis and tumor progression. As Twist1 expression has been associated with poor survival in many human cancers, this finding suggests that anti-CCL2 therapy may offer a rational strategy to treat Twist1-positive metastatic cancers.
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Affiliation(s)
- Janine M Low-Marchelli
- Biomedical Sciences Program, Department of Pharmacology, University of California, San Diego, CA 92093, USA
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Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 2012; 22. [PMID: 23201165 PMCID: PMC3522773 DOI: 10.1016/j.ccr.2012.09.022] [Citation(s) in RCA: 850] [Impact Index Per Article: 65.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Epithelial-mesenchymal transition (EMT) is implicated in converting stationary epithelial tumor cells into motile mesenchymal cells during metastasis. However, the involvement of EMT in metastasis is still controversial, due to the lack of a mesenchymal phenotype in human carcinoma metastases. Using a spontaneous squamous cell carcinoma mouse model, we show that activation of the EMT-inducing transcription factor Twist1 is sufficient to promote carcinoma cells to undergo EMT and disseminate into blood circulation. Importantly, in distant sites, turning off Twist1 to allow reversion of EMT is essential for disseminated tumor cells to proliferate and form metastases. Our study demonstrates in vivo the requirement of "reversible EMT" in tumor metastasis and may resolve the controversy on the importance of EMT in carcinoma metastasis.
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Affiliation(s)
- Jeff H. Tsai
- Department of Pharmacology, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0636
| | - Joana Liu Donaher
- Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142
| | | | - Sandra Chau
- Department of Pharmacology, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0636
| | - Jing Yang
- Department of Pharmacology, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0636
- Department of Pediatrics, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0636
- To whom correspondence should be addressed:
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25
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Wu CY, Hung JJ, Wu KJ. Linkage between Twist1 and Bmi1: molecular mechanism of cancer metastasis/stemness and clinical implications. Clin Exp Pharmacol Physiol 2012; 39:668-73. [PMID: 21883379 DOI: 10.1111/j.1440-1681.2011.05594.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Cancer metastasis is the major cause of cancer-related death despite significant improvements in multimodal cancer therapy. Epithelial-mesenchymal transition (EMT), a major mechanism of cancer metastasis, is a process that generates cells with stem cell-like properties (cancer stemness). Cancer stemness is a concept that describes a minor population of cells (cancer stem cells) residing within a tumour that are able to self-renew and are resistant to conventional therapy. The mechanisms delineating the generation of cancer stemness and its connection to cancer metastasis remain largely unknown. Twist1 is an EMT regulator and increased Twist1 expression, which has prognostic significance in various human cancers, has been widely reported. Bmi1 is a critical component of polycomb repressive complex (PRC) 1, which maintains self-renewal and stemness. Bmi1 is frequently overexpressed in different types of human cancers and can induce drug resistance (Table 2). Recent studies have shown that Twist1 directly activates Bmi1 expression and that these two molecules function together to mediate cancer stemness and EMT. These results present a unique mechanism of EMT-induced cancer metastasis and stemness. Further investigation of the mechanisms of EMT-mediated cancer metastasis and stemness will contribute to the management and treatment of metastatic cancers.
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Affiliation(s)
- Chung-Yin Wu
- Department of Occupational Medicine, Far Eastern Memorial Hospital, New Taipei City, Taipei, Taiwan
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Fan XJ, Wan XB, Yang ZL, Fu XH, Huang Y, Chen DK, Song SX, Liu Q, Xiao HY, Wang L, Wang JP. Snail promotes lymph node metastasis and Twist enhances tumor deposit formation through epithelial-mesenchymal transition in colorectal cancer. Hum Pathol 2012; 44:173-80. [PMID: 22974478 DOI: 10.1016/j.humpath.2012.03.029] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2011] [Revised: 03/03/2012] [Accepted: 03/07/2012] [Indexed: 12/15/2022]
Abstract
Snail and Twist, transcriptional repressors of E-cadherin as well as inducers of epithelial-mesenchymal transition, play pivotal roles in tumor invasion and metastasis. We investigated the expression of Snail, Twist, and E-cadherin by immunohistochemistry in 193 colorectal cancers, including 79 with positive lymph nodes, 36 with tumor deposits, 39 with both, and 39 with no metastases. Snail was expressed to a greater extent in the group with positive lymph nodes (68.4%), whereas Twist was overexpressed in patients with other metastases (75.0%). Ectopic expression of Snail and Twist correlated with reduced membranous expression of E-cadherin. Importantly, Snail overexpression correlated significantly with lymph node metastasis (P < .0001), whereas Twist up-regulation correlated strongly with other metastases (P < .0001). Multivariate logistic regression analysis showed that Snail was an independent predictor of lymph node metastasis (odds ratio, 4.445; 95% confidence interval, 2.250-8.781; P < .0001), whereas Twist displayed predictive value for metastasis formation (odds ratio, 5.606; 95% confidence interval, 2.829-11.111; P < .0001), suggesting that lymph node and other metastases may follow different signaling pathways. In conclusion, ectopic expression of Snail and Twist contributed to lymph node and disseminated metastasis, respectively, by reducing E-cadherin expression, providing a novel role for Snail and Twist in the progression of colorectal cancer.
