EMT leads to Metastasis, Breast Cancer

Whenever cell phenotype plasticity is crucial and under investigation, the reverse of EMT, known as the mesenchymal-epithelial transition (MET), may be one of the prospects for anti-cancer therapy (Shibue & Weinberg, 2017).

TGFbeta and Twist induce EMT by upregulating the expression of EMT markers such Snail, Vimentin, N-cadherin, and ABC transporters like ABCA3, ABCC1, ABCC3, and ABCC10 (Saxena et al., 2011).In the treatment with about 0.3, 3, 30 mM of doxorubicin, human mammary epithelial cells (HMLE) stably expressing Twist, FOXC2 or Snail demonstrate increased cell viability compared to control HMLE, dose-dependently (Saxena et al., 2011).

When Twist/FOXC2/Snail overexpressed HMLE is treated with doxorubicin for 48 hours, cell viability increases compared to control HMLE (Saxena et al., 2011).When Twist or Zeb1 were inhibited with small interference RNA (siRNA), cell viability was reduced relative to control MDAMB231 cells treated with doxorubicin for 48 hours (Saxena et al., 2011).

• Understanding the association between EMT and cancer malignancy necessitates further research into the EMT-cancer stem cells (CSC) relationship. Non-CSCs in cancer can spontaneously undergo EMT and dedifferentiate into new CSCs, resulting in tumorigenic potential renewal (Marjanovic, Weinberg, & Chaffer, 2013; Shibue & Weinberg, 2017).The plastic CSC theory demonstrates bidirectional conversions between non-CSCs and CSCs, which could help EMT-activated cells acquire cancer malignancy (Marjanovic et al., 2013).

• Long non-coding RNAs (lncRNAs) play crucial roles in many biological and pathological processes, including tumor metastasis. Kong et al reported a novel lncRNA, LINC01133 that was downregulated by TGF- β, which could inhibit epithelial–mesenchymal transition (EMT) and metastasis in colorectal cancer (CRC) cells (Kong et al.,2016). SRSF6, an alternative splicing factor that interacts directly with LINC01133, was found to enhance EMT and metastasis in CRC cells even when LINC01133 was not present. The study also found that the EMT process in CRC cells was regulated by LINC01133 in the presence of SRSF6. In vivo, the ability of LINC01133 to prevent metastasis was confirmed. Furthermore, clinical data revealed that LINC01133 expression was favourably correlated with E-cadherin and negatively correlated with Vimentin, and that low LIINC01133 expression in tumours was associated with poor CRC survival. These findings show that LINC01133, by directly binding to SRSF6 as a target mimic and inhibiting EMT and metastasis, could be used as a predictive biomarker and an effective target for anti-metastasis therapy in CRC.
• MiR-148a inhibited Met expression directly by binding to its 30-UTR, according to Zhang et al's findings. Furthermore, reintroducing miR-148a reduced the nuclear accumulation of Snail, a transcription factor that promotes EMT, by inhibiting Met's downstream signalling, such as activating phosphorylation of AKT-Ser473 and inhibitory phosphorylation of GSK-3b-Ser9 (Zhang et al.,2015). MiR-148a, when combined, may suppress hepatoma cell EMT and metastasis by adversely regulating Met/Snail signalling.