CSC-3436 inhibits TWIST-induced epithelial-mesenchymal transition via the suppression of Twist/Bmi1/Akt pathway in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer deaths worldwide, especially in male. With poor prognosis, significant portions of patients with HNSCC die due to cancer recurrence and tumor metastasis after chemotherapy and targeted therapies. The HNSCC FaDu cell ectopic expression of Twist, a key transcriptional factor of epithelial-mesenchymal transition (EMT), which triggers EMT and results in the acquisition of a mesenchymal phenotype, was used as the cell model. Our results demonstrated that treatment with newly synthesized 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436), a flavonoid derivative, elicited changes in its cell morphology, upregulated E-cadherin messenger RNA and protein expression, downregulated N-cadherin, vimentin, and CD133 (a marker associated with tumor-initiating cells) in FaDu-pCDH-Twist cells. Moreover, CSC-3436 exposure reduced B cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) expression regulated by Twist and further suppressed the direct co-regulation of E-cadherin by Twist and Bmi1. Interestingly, CSC-3436 reduced EMT, cancer stemness, and migration/invasion abilities through the inhibition of the Twist/Bmi1-Akt/β-catenin pathway. Most importantly, our findings provided new evidence that CSC-3436 played a crucial role in therapeutic targeting to Bmi1 and its molecular pathway in HNSCC, and it will be valuable in prognostic prediction and treatment.

Lai YJ ，Yu WN ，Kuo SC ，Ho CT ，Hung CM ，Way TD ，Chen CT ... -  《-》

Emodin represses TWIST1-induced epithelial-mesenchymal transitions in head and neck squamous cell carcinoma cells by inhibiting the β-catenin and Akt pathways.

Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer deaths worldwide. In recent studies, a crucial link has been discovered between the acquisition of metastatic traits and tumour-initiating abilities in cancer cells during the epithelial-mesenchymal transition (EMT). Herein, we demonstrated that the ectopic expression of TWIST1, the EMT regulator, in HNSCC FaDu cells triggered EMT and resulted in the acquisition of a mesenchymal phenotype. Moreover, FaDu-pFLAG-TWIST1 cancer cell populations that were induced to EMT displayed an increased proportion of cells with the CD44 marker, which is associated with tumour initiation. Interestingly, we found that emodin treatment reduced the tumour-initiating abilities and inhibited cell migration and invasion in FaDu-pFLAG-TWIST1 cells. Emodin directly inhibited TWIST1 expression, upregulated E-cadherin mRNA and protein expression, and downregulated vimentin mRNA and protein expression. Moreover, we found that emodin inhibited TWIST1 binding to the E-cadherin promoter and repressed E-cadherin transcription activity. We also found that emodin inhibited TWIST1-induced EMT by inhibiting the β-catenin and Akt pathways. More interestingly, emodin significantly inhibited TWIST1-induced invasion in vivo. Therefore, emodin might be applicable to anticancer therapy and could be a potential new therapeutic drug for HNSCC.

Way TD ，Huang JT ，Chou CH ，Huang CH ，Yang MH ，Ho CT ... -  《-》

Antrodia camphorata inhibits epithelial-to-mesenchymal transition by targeting multiple pathways in triple-negative breast cancers.

Antrodia camphorata (AC) exhibits potential for engendering cell-cycle arrest as well as prompting apoptosis and metastasis inhibition in triple-negative breast cancer (TNBC) cells. We performed the current study to explore the anti-epithelial-to-mesenchymal transition (EMT) properties of fermented AC broth in TNBC cells. Our results illustrated that noncytotoxic concentrations of AC (20-60 μg/ml) reversed the morphological changes (fibroblastic-to-epithelial phenotype) as well as the EMT by upregulating the observed E-cadherin expression. Furthermore, we discovered treatment with AC substantially inhibit the Twist expression in human TNBC (MDA-MB-231) cells as well as in those that were transfected with Twist. In addition, we determined AC to decrease the observed Wnt/β-catenin nuclear translocation through a pathway determined to be dependent on GSK3β. Notably, AC treatment consistently inhibited the EMT by downregulating mesenchymal marker proteins like N-cadherin, vimentin, Snail, ZEB-1, and fibronectin; at that same time upregulating epithelial marker proteins like occludin and ZO-1. Bioluminescence imaging that was executed in vivo demonstrated AC substantially suppressed breast cancer metastasis to the lungs. Notably, we found that western blot analysis confirmed that AC decreased lung metastasis as demonstrated by upregulation of E-cadherin expression in biopsied lung tissue. Together with our results support the anti-EMT activity of AC, indicating AC as having the potential for acting as an anticancer agent for the treatment of human TNBC treatment.

Hseu YC ，Chang GR ，Pan JY ，Rajendran P ，Mathew DC ，Li ML ，Liao JW ，Chen WT ，Yang HL ... -  《-》

miR-300 inhibits epithelial to mesenchymal transition and metastasis by targeting Twist in human epithelial cancer.

Yu J ，Xie F ，Bao X ，Chen W ，Xu Q ... -  《Molecular Cancer》

Hypoxia induces TWIST-activated epithelial-mesenchymal transition and proliferation of pancreatic cancer cells in vitro and in nude mice.

The epithelial-mesenchymal transition (EMT) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) development and progression. TWIST activated by intra-tumoral hypoxia functions to promote the EMT. We hypothesized that TWIST and the downstream gene pathway could mediate PDAC progression under hypoxia. Therefore, 90 PDAC tissue specimens were immunostained for TWIST and other proteins. Pancreatic cancer cell lines were used for in vitro experiments and nude mice were used to confirm the in vivo data. Expression of TWIST and HIF-1α proteins was significantly upregulated, whereas expression of E-cadherin and p16 was down-regulated in PDAC tissues compared to that of non-tumor tissues and in tumor tissues obtained from patients with tumor involving splenic artery than those without splenic artery involvement. Up-regulated TWIST in tumor tissues were associated with worse prognosis in PDAC patients. The in vitro data showed that HIF-1α-induced TWIST overexpression promoted tumor cell growth and EMT under a hypoxic condition via TWIST interaction with Ring1B and EZH2. In vivo data showed that TWIST overexpression or a hypoxic condition induce xenograft growth, abdominal metastasis and low mouse survival, whereas knockdown of either Ring1B or EZH2 expression suppressed tumor xenograft growth and metastasis and prolonged survival of nude mice. TWIST was the key player in promotion of pancreatic cancer development and metastasis under a hypoxic condition through interaction with Ring1B and EZH2 to regulate expression of E-cadherin and p16 proteins in pancreatic cancer cells.

Chen S ，Chen JZ ，Zhang JQ ，Chen HX ，Yan ML ，Huang L ，Tian YF ，Chen YL ，Wang YD ... -  《-》