Twist1 and Y-box-binding protein-1 promote malignant potential in bladder cancer cells (original) (raw)
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Twist1 and Y-box-binding protein-1 are potential prognostic factors in bladder cancer
Urologic oncology, 2014
To investigate the expression and possible roles of Twist1 and Y-box-binding protein-1 (YB-1) in bladder cancer tissue. Twist1 belongs to the family of basic helix-loop-helix transcription factors. A functional link between Twist1 and YB-1 has recently been determined to play an important role in bladder cancer cell lines. Frozen samples from 75 patients with bladder cancer were analyzed by quantitative real-time polymerase chain reaction (PCR). Formalin-fixed and paraffin-embedded tissues from 53 patients with bladder cancer were examined by immunohistochemistry. Twist1 transcript levels were positively correlated with YB-1 transcript levels (coefficient of correlation = 0.42, P<0.001), tumor grade (low grade vs. high grade; P<0.001), invasiveness (non-muscle-invasive bladder cancer vs. muscle invasive bladder cancer; P = 0.0018), and metastasis (meta- vs. meta+; P<0.001). YB-1 transcript level was also correlated with grade (P = 0.029) and invasiveness (P = 0.006). By imm...
Twist-1 Up-Regulation in Carcinoma Correlates to Poor Survival
International Journal of Molecular Sciences, 2014
Epithelial-to-mesenchymal transition (EMT) facilitates tumor metastasis. Twist is a basic helix-loop-helix protein that modulates many target genes through E-box-responsive elements. There are two twist-like proteins, Twist-1 and Twist-2, sharing high structural homology in mammals. Twist-1 was found to be a key factor in the promotion of metastasis of cancer cells, and is known to induce EMT. Twist-1 participation in carcinoma progression and metastasis has been reported in a variety of tumors. However, controversy exists concerning the correlation between Twist-1 and prognostic value with respect to carcinoma. A systematic review and meta-analysis were performed to determine whether the expression of Twist-1 was associated with the prognosis of carcinoma patients. This analysis included 17 studies: four studies evaluated lung cancer, three evaluated head and neck cancer, two evaluated breast cancer, two evaluated esophageal cancer, two evaluated liver cancer and one each evaluated osteosarcoma, bladder, cervical and ovarian cancer. A total of 2006 patients
Twist Promotes Tumor Cell Growth through YB-1 Expression
Cancer Research, 2008
YB-1 controls gene expression through both transcriptional and translational mechanisms and is involved in various biological activities such as brain development, chemoresistance, and tumor progression. We have previously shown that YB-1 is overexpressed in cisplatin-resistant cells and is involved in resistance against DNA-damaging agents. Structural analysis of the YB-1 promoter reveals that several Eboxes may participate in the regulation of YB-1 expression. Here, we show that the E-box-binding transcription factor Twist is overexpressed in cisplatin-resistant cells and that YB-1 is a target gene of Twist. Silencing of either Twist or YB-1 expression induces G 1 phase cell cycle arrest of tumor cell growth. Significantly, reexpression of YB-1 led to increase colony formation when Twist expression was down-regulated by small interfering RNA. However, cotransfection of Twist expression plasmid could not increase colony formation when YB-1 expression was down-regulated. Collectively, these data suggest that YB-1 is a major downstream target of Twist. Both YB-1 and Twist expression could induce tumor progression, promoting cell growth and driving oncogenesis in various cancers. Thus, both YB-1 and Twist may represent promising molecular targets for cancer therapy. [Cancer Res 2008;68(1):98-105]
Open Access Macedonian Journal of Medical Sciences
BACKGROUND: Twist2 is a transcription factor and an epithelial-to-mesenchymal transition that plays an important role in cell polarity, cell adhesion, and has a role in tumour invasion and metastases.AIM: In this study, we examined the expression of Twist2 in non-muscle invasive bladder carcinoma (NMIBC) and correlated the expression with response to treatment and tumour progression.METHODS: Data of 305 patients with NMIBC of Ta, T1 were retrieved from hospitals archives. Twist2 expression was examined in tissue samples by immunohistochemistry at initial diagnosis and final follow-up, normal control was 10 normal urothelium, 10 patients with muscle-invasive bladder cancer (MIBC) were a positive control. Treatment of NMIBC was implemented according to the European Association of Urology guidelines on NMIBC. The descriptive statistical analysis included means, standard deviation, p-value; Univariate and multivariate Cox regression analyses.RESULTS: Twist2 expression score was identifi...