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Affiliation(s)
- Xin-Juan Fan
- Department of Pathology, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
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27
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Huang SD, Yuan Y, Zhuang CW, Li BL, Gong DJ, Wang SG, Zeng ZY, Cheng HZ. MicroRNA-98 and microRNA-214 post-transcriptionally regulate enhancer of zeste homolog 2 and inhibit migration and invasion in human esophageal squamous cell carcinoma. Mol Cancer 2012; 11:51. [PMID: 22867052 PMCID: PMC3496689 DOI: 10.1186/1476-4598-11-51] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2012] [Accepted: 07/26/2012] [Indexed: 12/22/2022] Open
Abstract
Background The enhancer of zeste homolog 2 (EZH2) was found to be overexpressed and associated with tumor metastasis in esophageal squamous cell carcinoma (ESCC). On the other hand, it was reported that miR-26a, miR-98, miR-101, miR-124, miR-138 and miR-214 could inhibit the expression of EZH2 in some tumors. However, the role of miRNAs in the regulation of EZH2 expression in human ESCC has not been documented. The aim of this study was to determine the role of these miRNAs in the regulation of tumor metastasis via EZH2 overexpression in human ESCC. Methods and results The expression of these miRNAs and EZH2 mRNA were examined by qPCR and the expression of EZH2 protein was detected by western blot. The role of these miRNAs in migration and invasion was studied in ESCC cell line (Eca109) transfected with miRNA mimics or cotransfected with miRNA mimics and pcDNA-EZH2 plasmid (without the 3’-UTR of EZH2). Through clinical investigation, we found that miR-98 and miR-214 expression was significantly lower in ESCC tissues than in matched normal tissues, and the expression level of miR-98 and miR-214 was inversely correlated to EZH2 protein expression and the clinical features such as pathological grade, tumor stage and lymph node metastasis in ESCC. In Eca109 cells, overexpression of miR-98 and miR-214 significantly inhibited the migration and invasion of ESCC cells, which was reversed by transfection of EZH2. Conclusions These findings suggest that decreased expression of miR-98 and miR-214 might promote metastasis of human ESCC by inducing accumulation of EZH2 protein.
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Affiliation(s)
- Sheng-Dong Huang
- Institute of Cardiothoracic Surgery, Changhai Hospital, 168, Changhai Rd, Shanghai, PR China
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28
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Gong T, Xue Z, Tang S, Zheng X, Xu G, Gao L, Zhao G, Hong L, Tang G, Zhang H, Wang R, Jiang Y, Fan D. Nuclear expression of Twist promotes lymphatic metastasis in esophageal squamous cell carcinoma. Cancer Biol Ther 2012; 13:606-13. [PMID: 22441818 DOI: 10.4161/cbt.19851] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Twist-1 protein (also called Twist) has been suggested to be involved in tumor epithelial-mesenchymal transition (EMT) related progression, however, the mechanism by which twist promotes lymph node metastasis is not fully understood. In the present study, we found that nuclear twist expression is clearly correlated with lymph node (LN) metastasis as determined by immunohistochemistry (IHC). A highly invasive EC109 cell subline, EC109-P, was established by repeated in vitro transwell isolations for the cell model. Immunofluorescence (IF) assay demonstrated that nuclear twist expression was markedly higher in the highly invasive EC109-P cell line when compared with EC109 and EC9706 cells. Based on our cell model, the function and mechanism by which twist regulates LN metastasis in ESCC was investigated. The results showed that the overexpression of Twist could significantly increase the invasion and VEGF-C expression of EC9706 cells, whereas the knockdown of twist expression results in the opposite effects. This finding was further strengthened by the results of the analysis of co-expression of twist and VEGF-C by IHC in ESCC clinical samples. In summary, our study indicates that nuclear twist plays an important role in ESCC lymphatic metastasis by increasing the expression of VEGF-C. The combination of twist and VEGF-C detection could be a reliable prediction of LN metastasis in ESCC.
