Epithelial to mesenchymal transition (EMT) is a process during which cells lose their epithelial characteristics, for instance cell polarity and cell-cell contact, and gain mesenchymal properties, such as increased motility. In colorectal cancer (CRC), EMT is associated with an invasive or metastatic phenotype. In this review, we discuss recent studies exploring novel regulation mechanisms of EMT in CRC, including the identification of new CRC EMT regulators. Upregulation of inducers can promote EMT, leading to increased invasiveness and metastasis in CRC. These inducers can downregulate E-cadherin and upregulate N-cadherin and vimentin (VIM) through modulating EMT-related signaling pathways, for instance WNT/β-catenin and TGF-β, and EMT transcription factors, such as zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2. In addition, several microRNAs (miRNAs), including members of the miR-34 and miR-200 families, are found to target mRNAs of EMT-transcription factors, for example ZEB1, ZEB2, or SNAIL. Downregulation of these miRNAs is associated with distant metastasis and advanced stage tumors. Furthermore, the role of EMT in circulating tumor cells (CTCs) is also discussed. Mesenchymal markers on the surface of EMT CTCs were found to be associated with metastasis and could serve as potential biomarkers for metastasis. Altogether, these studies indicate that EMT is orchestrated by a complicated network, involving regulators of different signaling pathways. Further studies are required to understand the mechanisms underlying EMT in CRC.

https://www.mdpi.com/2072-6694/9/12/171/pdf

Regulation of EMT in Colorectal Cancer: A Culprit in Metastasis.

Acting as inflammatory mediators, tumor oncogenes or suppressors, microRNAs are involved in cell survival, death, epithelial–mesenchymal transition and metastasis, etc. Investigating the communication between microRNAs and tumorigenesis is critical to our understanding of the pathogenesis of multiple disease states. Currently, colorectal carcinoma (CRC), one of the most common malignancies worldwide, has a poor prognosis due to lack of an effective therapeutic option. Increasing evidence has identified altered profiles and regulatory potential of microRNAs in conditions related to environmentally-caused colorectal inflammation and colitis-associated cancer. Many studies have shed light on a more thorough understanding of the function and distribution of microRNAs in CRC initiation and emergence. However, the molecular mechanisms by which microRNAs modulate cellular processes still need to be further elucidated and may offer a foundation for evaluating microRNA-based therapeutic potential for CRC in both animal models and clinical trials. In this review, the roles and mechanisms of microRNAs involved in CRC from pathogenesis to therapy are summarized and discussed, which may provide more useful hints for CRC prevention and therapy.

/pdf/micrornas-in-colorectal-carcinoma-from-pathogenesis-to-3io4naca1n.pdf

MicroRNAs in colorectal carcinoma--from pathogenesis to therapy.

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial–mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.

https://www.mdpi.com/1422-0067/19/12/3711/pdf

The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases.

Zinc finger E-box binding homeobox 2 (ZEB2) is a DNA-binding transcription factor, which is mainly involved in epithelial-to-mesenchymal transition (EMT). EMT is a conserved process during which mature and adherent epithelial-like state is converted into a mobile mesenchymal state. Emerging data indicate that ZEB2 plays a pivotal role in EMT-induced processes such as development, differentiation, and malignant mechanisms, for example, drug resistance, cancer stem cell-like traits, apoptosis, survival, cell cycle arrest, tumor recurrence, and metastasis. In this regard, the understanding of mentioned subjects in the development of normal and cancerous cells could be helpful in cancer complexity of diagnosis and therapy. In this study, we review recent findings about the biological properties of ZEB2 in healthy and cancerous states to find new approaches for cancer treatment.

The crucial role of ZEB2: From development to epithelial-to-mesenchymal transition and cancer complexity.

// Silvia Prislei 1 , Enrica Martinelli 1 , Gian Franco Zannoni 1, 2 , Marco Petrillo 1 , Flavia Filippetti 1 , Marisa Mariani 3 , Simona Mozzetti 1 , Giuseppina Raspaglio 1 , Giovanni Scambia 1 , Cristiano Ferlini 1, 3 1 Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy 2 Department of Pathology, Catholic University of the Sacred Heart, Rome, Italy 3 Reproductive Tumor Biology Research, Biomedical Lab, Department of Obstetrics and Gynecology, Danbury Hospital, Danbury, CT, USA Correspondence to: Silvia Prislei, e-mail: silvia.prislei@rm.unicatt.it Keywords: ZEB2, EMT, HuR, ovarian cancer Received: December 09, 2014      Accepted: May 05, 2015      Published: May 15, 2015 ABSTRACT ZEB2 is a key factor in epithelial-mesenchymal transition (EMT), a program controlling cell migration in embryonic development and adult tissue homeostasis. We demonstrated a role of ZEB2 in migration and anchorage-independent cell growth in ovarian cancer, as shown by ZEB2 silencing. We found that the RNA-binding protein HuR bound the 3′UTR of ZEB2 mRNA, acting as a positive regulator of ZEB2 protein expression. In Hey ovarian cell line, HuR silencing decreased ZEB2 and ZEB1 nuclear expression and impaired migration. In hypoglycemic conditions ZEB2 expression decreased, along with ZEB1, vimentin and cytoplasmic HuR, and a reduced cellular migration ability was observed. Analysis of ZEB2 and HuR expression in ovarian cancers revealed that nuclear ZEB2 is localized in tumor leading edge and co-localizes with cytoplasmic HuR. In a series of 143 ovarian cancer patients high expression of ZEB2 mRNA significantly correlated with a poor prognosis in term of both overall survival and progression- free survival. Moreover, at immunohistochemical evaluation, we found that prognostic significance of ZEB2 protein relies on its nuclear expression and co-localization with cytoplasmic HuR. In conclusion our findings indicated that nuclear ZEB2 may enhance progression of EMT transition and acquisition of an aggressive phenotype in ovarian cancer.

/pdf/role-and-prognostic-significance-of-the-epithelial-2yb83tykh8.pdf

Role and prognostic significance of the epithelial-mesenchymal transition factor ZEB2 in ovarian cancer

MicroRNAs have been suggested to play a vital role in regulate tumor progression and invasion. However, the expression of miR-335 in colorectal cancer (CRC) and its clinical significance are not known. Here, we report that miR-335 is a tumor suppressor by regulating expression of ZEB2. In this study, we showed that downregulated miR-335 levels in highly invasive CRC cell lines and tissues. Kaplan–Meier survival analysis indicated that patients with reduced miR-335 had a poor overall survival. Furthermore, enhancing the expression of miR-335 inhibited CRC cell migration and invasion in vitro and lung and liver metastasis in vivo, while silencing its expression resulted in increased migration and invasion. Additionally, we identified a novel miR-335 target, ZEB2, and the direct interaction between them was verified by 3′-untranslated region dual-luciferase reporter assay. In conclusion, our results demonstrate that miR-335 functions as a tumor suppressor and play a role in inhibiting metastasis of CRC cells through targeting ZEB2. These findings suggest that miR-335 may be useful as a new potential therapeutic target for CRC.

Bo Qiu

Papers

MicroRNA-335 inhibits invasion and metastasis of colorectal cancer by targeting ZEB2