TESC Promotes TGF-α/EGFR-FOXM1-Mediated Tumor Progression in Cholangiocarcinoma

Abstract

Cholangiocarcinoma is a relatively uncommon but highly lethal malignancy. Improving outcomes in patients depends on earlier diagnosis and appropriate treatment; however, no satisfactory diagnostic biomarkers or targeted therapies are currently available. To address this shortcoming, we analyzed the transcriptomic datasets of cholangiocarcinoma from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and found that TESC is highly expressed in cholangiocarcinoma. Elevated cellular levels of TESC are correlated with larger tumor size and predict a poor survival outcome for patients. Knockdown of TESC via RNA interference suppresses tumor growth. RNA-sequencing analysis showed that silencing of TESC decreases the level of FOXM1, leading to cell cycle arrest. Correlation analysis revealed that the cellular level of TESC is correlated with that of FOXM1 in cholangiocarcinoma patients. We further observed that upon TGF-α induction, TESC is upregulated through the EGFR-STAT3 pathway and mediates TGF-α-induced tumor cell proliferation. In vivo experiments revealed that knockdown of TESC significantly attenuates tumor cell growth. Therefore, our data provide novel insight into TESC-mediated oncogenesis and reveal that TESC is a potential biomarker or serves as a therapeutic target for cholangiocarcinoma.

FOXM1 and Cancer: Faulty Cellular Signaling Derails Homeostasis

“…Whether FOXM1/MET overexpression have any association with metastasis of PDA need to be validated, however, its role in lymph node metastases of gastric cancer has already been established ( 30 ). Another signaling of FOXM1 via TGF-α/EGFR-STAT3-TESC was observed in cholangiocarcinoma progression ( 31 ).…”

CRISPR/Cas9 in Gastrointestinal Malignancies

“…Similar to the other types of GI cancer, CRISPR/Cas9 has also been used to study the functional role of single genes in the development of biliary tract cancer. This includes studies on the role of the protein kinase CK2, TESC or ARID1A ( Di Maira et al, 2019 ; Hsieh et al, 2020 ; Yoshino et al, 2020 ). Furthermore, CRISPR/Cas9 has been used to study mechanisms responsible for a response or resistance to anti-cancer therapeutics ( Saha et al, 2016 ; Xu et al, 2019 ) or as a strategy for gene therapy ( Carotenuto et al, 2020 ).…”

ErBb Family Proteins in Cholangiocarcinoma and Clinical Implications

“…TESC is highly upregulated in patients with ICC and is associated with poor survival. TESC induced by the TGFα/EGFR/signal transducer and activator of transcription 3 (STAT3) signaling pathway promotes cell proliferation and tumor growth in vivo and in vitro by increasing the expression of forkhead box M1 (FOXM1) [ 31 ]. Protein tyrosine kinase 6 (PTK6) expression is significantly elevated in patients with distal and perihilar CC (compared with patients with ICC or well-differentiated tumors) and colocalized with EGFR and ERBB2.…”