Invasion and metastasis of carcinomas are often activated by induction of aberrant epithelial–mesenchymal transition (EMT). This is mainly driven by the transcription factor ZEB1, promoting tumor‐initiating capacity correlated with increased expression of the putative stem cell marker CD44. However, the direct link between ZEB1, CD44 and tumourigenesis is still enigmatic. Remarkably, EMT‐induced repression of ESRP1 controls alternative splicing of CD44, causing a shift in the expression from the variant CD44v to the standard CD44s isoform. We analyzed whether CD44 and ZEB1 regulate each other and show that ZEB1 controls CD44s splicing by repression of ESRP1 in breast and pancreatic cancer. Intriguingly, CD44s itself activates the expression of ZEB1, resulting in a self‐sustaining ZEB1 and CD44s expression. Activation of this novel CD44s‐ZEB1 regulatory loop has functional impact on tumor cells, as evident by increased tumor‐sphere initiation capacity, drug‐resistance and tumor recurrence. In summary, we identified a self‐enforcing feedback loop that employs CD44s to activate ZEB1 expression. This renders tumor cell stemness independent of external stimuli, as ZEB1 downregulates ESRP1, further promoting CD44s isoform synthesis.

A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer

The ZEB1/miR-200c feedback loop regulates invasion via actin interacting proteins MYLK and TKS5

Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance therapy with anti-angiogenic agents or Poly ADP-ribose polymerase (PARP) inhibitors provided a substantial benefit concerning progression-free survival among certain women with advanced EOC. However, effective treatment options remain limited in most recurrent cases. Therefore, validated novel molecular therapeutic targets remain urgently needed in the management of EOC. Signal transducer and activator of transcription-3 (STAT3) and STAT5 are aberrantly activated through tyrosine phosphorylation in a wide variety of cancer types, including EOC. Extrinsic tumor microenvironmental factors in EOC, such as inflammatory cytokines, growth factors, hormones, and oxidative stress, can activate STAT3 and STAT5 through different mechanisms. Persistently activated STAT3 and, to some extent, STAT5 increase EOC tumor cell proliferation, survival, self-renewal, angiogenesis, metastasis, and chemoresistance while suppressing anti-tumor immunity. By doing so, the STAT3 and STAT5 activation in EOC controls properties of both tumor cells and their microenvironment, driving multiple distinct functions during EOC progression. Clinically, increasing evidence indicates that the activation of the STAT3/STAT5 pathway has significant correlation with reduced survival of recurrent EOC, suggesting the importance of STAT3/STAT5 as potential therapeutic targets for cancer therapy. This review summarizes the distinct role of STAT3 and STAT5 activities in the progression of EOC and discusses the emerging therapies specifically targeting STAT3 and STAT5 signaling in this disease setting.

Aberrant activation of epithelial to mesenchymal transition (EMT) associated factors were highly correlated with increased mortality in cancer patients. SNAIL family of transcriptional repressors comprised of three members, each of which were essentially associated with gastrulation and neural crest formation. Among which, SNAI1 and SNAI2 were efficiently induced during EMT and their expressions were correlated with poor clinical outcome in patients with breast, colon and ovarian carcinoma. In an ovarian cancer cell lines panel, we identified that SNAI1 and SNAI2 expressions were mutually exclusive, where SNAI1 predominantly represses SNAI2 expression. Detailed analysis of SNAI2 promoter region revealed that SNAI1 binds to two E-box sequences that mediated transcriptional repression. Through epigenetic inhibitor treatments, we identified that inhibition of histone deacetylase (HDAC) activity in SNAI1 overexpressing cells partially rescued SNAI2 expression. Importantly, we demonstrated a significant deacetylation of histone H3 and significant enrichments of HDAC1 and HDAC2 corepressors in both E-box regions of SNAI2 promoter. Our results suggested that SNAI1 repression on SNAI2 expression was predominantly mediated through the recruitment of the histone deacetylation machinery. Utilization of HDAC inhibitors would require additional profiling of SNAI1 activity and combined targeting of SNAI1 and HDACs might render efficient cancer treatment.

Over two decades of studies on small noncoding RNA molecules illustrate the significance of microRNAs (miRNAs/miRs) in controlling multiple physiological and pathological functions through post-transcriptional and spatiotemporal gene expression. Among the plethora of miRs that are essential during animal embryonic development, in this review, we elaborate the indispensable role of the miR-200 family (comprising miR-200a, -200b, 200c, -141, and -429) in governing the cellular functions associated with epithelial homeostasis, such as epithelial differentiation and neurogenesis. Additionally, in pathological contexts, miR-200 family members are primarily involved in tumor-suppressive roles, including the reversal of the cancer-associated epithelial–mesenchymal transition dedifferentiation process, and are dysregulated during organ fibrosis. Moreover, recent eminent studies have elucidated the crucial roles of miR-200s in the pathophysiology of multiple neurodegenerative diseases and tissue fibrosis. Lastly, we summarize the key studies that have recognized the potential use of miR-200 members as biomarkers for the diagnosis and prognosis of cancers, elaborating the application of these small biomolecules in aiding early cancer detection and intervention.