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Affiliation(s)
- Taiqian Gong
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
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Fernandez CA, Millholland JM, Zwarthoff EC, Feldman AS, Karnes RJ, Shuber AP. A noninvasive multi-analyte diagnostic assay: combining protein and DNA markers to stratify bladder cancer patients. Res Rep Urol 2012; 4:17-26. [PMID: 24199176 PMCID: PMC3806439 DOI: 10.2147/rru.s28959] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Purpose The authors recently reported the development of a noninvasive diagnostic assay using urinary matrix metalloproteinases (MMPs) as monitors of disease-free status and bladder cancer in high-risk populations. Using an approach called clinical intervention determining diagnostic (CIDD), they identified with high confidence those patients who could be excluded from additional intervention. To maximize performance, MMPs were combined with DNA-based markers and CIDD was applied to a population of patients undergoing monitoring for recurrence. Patients and methods Urine samples were obtained from 323 patients, 48 of whom had a recurrence and 275 of whom did not have cancer upon cytoscopic evaluation. Twist1 and Nid2 methylation status was determined using methylation-specific polymerase chain reaction, FGFR3 mutational status by quantitative PCR, and MMP levels by enzyme-linked immunosorbent assay. Results Using a combination of these DNA and protein markers, the authors identified with high confidence (97% negative predicted value) those patients who do not have cancer. Cutoffs were adjusted such that at 92% sensitivity, 51% of disease-free patients might be triaged from receiving further tests. Conclusion The multi-analyte diagnostic readout assay described here is the first to combine protein and DNA biomarkers into one assay for optimal clinical performance. Using this approach, the detection of FGFR3 mutations and Twist1 and Nid2 methylation in the urine of patients undergoing bladder cancer recurrence screening increase the sensitivity and negative predictive value at an established MMP protein cutoff. This noninvasive urinary diagnostic assay could lead to the more efficient triage of patients undergoing recurrence monitoring.
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30
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Silva BSDF, Yamamoto FP, Pontes FSC, Cury SEV, Fonseca FP, Pontes HAR, Pinto-Júnior DDS. TWIST and p-Akt immunoexpression in normal oral epithelium, oral dysplasia and in oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal 2012; 17:e29-34. [PMID: 21743395 PMCID: PMC3448197 DOI: 10.4317/medoral.17344] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2010] [Accepted: 01/06/2011] [Indexed: 12/21/2022] Open
Abstract
Objectives: The aim of this study was to evaluate the immunoexpression of TWIST and p-Akt proteins in oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC), correlating their expressions with the histological features of the lesions.
Study design: Immunohistochemical studies were carried out on 10 normal oral epithelium, 30 OL and 20 OSCC formalin-fixed, paraffin-embedded tissue samples. Immunoperoxidase reactions for TWIST and p-Akt proteins were applied on the specimens and the positivity of the reactions was calculated for 1000 epithelial cells.
Results: Kruskal-Wallis and Dunn’s post tests revealed a significant difference in TWIST and p-Akt immunoexpression
among normal oral mucosa, OL and OSCC. In addition, a significant positive correlation was found between TWIST and p-Akt expressions according to the Pearson’s correlation test.
Conclusions: The results obtained in the current study suggest that TWIST and p-Akt may participate of the multi-step process of oral carcinogenesis since its early stages.
Key words: Oral cancer, oral leukoplakia, dysplasia, immunohistochemistry.
