EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression

Abstract

Epithelial-to-mesenchymal transition (EMT) is associated with metastasis formation as well as with generation and maintenance of cancer stem cells. In this way, EMT contributes to tumor invasion, heterogeneity and chemoresistance. Morphological and functional changes involved in these processes require robust reprogramming of gene expression, which is only partially accomplished at the transcriptional level. Alternative splicing is another essential layer of gene expression regulation that expands the cell proteome. This step in post-transcriptional regulation of gene expression tightly controls cell identity between epithelial and mesenchymal states and during stem cell differentiation. Importantly, dysregulation of splicing factor function and cancer-specific splicing isoform expression frequently occurs in human tumors, suggesting the importance of alternative splicing regulation for cancer biology.In this review, we briefly discuss the role of EMT programs in development, stem cell differentiation and cancer progression. Next, we focus on selected examples of key factors involved in EMT and stem cell differentiation that are regulated post-transcriptionally through alternative splicing mechanisms. Lastly, we describe relevant oncogenic splice-variants that directly orchestrate cancer stem cell biology and tumor EMT, which may be envisioned as novel targets for therapeutic intervention.

TGF‐β‐mediated LEFTY/Akt/GSK‐3β/Snail axis modulates epithelial‐mesenchymal transition and cancer stem cell properties in ovarian clear cell carcinomas

“…Interestingly, cancer stemness seems to be associated with a partial EMT phenotype rather than full-blown EMT. [47][48][49] Together, our results suggest a novel functional role of LEFTY in OCCCas (Figure 7). Researcher.…”

“…Along this line, it appears that LEFTY may also serve as a regulator for establishment and maintenance of a hybrid E/M stage in OCCCa cells. Interestingly, cancer stemness seems to be associated with a partial EMT phenotype rather than full‐blown EMT …”

HnRNPM and CD44s expression affects tumor aggressiveness and predicts poor prognosis in breast cancer with axillary lymph node metastases

“…According to our knowledge, our study is the first to identify the relationship between hnRNPM and ALDH1. The study that hnRNPM potentiates TGFβ signaling and promotes EMT in breast cancer aggressiveness may help to provide a better understanding for the relationship of hnRNPM and ALDH1, since there are lots of experiments demonstrating that the generation of EMT can induce a population with stem cell characteristics from well differentiated epithelial cells and cancer cells . It is possible that hnRNPM promotes CSCs phenotype development through the induction of EMT and the underlying mechanism needs to be further explored.…”

Alpha B‐crystallin promotes the invasion and metastasis of gastric cancer via NF‐κB‐induced epithelial‐mesenchymal transition

“…Migration and invasion are hallmarks for cancer metastasis and related to EMT 16, 17. To evaluate the effects of CRYAB on migration and invasion of gastric cancer cells in vitro, the wound‐healing assay was first performed.…”