X-linked inhibitor of apoptosis protein accelerates migration by inducing epithelial–mesenchymal transition through TGF-β signaling pathway in esophageal cancer cells

Abstract

Background The prognosis of esophageal cancer is still dismal because of its high probability of metastasis that is likely related to the cellular process of epithelial–mesenchymal transition (EMT). Recent studies have shown a novel role of X-linked inhibitor of apoptosis protein (XIAP) in regulating the migration process of cancer cells and, therefore, linking to progression and poor prognosis of cancer. Methods The expression of XIAP in esophageal squamous cell cancer (ESCC) tissues was determined by immunohistochemistry assay. Cell migration was analyzed by wound healing assay and Transwell assay. The expression of EMT markers (E-cadherin, N-cadherin and Vimentin) was revealed by immunofluorescence assay. Quantitative real‑time PCR analysis and Western blot analysis were used to detect the expression of XIAP and EMT markers as well as transforming growth factor-β (TGF-β) at mRNA and protein level, respectively. Results We found that the expression of XIAP closely correlated to the probability of lymphatic metastasis in patients and that ESCC patients with the high XIAP expression were associated with worse overall survival (OS). Univariate and multivariate analysis also revealed XIAP as an independent prognostic factor for overall survival in ESCC patients. In both EC9706 and TE13 cell lines, knockdown of XIAP decreased the migration of cancer cells by inhibiting EMT process through regulating the TGF-β signaling pathway, pinpointing a regulatory role of XIAP in migratory process upon TGF-β activation. Conclusions Taken together, our results suggest XIAP as a important prognostic and regulative factor in ESCC patients. XIAP may promote migration of esophageal cancer cells through the activation of TGF-β mediated EMT.

BACH1 promotes the progression of esophageal squamous cell carcinoma by inducing the epithelial–mesenchymal transition and angiogenesis

“…Tumor cells that undergo the EMT lose cell–cell adhesion and polarity and acquire mesenchymal characteristics with stronger migration and invasion properties 26 . Accumulating recent evidence indicated that the EMT is common in tumor cells during tumor progression and correlates with local invasiveness and metastatic potential of various tumors, including ESCC 15,17,27‐29 . Morphological changes caused by BACH1 were observed in the present study; BACH1 overexpression increased the expression of N‐cadherin, vimentin, and Slug and decreased the level of the epithelial marker E‐cadherin, and knockdown of BACH1 showed the opposite effects.…”

The Multiple Roles of the IAP Super-family in cancer

“…XIAP has been reported to act as a cofactor in TGFβ signaling independent of its role in apoptosis by associating with members of the type I class of TGFβ receptors (Birkey Reffey, Wurthner, Parks, Roberts, & Duckett, 2001). Also, in esophageal carcinoma cell lines, XIAP has been reported to enhance cell migration by activating TGFβ, which then promotes EMT (Jin, Lu, Wang, Zhao, & Xue, 2019). As discussed previously, IAPs are now well-known regulators of the canonical and non-canonical NFB signaling, which is also known to play an important role in cancer cell migration/invasion by regulating Snail and other EMT regulators (Y.…”

ATAD2 interacts with C/EBPβ to promote esophageal squamous cell carcinoma metastasis via TGF-β1/Smad3 signaling

“…Several studies have devoted to investigate the role of TGF-β signaling pathway in ESCC. The majority demonstrated the tumor-promoting role of TGF-β signaling pathway in ESCC [ 32 – 34 ], while several studies draw the contrary conclusion [ 35 , 36 ]. We discovered TGF-β signaling pathway listed on the top one of the pathways associated with ATAD2 via RNA-sequencing and proved the regulation role of ATAD2 on TGF-β1, which clarified a tumor-promoting role of TGF-β signaling pathway in ESCC.…”