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Nakajima TE, Yoshida H, Okamoto N, Nagashima K, Taniguchi H, Yamada Y, Shimoda T, Masutomi K. Nucleostemin and TWIST as predictive markers for recurrence after neoadjuvant chemotherapy for esophageal carcinoma. Cancer Sci 2011; 103:233-8. [PMID: 22050045 DOI: 10.1111/j.1349-7006.2011.02142.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
We recently demonstrated that overexpression of the nucleolar GTP-binding protein nucleostemin drives the fraction of genetically-defined tumor cells that exhibit markers and tumorigenic properties of tumor initiating cells. More specifically, cells that constitutively express elevated levels of nucleostemin exhibit increased TWIST expression; expression of genes that induced pluripotent stem cells; enhanced radioresistance; tumor formation, even when small numbers of cells are implanted; and an increased propensity to metastasize. An immunohistochemical analysis of cancer stem cell markers, such as nucleostemin and TWIST has not been conducted in surgically-resected esophageal squamous cell carcinomas after neoadjuvant chemotherapy. In the present study, we examined the expression of CD133, CD44, nucleostemin, guanine nucleotide-binding protein-like 3-like, and TWIST by immunohistochemistry in a series of 54 surgically-resected specimens of esophageal squamous cell carcinomas after neoadjuvant chemotherapy. We identified that high nucleostemin proportion, TWIST intensity, and advanced pathological N stage were significantly correlated with poor relapse-free survival. Together, these observations imply nucleostemin and TWIST as the predictive markers for postoperative recurrence.
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Affiliation(s)
- Takako E Nakajima
- Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan
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32
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Lee CC, Chen WS, Chen CC, Chen LL, Lin YS, Fan CS, Huang TS. TCF12 protein functions as transcriptional repressor of E-cadherin, and its overexpression is correlated with metastasis of colorectal cancer. J Biol Chem 2011; 287:2798-809. [PMID: 22130667 DOI: 10.1074/jbc.m111.258947] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
A correlation of TCF12 mRNA overexpression with colorectal cancer (CRC) metastasis was suggested by microarray data and validated by the survey of 120 patients. Thirty-three (27.5%) of the 120 patients showed tumor TCF12 mRNA overexpression and had a higher rate of metastatic occurrence (p = 0.020) and a poorer survival outcome (p = 0.014). Abundant TCF12 levels were also observed in human CRC cell lines such as SW620 and LoVo, but a relatively low level was detected in SW480 cells. Knockdown of TCF12 expression in SW620 and LoVo cells drastically reduced their activities of migration, invasion, and metastasis. Tight cell-cell contact and an increase in E-cadherin but a concomitant decrease in fibronectin were observed in TCF12-knockdown cells. Connexin 26, connexin 43, and gap-junction activity were also increased upon TCF12-knockdown. In contrast, ectopic TCF12 overexpression in SW480 cells facilitated fibronectin expression and cell migration and invasion activities but diminished cellular levels of E-cadherin, connexin 26, connexin 43, and gap junction. A physical association of TCF12 with the E-cadherin promoter was evidenced by chromatin immunoprecipitation assay. TCF12 was tightly correlated with cellular expression of Bmi1 and EZH2 and was co-immunoprecipitable with Bmi1 and EZH2, suggesting that TCF12 transcriptionally suppressed E-cadherin expression via polycomb group-repressive complexes. Clinically, TCF12 mRNA overexpression was also correlated with E-cadherin mRNA down-regulation in the tumor tissues of our 120 patients (p = 0.013). These studies suggested that TCF12 functioned as a transcriptional repressor of E-cadherin and its overexpression was significantly correlated with the occurrence of CRC metastasis.
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Affiliation(s)
- Chun-Chung Lee
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 350, Taiwan
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Expression of Y-box-binding protein YB-1 allows stratification into long- and short-term survivors of head and neck cancer patients. Br J Cancer 2011; 105:1864-73. [PMID: 22095225 PMCID: PMC3251888 DOI: 10.1038/bjc.2011.491] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background: Histology-based classifications and clinical parameters of head and neck squamous cell carcinoma (HNSCC) are limited in their clinical capacity to provide information on prognosis and treatment choice of HNSCC. The primary aim of this study was to analyse Y-box-binding protein-1 (YB-1) protein expression in different grading groups of HNSCC patients, and to correlate these findings with the disease-specific survival (DSS). Methods: We investigated the expression and cellular localisation of the oncogenic transcription/translation factor YB-1 by immunohistochemistry on tissue micro arrays in a total of 365 HNSCC specimens and correlated expression data with clinico-pathological parameters including DSS. Results: Compared with control tissue from healthy individuals, a significantly (P<0.01) increased YB-1 protein expression was observed in high-grade HNSCC patients. By univariate survival data analysis, HNSCC patients with elevated YB-1 protein expression had a significantly (P<0.01) decreased DSS. By multivariate Cox regression analysis, high YB-1 expression and nuclear localisation retained its significance as a statistically independent (P<0.002) prognostic marker for DSS. Within grade 2 group of HNSCC patients, a subgroup defined by high nuclear and cytoplasmic YB-1 levels (co-expression pattern) in the cells of the tumour invasion front had a significantly poorer 5-year DSS rate of only 38% compared with overall 55% for grade 2 patients. Vice versa, the DSS rate was markedly increased to 74% for grade 2 cancer patients with low YB-1 protein expression at the same localisation. Conclusion: Our findings point to the fact that YB-1 expression in combination with histological classification in a double stratification strategy is superior to classical grading in the prediction of tumour progression in HNSCC.
