Esophageal cancer is one of the most widespread types of malignant tumor, which is the sixth leading cause of cancer-related deaths in the world and third in China [
1,
2]. Esophageal squamous cell carcinoma (ESCC), the predominant histologic subtype of esophagus cancer, is prevalent in Asia, accounting for 90% cases especially in China [
3‐
5]. Due to a spectrum of aberrantly aggressive phenotypes and lack of early detection, most of the patients are diagnosed with advanced disease and have to give up the main curative option of surgical resection. Despite recent advances in multimodality therapies, the prognosis remains dismal. Like other malicious tumors, the pathogenesis and progression of ESCC are a long procedure involving activation of oncogenes and/or inactivation of tumor suppressor genes. Recently, promising molecular genetic alterations with clinical outcome in ESCC have been predicted [
6,
7]. Therefore, specific molecular markers associated with the progression and therapeutic targets are immediately needed for patient classification and the improvement of individualized therapy regimens.
MicroRNAs (miRNAs) are a class of highly-conserved, non-coding RNAs of 18 to 25 nucleotides in length and could function as indispensable and negative regulators of gene expression at the post-transcription level. The mature forms of miRNAs silence the gene expression by binding to the 3′-untranslated region (3′-UTR) of mRNAs and initiate the translational repression and/or target them for degradation. Mounting evidences indicate that miRNAs can donate to the malignant tumor progression and metastasis process, such as cell proliferation, invasion, angiogenesis, and the epithelial to mesenchymal transition (EMT) [
8‐
10]. Among the most frequently altered miRNAs identified, miR-31, which is located on the common homozygous deletion region on chromosome 9p21.3, is emerging as a complex player in an ocean of cancers. Evidence proposes that miR-31 can function as either an oncogene or a tumor suppressor in type-specific cancers, respectively. For example, increased expression of miR-31 has been identified in colorectal [
11], lung cancer [
12]and HNSCC [
13], whereas it plays a tumor-suppressive role in ovarian [
14] prostate [
15], breast cancer [
16] and melanoma [
17]. Moreover, downregulation of miR-31 in esophageal adenocarcinoma (EAC) correlates with poor prognosis [
18,
19]. Inversely, miR-31 is up-regulated in tissue and serum samples of ESCC, with expression relating to staging [
20]. Still, in another ESCC miR-31 expression was diminished [
21]. These studies emphasize the complexity of miR-31-associated malignant phenotypes. Challenges have to be resolved before miR-31 could be investigated in clinical trials, including definition of miR-31 targets, as well as pathways regulating miR-31 expression in ESCC.
The Hippo pathway is an evolutionarily conserved pathway that exerts profound effects on the regulation of organ size, tumorigenesis, embryonic development, stem cell homeostasis, and epithelial to mesenchymal transition [
22]. One of the cores of Hippo signaling complex in mammals is Lats1 or Lats2 (Lats1/2) kinases, others including MST1/2, MOB1 and YAP1 [
23,
24]. LATS2 kinases are members of the LATS/NDR kinase family, which encodes a serine/threonine protein kinase belonging to a sub-group of AGC (protein kinase A (PKA)/PKG/PKC-like) kinases [
25]. LATS2 gene has been located onto chromosome 13q11–12, a hot spot region as a tumor suppressor [
26]. LATS2 acts a meaningful role in centrosome duplication and maintenance of mitotic fidelity, because its protein localizes to centrosomes during interphase as well as early and late metaphases [
27]. LATS2 can inhibit cell growth at the G1/S transition via downregulating cyclin E/CDK2 kinase activity [
28], and induction of apoptosis via down-regulation of apoptosis inhibitors such as Bcl-2 and Bcl-xL [
29]. Once Hippo is activated, MST1/2 phosphorylates LATS1/2. Then the activated Lats1/2, in association with the tumor suppressor Mob1, in turn phosphorylates and inactivates transcriptional coactivators TAZ and YAP by their cytoplasmic retention and proteasome-mediated degradation [
30]. However, TAZ and YAP can be recruited to their target promoters through binding to the TEAD/TEF transcription factors instead of directly binding to DNA [
31] where they control the transcription of genes critical for EMT, cell proliferation, apoptosis, survival, differentiation, and cancer stem cell expansion [
32‐
35]. The activity of the Hippo pathway, especially TAZ/YAP, can be regulated by growth factors and extracellular diffusible signals as well as signals generated through cell-cell junction, tissue architecture, and mechanotransduction [
36]. It was also shown that dysregulation of the Hippo pathway is associated with epithelial-mesenchymal transition and cancer development, mainly driven by TAZ and YAP [
37]. Obviously, a bidirectional relationship exists between EMT and TAZ/YAP, whereby the loss of polarity and cell contacts stimulates the activation of both factors, which in turn participate in the EMT program [
38]. Furthermore, Muramatsu T et al. has demonstrated that YAP was frequently overexpressed in ESCC and they also showed that patients with YAP-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors. Their results have ultimately indicated that YAP is a putative oncogene in ESCC and it represents a potential diagnostic and therapeutic target [
39]. Thus we tended to focus on exploring the roles of TAZ in the ESCC epithelial-mesenchymal transition and chemoresistance. To date, numerous miRNAs have been verified to target LATS2 and involved in Hippo pathway in diverse types of cancer, like miR-181b, miR-93, and miR-372 [
40‐
42]. However, the specific expression features of miR-31 in ESCC remains undefined, and the underlying mechanisms of miR-31/LATS2 axis regulating epithelial-mesenchymal transition are still unknown.
Herein, the role of LATS2 and TAZ in miR-31 repression and the contribution of miR-31 to proliferation, migration, invasion and EMT of ESCC was explored. We identified that miR-31 directly suppressed LATS2 expression, which inactivated TAZ and led to the subsequent action of ESCC tumorigenicity. Significantly, it was showed that LATS2 and its downstream gene TAZ highly correlated with ESCC progression with poor prognosis. Altogether, these results suggested that miR-31 might act as a biomarker in ESCC and a novel functional axis of miR-31/LATS2/TAZ might propose a feasible therapeutic approach for ESCC that merited further evaluation.