Correlation of Twist upregulation and senescence bypass during the progression and metastasis of cervical cancer.

Cervical carcinoma is associated with high propensity for local invasion and lymph node metastasis. However, the molecular alterations that drive progression and metastasis of cervical cancer remain unclear. Cellular senescence has been proposed as the mechanism that protects an organism against cancer progression and metastasis. In addition, Twist, a basic helix-loop-helix transcription factor, has been suggested as an oncogene because it is overexpressed in many types of human cancer. This gene also exhibits a positive function in regulating invasion and metastasis. In this study, Twist was strongly and positively expressed in normal tissue, squamous cell carcinoma (SCC) IA-IIA, and SCC IIB-IIIB (4.3%, 44%, and 88.9%, respectively). The strong positive expressions of the senescence marker CBX3 were 39.1%, 32%, and 15.6%, respectively. The strong positive expressions of Twist in the SCC groups with or without lymph node metastasis were 80.8% and 50%. For CBX3, such expressions were 7.7% and 29.5%, respectively. Results also showed that the expression of Twist was inversely correlated with that of CBX3. Moreover, the knockdown of Twist with target siRNA in SiHa triggered the induction of the chromatin marker of the cellular senescence CBX3 and senescence-associated ß-galactosidase activity. Our results suggested that the expression of Twist increased during the progression and metastasis of cervical cancer. Furthermore, Twist-induced senescence bypass is important in this process.

Twist2 contributes to cisplatin-resistance of ovarian cancer through the AKT/GSK-3ß signaling pathway.

Cisplatin is regularly used in the treatment of ovarian cancer. However, the drug only provides a modest survival advantage, primarily due to chemoresistance and the upregulation of antiapoptotic machineries in ovarian cancer cells. Therefore, targeting the mechanisms responsible for cisplatin resistance in ovarian cancer cells may improve the therapeutic outcomes. Twist basic helix-loop-helix transcription factor 2 (Twist2) is a novel zinc finger transcription factor that has been indicated to be an important inducer of epithelial-mesenchymal transition, which has been shown to be involved in various phases of tumorigenicity and progression. However, whether Twist2 suppression increases the chemosensitivity of ovarian cancer cells to chemotherapeutic agents remains unclear. In the present study, Twist2 expression was found to differ between human ovarian cisplatin-sensitive cancer cell line, OV2008, and the resistant variant, C13K cells. Twist2 plasmids or RNA interference were then utilized to alter Twist2 expression in OV2008 or C13K cells, respectively, to further assess apoptosis, cell viability and cell growth, as well as a possible mechanism. The results of the present study indicated that Twist2 plays a crucial role in the chemoresistance of ovarian cancer. In addition, the downregulation of Twist2 expression may facilitate apoptosis and recover the sensitivity of chemoresistant ovarian cancer through the protein kinase B/glycogen synthase kinase-3ß pathway. Therefore, Twist2 depletion may be a promising approach to ovarian cancer therapy.

Twist2, the key Twist isoform related to prognosis, promotes invasion of cervical cancer by inducing epithelial-mesenchymal transition and blocking senescence.

In response to tumor development, cells initially undergo invasion and metastasis followed by epithelial-mesenchymal transition (EMT, a process by which cells acquire motility) and overriding senescence (an endogenous defense mechanism against tumor progression). Oncogenic activation of Twist1 and Twist2 is essential for EMT and senescence; however, little is known about the specific contributions of Twist1 versus Twist2 to prognosis, metastasis, and the mechanism underlying cervical carcinoma. Here, we investigated the similarities and differences between Twist1 and Twist2 in assessing prognosis and promoting invasion and metastasis of cervical carcinoma as well as their roles in the underlying molecular mechanisms. By monitoring the survival of 144 clinical cervical cancer patients, we demonstrated that Twist2 shows more effective predictive performance compared with Twist1 and is more closely correlated with International Federation of Gynecology and Obstetrics stage and lymph node metastasis. Compared with Twist1, Twist2 more strongly promotes invasivity and motility by inducing EMT and overriding senescence. Differences between Twist1 and Twist2 in regulating senescence and the cell cycle might be due to their individual roles in regulating the cyclin D1/cyclin dependent kinase 4 (Cdk4) pathway. Overall, our data indicate that Twist2 is the key Twist isoform coupling aberrant signals from EMT to senescence and is an important candidate biomarker for cervical cancer prognosis.