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Banerjee A, Wu ZS, Qian P, Kang J, Pandey V, Liu DX, Zhu T, Lobie PE. ARTEMIN synergizes with TWIST1 to promote metastasis and poor survival outcome in patients with ER negative mammary carcinoma. Breast Cancer Res 2011; 13:R112. [PMID: 22060274 PMCID: PMC3326554 DOI: 10.1186/bcr3054] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2011] [Revised: 07/28/2011] [Accepted: 11/07/2011] [Indexed: 12/20/2022] Open
Abstract
Introduction ARTEMIN (ARTN) is an estrogen regulated growth factor, the expression of which promotes resistance to antiestrogen therapies and predicts poorer survival outcome of patients with estrogen receptor (ER) positive mammary carcinoma (ER+MC) treated with tamoxifen. ARTN is also expressed in ER negative mammary carcinoma (ER-MC). Herein, we determined the role of ARTN in ER-MC and defined the mechanism of action producing poor patient prognosis. Methods We modulated the expression of ARTN in two ER- (mesenchymal/claudin-low) mammary carcinoma cell lines (BT549 and MDA-MB-231) by forced expression or small interfering RNA (siRNA) mediated depletion. The effects of modulation of ARTN expression were examined by various in vitro measures of oncogenicity, including the expression of TWIST1 messenger RNA (mRNA) and protein. In vitro results were correlated to xenograft studies in immunodeficient mice. Co-expression of ARTN and TWIST1 and their association to poor survival outcome were examined in a cohort of patients with ER-MC. Pathway analysis was performed by pharmacological inhibition of phosphorylation of AKT (pAKT-Ser 473) or modulation of TWIST1 expression. Results ARTN expression resulted in ER-MC cells with enhanced mesenchymal characteristics, including increased invasion and a gene expression profile consistent with enhanced mesenchymal phenotype. ARTN stimulated ER-MC cell anchorage independent and 3D matrigel growth, endothelial cell adhesion and transmigration of ER-MC cells through an endothelial cell barrier. Forced expression of ARTN produced a larger, locally invasive tumour mass with tumour emboli that produced distant metastasis. ARTN regulated TWIST1 expression in ER-MC cells and ARTN expression was significantly correlated to TWIST1 expression in a panel of mammary carcinoma cell lines and in a cohort of patients with ER-MC. Low expression of both ARTN and TWIST1 predicted 100% relapse free and overall survival in patients with ER-MC, whereas high expression of both ARTN and TWIST1 was associated with a poor survival outcome. ARTN stimulated an increase in TWIST1 expression via increased AKT activity. siRNA mediated depletion of TWIST1 abrogated ARTN stimulated cellular behaviour associated with metastasis, and forced expression of TWIST1 abrogated the functional effects of ARTN depletion. Conclusions ARTN and TWIST1 synergize to produce a worse outcome in ER-MC and combined inhibition of ARTN and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) may therefore provide a novel therapeutic strategy in this subtype of mammary carcinoma.