Up-Regulation of TWIST in Prostate Cancer and Its Implication as a Therapeutic Target
2005
Androgen-independent metastatic prostate cancer is the main obstacle in the treatment of this cancer. Unlike a majority of solid cancers, prostate cancer usually shows poor response to chemotherapeutic drugs. In this study, we have shown a potential novel target, TWIST, a highly conserved bHLH transcription factor, in the treatment of prostate cancer. Using malignant and nonmalignant prostate tissues, we found that TWIST expression was highly expressed in the majority (90%) of prostate cancer tissues but only in a small percentage (6.7%) of benign prostate hyperplasia. In addition, the TWIST expression levels were positively correlated with Gleason grading and metastasis, indicating its role in the development and progression of prostate cancer. Furthermore, down-regulation of TWIST through small interfering RNA in androgen-independent prostate cancer cell lines, DU145 and PC3, resulted in increased sensitivity to the anticancer drug taxol-induced cell death which was associated with decreased Bcl/Bax ratio, leading to activation of the apoptosis pathway. More importantly, inactivation of TWIST suppressed migration and invasion abilities of androgen-independent prostate cancer cells, which was correlated with induction of E-cadherin expression as well as morphologic and molecular changes associated with mesenchymal to epithelial transition. These results were further confirmed on the androgen-dependent LNCaP cells ectopically expressing the TWIST protein. Our results have identified TWIST as a critical regulator of prostate cancer cell growth and suggest a potential therapeutic approach to inhibit the growth and metastasis of androgen-independent prostate cancer through inactivation of the TWIST gene. (Cancer Res 2005; 65(12): 5153-62)
Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis
Cell, 2004
The first step-invasion-requires neoplastic epithelial 1 Whitehead Institute for Biomedical Research cells to lose cell-cell adhesion and to gain motility, which 9 Cambridge Center enables them to invade the adjacent tissue. During the Cambridge, Massachusetts 02142 second step, intravasation, tumor cells penetrate 2 Cancer Genomics Program through the endothelium of blood or lymphatic vessels Broad Institute to enter the systemic circulation. Only some circulating Cambridge, Massachusetts 02141 tumor cells appear to be able to survive the passage 3 MGH Center for Cancer Research through circulation. Some of these survivors manage to Charlestown, Massachusetts 02129 complete the next step-extravasation-as they extrav-4 Ecole Normale Superieure asate through the capillary endothelium at distal sites. 75230 Paris Cedex 05 Finally, in the new host environment, an even smaller France subset of such metastasizing cells succeeds in prolifer-5 EMI 0229 INSERM ating from minute growths (micrometastases) into malig-CRLC Val d'Aurelle-Paul Lamarque nant, secondary tumors (Fidler, 2003). A central aim in 34298 Montpellier Cedex 5 the study of tumor metastasis is to understand the na-France ture of the distinct genetic and epigenetic changes that 6 Department of Molecular Genetics & Development program these individual steps. Ben Gurion University of the Negev Recently, our understanding of metastasis has been Beer Sheva 84105 expanded through microarray analyses of various hu-Israel man tumor samples. For example, several studies of 7 Department of Pathology human primary breast tumors have generated gene ex-Brigham and Women's Hospital pression profiles that are predictive of metastasis or Harvard Medical School poor survival rate (Ramaswamy et al., 2003; van't Veer et Boston, Massachusetts 02115 al., 2002). Such analyses are very powerful for producing fingerprints of metastatic tumor cells, which could be used as prognostic markers of metastatic diseases. However, due to the lack of further experimental manip-Summary ulation of human tumor samples, it has been very difficult to elucidate the specific contributions of such genes to Metastasis is a multistep process during which cancer tumor metastasis. cells disseminate from the site of primary tumors and Experimental animal models have been successfully establish secondary tumors in distant organs. In a used to identify molecular elements during metastasis. search for key regulators of metastasis in a murine For example, in an expression profile analysis comparbreast tumor model, we have found that the transcriping melanoma cells and their highly metastatic derivation factor Twist, a master regulator of embryonic mortives, RhoC was identified as essential for pulmonary phogenesis, plays an essential role in metastasis. Supmetastasis by melanoma cells that were injected intrapression of Twist expression in highly metastatic venously into mice (Clark et al., 2000). Recently, a set mammary carcinoma cells specifically inhibits their of genes, including osteopontin and IL-11, were shown ability to metastasize from the mammary gland to the to promote bone metastasis when human breast cancer lung. Ectopic expression of Twist results in loss of cells were injected via the intracardiac route (Kang et E-cadherin-mediated cell-cell adhesion, activation of al., 2003). Most of these models rely on the introduction mesenchymal markers, and induction of cell motility, of tumor cells directly into the systemic circulation. Such suggesting that Twist contributes to metastasis by approaches obviate the steps of invasion and intravasapromoting an epithelial-mesenchymal transition (EMT). tion and therefore are unlikely to reveal genes involved In human breast cancers, high level of Twist expresin these early steps of metastasis. sion is correlated with invasive lobular carcinoma, a Given the complexity of the process of metastasis, it highly infiltrating tumor type associated with loss of is essential to exploit experimental models in which each E-cadherin expression. These results establish a of the steps of metastasis is represented and can be mechanistic link between Twist, EMT, and tumor memanipulated individually. In this report, we exploit a tastasis. mouse mammary tumor model, in which a set of otherwise isogenic tumor cell populations is able to complete distinct steps of metastasis when implanted into the
Oncogene, 2012
TWIST1 is a highly conserved basic helix-loop-helix transcription factor that promotes epithelial-mesenchymal transition (EMT). Its misregulation has been observed in various types of tumors. Using the MCF-10A-series of cell lines that recapitulate the early stages of breast cancer formation and EMT, we found TWIST1 to be upregulated during EMT and downregulated early in carcinogenesis. The TWIST1 3 0 UTR contains putative regulatory elements, including miRNA target sites and two cytoplasmic polyadenylation elements (CPE). We found that miR-580, CPEB1, and CPEB2 act as negative regulators of TWIST1 expression in a sequence-specific and additive/cooperative manner.
