Editorial: Epithelial-mesenchymal transition (EMT) as a therapeutic target in cancer, Volume II

COPYRIGHT © 2023 Zhong and Sun. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Editorial PUBLISHED 20 June 2023 DOI 10.3389/fonc.2023.1218855

1 Strategies to suppress EMT process mainly include the following aspects 1

.1 Targeting EMT transcription factors
EMT transcription factors are key regulatory factors in the EMT process, including Snail, Slug, Twist, etc. By targeting these transcription factors, EMT process can be inhibited, thereby preventing cancer cell metastasis and invasion.

Targeting EMT-related proteins
The EMT process also involves various proteins, including Ecadherin, N-cadherin, Vimentin, etc. By targeting these proteins, EMT process can be inhibited, thereby preventing cancer cell metastasis and invasion. In Liu et al.'s study, the combination of network pharmacology prediction and experimental validation showed that Ginkgolide K (GK) inhibits the invasion and metastasis of human lung adenocarcinoma cells through the Akt/GSK-3b/Snail and Wnt/bcatenin pathways. Lung cancer is one of the most common malignant tumors, with high mortality rates and increasing numbers of new cases worldwide. Ginkgo leaves have been used for the treatment of lung cancer for many years. Ginkgolide K is an important active ingredient extracted from Ginkgo. However, the mechanism by which Ginkgolide K inhibits the invasive and metastatic properties of lung cancer is not clear. The authors used network pharmacology methods to study the molecular mechanism of Ginkgolide K in inhibiting lung cancer metastasis. Then, potential target proteins between Ginkgolide K and lung cancer were analyzed. Finally, molecular docking and experimental validation were performed. The study found that there were 79 common genes involved in cell migration positively regulated by the cross-talk between lung cancer and Ginkgolide K. In vitro experiments showed that GK had a significant inhibitory effect on the invasion and metastasis of A549 and H1299 cells. In animal experiments, GK had a significant inhibitory effect on the metastasis of LLC. The experiment confirmed that GK can inhibit the Akt/ GSK-3b/Snail and Wnt/b-catenin cascades in A549, H1299, and LLC cells, preventing metastasis. The results of this study are consistent with the hypothesis of network pharmacology analysis.
2 The strategies to reverse the EMT process mainly include the following aspects

Targeting EMT-related signaling pathways
By targeting EMT-related signaling pathways, the EMT process can be reversed, thereby restoring the epithelial characteristics of cancer cells and making them more sensitive to treatment. Xi et al. found that ACT001, a novel PAI-1 inhibitor, exerts a synergistic effect with cisplatin by inhibiting the PI3K/AKT pathway in glioblastoma (10). PAI-1 plays an important role in the occurrence, recurrence, and multidrug resistance of tumors and is highly expressed in tumors. ACT001 is currently in phase III clinical trials for the treatment of glioblastoma (GBM). However, the specific molecular mechanism of ACT001 is not clear. In this study, Xi et al. investigated the effect of ACT001 on the proliferation of glioblastoma cells and elucidated its mechanism. They found that ACT001 directly binds to PAI-1 to inhibit the PI3K/AKT pathway, thereby inducing the inhibition of glioblastoma cell proliferation, invasion, and migration. In addition, the combination of ACT001 and cisplatin showed a synergistic inhibitory effect on glioblastoma in vitro and in vivo.
In addition, Qiao and Tian reported that ATL-1 inhibits EMT by targeting Hsp27 and enhances the anti-tumor effect of cabozantinib in prostate cancer. MTT experiments showed that compared with the control group, ATL-1 had an inhibitory effect on the proliferation of prostate cancer cells DU145 and PC-3. TUNEL results showed that compared with the control group, silencing Hsp27 and ATL-1 treatment significantly promoted apoptosis of DU145 and PC-3 prostate cancer cells. qRT-PCR results showed that compared with the control group, ATL-1 promoted the expression of caspase-3, PARP, and Bax in DU145 and PC-3 prostate cancer cells. ATL-1 inhibits Hsp27, reduces cell viability, and induces cell apoptosis. ATL-1 inhibits Hsp27 to enhance the anti-tumor effect of cabozantinib. Hsp27 regulates eIF4E and mediates cell protection. ATL-1 can inhibit the malignant evolution of prostate cancer cells by inhibiting Hsp27/eIF4E. ATL-1 also enhances the chemosensitivity of cabozantinib in prostate cancer.

Targeting EMT-related proteins
By targeting EMT-related proteins, the EMT process can be reversed, thereby restoring the epithelial characteristics of cancer cells and making them more sensitive to treatment. Zhong et al. found that cartilage oligomeric matrix protein (COMP) promotes epithelial-mesenchymal transition (EMT) in colorectal cancer by interacting with Transgelin (11). The study found that COMP interacts with TAGLN in colorectal cancer EMT, regulates cell cytoskeleton remodeling, and promotes malignant progression.
COMP is highly expressed in high-grade colorectal cancer and is positively correlated with TAGLN expression. Knockdown of COMP can inhibit the metastasis and invasion of colorectal cancer, while overexpression of COMP can promote EMT in colorectal cancer. Through virtual screening of protein interaction interfaces, the flavonoid compound chrysin was found to have the highest docking score with the COMP/TAGLN complex. Chrysin inhibits COMP, thereby preventing EMT and malignant progression of colorectal cancer. This study elucidates the role of COMP in EMT and suggests that COMP/TAGLN may be a potential therapeutic target for tumors. Chrysin has significant anti-tumor effects. This study provides a preliminary anti-tumor treatment method for inhibiting EMT by targeting COMP or its interacting proteins.

Conclusion
EMT is of great significance as a therapeutic target for cancer. By inhibiting the EMT process or reversing the EMT process, the metastasis and invasion of cancer cells can be prevented, thus improving the therapeutic effect.