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Affiliation(s)
- Arindam Banerjee
- Liggins Institute, University of Auckland, 2-6 Park Avenue, Auckland, 1023, New Zealand
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Li Y, Wang W, Wang W, Yang R, Wang T, Su T, Weng D, Tao T, Li W, Ma D, Wang S. Correlation of TWIST2 up-regulation and epithelial-mesenchymal transition during tumorigenesis and progression of cervical carcinoma. Gynecol Oncol 2011; 124:112-8. [PMID: 22018873 DOI: 10.1016/j.ygyno.2011.09.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Revised: 09/02/2011] [Accepted: 09/03/2011] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Globally, cervical cancer is the second most common cancer among women, and determining potential targets involved in tumor progression is necessary. This study investigated the clinic-pathological significance of twist homolog 2 (TWIST2), a basic helix-loop-helix transcription factor, and correlated TWIST2 and E-cadherin expression in cervical cancer. METHODS A series of 142 samples, including 14 cases of normal cervical tissues, 58 cases of cervical intraepithelial neoplasia (CIN) and 70 cases of squamous cell carcinoma (SCC), were examined TWIST2 and E-cadherin immunohistochemical staining and statistical analysis. RESULTS Increased cytoplasmic and nuclear expression levels of TWIST2 were associated with the malignant transformation of cervical epithelium and the histological progression of cervical cancer. A logistic test showed that TWIST2 was a relatively independent predictor of lymph node metastasis of SCC. Further, increased levels of TWIST2 were also associated with aberrant expression of E-cadherin, an important EMT indicator. CONCLUSIONS The present data suggest that TWIST2 overexpression was significantly linked to cervical cancer progression, which makes it a promising marker for determining the metastatic potential of cervical cancer, and up-regulation of TWIST2, in combination with aberrant E-cadherin expression in primary cervical cancer tissues, may predict the malignant transformation and distal metastasis of carcinomas.
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Affiliation(s)
- Yan Li
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
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Qin Q, Xu Y, He T, Qin C, Xu J. Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms. Cell Res 2011; 22:90-106. [PMID: 21876555 DOI: 10.1038/cr.2011.144] [Citation(s) in RCA: 349] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
This article reviews the molecular structure, expression pattern, physiological function, pathological roles and molecular mechanisms of Twist1 in development, genetic disease and cancer. Twist1 is a basic helix-loop-helix domain-containing transcription factor. It forms homo- or hetero-dimers in order to bind the Nde1 E-box element and activate or repress its target genes. During development, Twist1 is essential for mesoderm specification and differentiation. Heterozygous loss-of-function mutations of the human Twist1 gene cause several diseases including the Saethre-Chotzen syndrome. The Twist1-null mouse embryos die with unclosed cranial neural tubes and defective head mesenchyme, somites and limb buds. Twist1 is expressed in breast, liver, prostate, gastric and other types of cancers, and its expression is usually associated with invasive and metastatic cancer phenotypes. In cancer cells, Twist1 is upregulated by multiple factors including SRC-1, STAT3, MSX2, HIF-1α, integrin-linked kinase and NF-κB. Twist1 significantly enhances epithelial-mesenchymal transition (EMT) and cancer cell migration and invasion, hence promoting cancer metastasis. Twist1 promotes EMT in part by directly repressing E-cadherin expression by recruiting the nucleosome remodeling and deacetylase complex for gene repression and by upregulating Bmi1, AKT2, YB-1, etc. Emerging evidence also suggests that Twist1 plays a role in expansion and chemotherapeutic resistance of cancer stem cells. Further understanding of the mechanisms by which Twist1 promotes metastasis and identification of Twist1 functional modulators may hold promise for developing new strategies to inhibit EMT and cancer metastasis.
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Affiliation(s)
- Qian Qin
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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Correlation of increased twist with lymph node metastasis in patients with oral squamous cell carcinoma. J Oral Maxillofac Surg 2011; 70:1473-9. [PMID: 21864967 DOI: 10.1016/j.joms.2011.06.212] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Revised: 06/19/2011] [Accepted: 06/21/2011] [Indexed: 12/16/2022]
Abstract
PURPOSE To investigate the protein expression of Twist, Snail, and Slug in oral squamous cell carcinoma (OSCC) samples and evaluate the potential correlation between the expression status and clinicopathologic features in patients with OSCC. PATIENTS AND METHODS Twist, Snail, and Slug protein expression was assessed by immunohistochemistry in a total of 60 OSCC samples and 10 normal oral mucosal samples. The associations between the protein expression and clinicopathologic parameters were mainly detected using the χ(2) test. The survival analysis was performed using the Kaplan-Meier method, and the prognostic analysis was performed using Cox regression models. RESULTS Immunohistochemistry stain analysis showed that positive Twist, Snail, and Slug protein expression was observed in 70%, 63.3%, and 58.3% of the cases, respectively. Twist protein expression was positively associated with lymph node metastasis, pathologic grade, and tumor stage (P = .012, P = .008, and P = .004, respectively, χ(2) test). All patients were followed up for 6 to 59 months (mean 37). A correlation between Twist protein expression and tumor recurrence was detected (log-rank test, P = .025). Nevertheless, no correlation was found between the Snail and Slug protein expression and the clinicopathologic parameters. CONCLUSIONS Twist might serve as a useful molecular marker for lymph node metastasis and a poor prognosis in OSCC.
