Epithelial-to-mesenchymal transition in gallbladder cancer: from clinical evidence to cellular regulatory networks

Abstract

Gallbladder cancer (GBC), with late diagnosis, rapid disease progression and early metastasis, is a highly aggressive malignant tumor found worldwide. Patients with GBC have poor survival, low curative resection rates and early recurrence. For such a lethal tumor, uncovering the mechanisms and exploring new strategies to prevent tumor progression and metastasis are critically important. Epithelial-to-mesenchymal transition (EMT) has a prominent role in the early steps of tumor progression and metastasis by initiating polarized epithelial cell transition into motile mesenchymal cells. Accumulating evidence suggests that EMT can be modulated by the cooperation of multiple mechanisms affecting common targets. Signaling pathways, transcriptional and post-transcriptional regulation and epigenetic alterations are involved in the stepwise EMT regulatory network in GBC. Loss of epithelial markers, acquisition of mesenchymal markers and dysregulation of EMT-inducing transcription factors (EMT-TFs) have been observed and are associated with the clinicopathology and prognosis of GBC patients. Therefore, EMT may be a detectable and predictable event for predicting GBC progression and metastasis in the clinic. In this review, we will provide an overview of EMT from the clinical evidence to cellular regulatory networks that have been studied thus far in clinical and basic GBC studies.

Figure 1

Cell marker changes in EMT. During EMT, epithelial cells lose their cell membrane epithelial markers and acquire mesenchymal markers and metastatic traits.

Figure 2

Multiple signaling pathways drive EMT in GBC cells. The TGF-β signaling pathway, Wnt signaling pathway and the Hh signaling pathway can govern the switch from an epithelial to a mesenchymal phenotype by upregulating oncogenic or decreasing tumor-suppressive gene expression. In addition, these signaling pathways can be activated or inhibited by multiple cellular factors.

Figure 3

Transcription factor-mediated EMT regulation. EMT-TFs directly bind to their target gene promoter region to regulate target gene transcription and promote tumor cell migration, invasion and metastasis.