The Twist Box Domain Is Required for Twist1-induced Prostate Cancer Metastasis
Molecular Cancer Research, 2013
Twist1, a basic helix-loop-helix transcription factor, plays a key role during development and is a master regulator of the epithelial–mesenchymal transition (EMT) that promotes cancer metastasis. Structure–function relationships of Twist1 to cancer-related phenotypes are underappreciated, so we studied the requirement of the conserved Twist box domain for metastatic phenotypes in prostate cancer. Evidence suggests that Twist1 is overexpressed in clinical specimens and correlated with aggressive/metastatic disease. Therefore, we examined a transactivation mutant, Twist1-F191G, in prostate cancer cells using in vitro assays, which mimic various stages of metastasis. Twist1 overexpression led to elevated cytoskeletal stiffness and cell traction forces at the migratory edge of cells based on biophysical single-cell measurements. Twist1 conferred additional cellular properties associated with cancer cell metastasis including increased migration, invasion, anoikis resistance, and anchora...
IMMUNOHISTOCHEMICAL STUDY OF TWIST1 IN INVASIVE DUCT CARCINOMA OF THE BREAST
Twist1 is a key transcription factor, which confers tumor cells with cancer stem cell (CSC)-like characteristics and enhances epithelial-mesenchymal transition (EMT) in pathological conditions including tumor malignancy and metastasis. This study aimed to evaluate the expression patterns and clinical significance of Twist1 in invasive duct carcinoma of the breast. The cytoplasmic and nuclear expressions of Twist1 were examined in 70 tumor tissues by immunohistochemistry. The association between expression patterns of this marker and clinicopathologic parameters was analyzed separately. Twist1 was localized to the cytoplasm of tumor cells in (21.4%) of cases. It was localized to the nucleus of tumor cells in (48.6%) of cases. Increased cytoplasmic expression of Twist1 was associated with smaller tumor size (P = 0.011). Nuclear Twist1 was positively correlated with higher grade tumors (P = 0.002), lymph node status (>3 lymph nodes) (P = 0.049), poor Nottingham prognostic index (p=0.043), ER and PR negativity (p=0.048 and 0.016 respectively), Molecular subtypes (p=0.038) and distant metastasis (p=0.001). Increased nuclear expression of Twist1 had a critical role in worse prognosis in breast cancer. These findings suggest that nuclear, rather than cytoplasmic expression of Twist1 can be considered as a prognostic and therapeutic marker for targeted therapy of breast cancer patients.
Data from The Twist Box Domain Is Required for Twist1-induced Prostate Cancer Metastasis
2023
Twist1, a basic helix-loop-helix transcription factor, plays a key role during development and is a master regulator of the epithelial-mesenchymal transition (EMT) that promotes cancer metastasis. Structure-function relationships of Twist1 to cancer-related phenotypes are underappreciated, so we studied the requirement of the conserved Twist box domain for metastatic phenotypes in prostate cancer. Evidence suggests that Twist1 is overexpressed in clinical specimens and correlated with aggressive/metastatic disease. Therefore, we examined a transactivation mutant, Twist1-F191G, in prostate cancer cells using in vitro assays, which mimic various stages of metastasis. Twist1 overexpression led to elevated cytoskeletal stiffness and cell traction forces at the migratory edge of cells based on biophysical single-cell measurements. Twist1 conferred additional cellular properties associated with cancer cell metastasis including increased migration, invasion, anoikis resistance, and anchorage-independent growth. The Twist box mutant was defective for these Twist1 phenotypes in vitro. Importantly, we observed a high frequency of Twist1-induced metastatic lung tumors and extrathoracic metastases in vivo using the experimental lung metastasis assay. The Twist box was required for prostate cancer cells to colonize metastatic lung lesions and extrathoracic metastases. Comparative genomic profiling revealed transcriptional programs directed by the Twist box that were associated with cancer progression, such as Hoxa9. Mechanistically, Twist1 bound to the Hoxa9 promoter and positively regulated Hoxa9 expression in prostate cancer cells. Finally, Hoxa9 was important for Twist1-induced cellular phenotypes associated with metastasis. These data suggest that the Twist box domain is required for Twist1 transcriptional programs and prostate cancer metastasis. Implications: Targeting the Twist box domain of Twist1 may effectively limit prostate cancer metastatic potential. Mol Cancer Res; 11(11); 1387-400. Ó2013 AACR.