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Lee KW, Kim JH, Han S, Sung CO, Do IG, Ko YH, Um SH, Kim SH. Twist1 Is an Independent Prognostic Factor of Esophageal Squamous Cell Carcinoma and Associated with Its Epithelial–Mesenchymal Transition. Ann Surg Oncol 2011; 19:326-35. [DOI: 10.1245/s10434-011-1867-0] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Indexed: 12/28/2022]
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Liang X, Zheng M, Jiang J, Zhu G, Yang J, Tang Y. Hypoxia-inducible factor-1 alpha, in association with TWIST2 and SNIP1, is a critical prognostic factor in patients with tongue squamous cell carcinoma. Oral Oncol 2010; 47:92-7. [PMID: 21167768 DOI: 10.1016/j.oraloncology.2010.11.014] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Revised: 11/22/2010] [Accepted: 11/22/2010] [Indexed: 01/29/2023]
Abstract
It has become apparent that hypoxia and hypoxia-inducible factor-1 (HIF-1) activation have the potential of modulating the activity of major epithelial-mesenchymal transition (EMT)-triggering pathways by regulating the expression and activity levels of major transcriptional repressors. The aim of our study was to elucidate the role of HIF-1α and HIF-2α, and EMT regulators TWIST2 and SMAD nuclear interacting protein-1 (SNIP1) in tongue squamous cell carcinoma (TSCC). A retrospective analysis of 89 patients with TSCC from Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University between 2002 and 2005 was performed using immunohistochemistry in paraffin-embedded and formalin-fixed tissues to analyze HIF-1α, HIF-2α, TWIST2 and SNIP1 expression. The association between HIF-1α, HIF-2α, TWIST2 and SNIP1 expression and patient survivals was investigated. Our results showed that overexpression of HIF-1α, HIF-2α, TWIST2 and SNIP1 were shown in 49.44% (44/89), 55.06% (49/89), 44.94% (40/89) and 34.83% (31/89) of TSCC, respectively. Overexpression of HIF-1α, TWIST2 and SNIP1 in TSCC was associated with a shorter disease-free survival (P=0.003, P=0.001, P=0.040, respectively), and HIF-2α had no significant association with either overall survival (P=0.195) or disease-free survival (P=0.356). Co-expression of more than two markers of HIF-1α, TWIST2 and SNIP1 was an independent prognostic indicator for both overall survival and disease-free survival by multivariate Cox proportional hazards model. It is proposed that co-expression of more than two markers from HIF-1α, TWIST2 and SNIP1 might be a significant prognostic predictor in patients with TSCC.
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Affiliation(s)
- Xinhua Liang
- Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, No. 14, Sec. 3, Renminnan Road, Chengdu Sichuan 610041, People's Republic of China
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Cao Y, Zhang L, Kamimura Y, Ritprajak P, Hashiguchi M, Hirose S, Azuma M. B7-H1 Overexpression Regulates Epithelial–Mesenchymal Transition and Accelerates Carcinogenesis in Skin. Cancer Res 2010; 71:1235-43. [DOI: 10.1158/0008-5472.can-10-2217] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Abstract
Over the past decade, the reactivation of TWIST embryonic transcription factors has been described as a frequent event and a marker of poor prognosis in an impressive array of human cancers. Growing evidence now supports the premise that these cancers hijack TWIST's embryonic functions, granting oncogenic and metastatic properties. In this review, we report on the history and recent breakthroughs in understanding TWIST protein functions and the emerging role of the associated epithelial-mesenchymal transition (EMT) in tumorigenesis. We then broaden the discussion to address the general contribution of reactivating embryonic programs in cancerogenesis.
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