Trefoil factors: Tumor progression markers and mitogens via EGFR/MAPK activation in cholangiocarcinoma

Abstract

AIM:To investigate trefoil factor (TFF ) gene copy number, mRNA and protein expression as potential biomarkers in cholangiocarcinoma (CCA). METHODS:TFF mRNA levels, gene copy number and protein expression were determined respectively by quantitative reverse transcription polymerase chain reaction (PCR), quantitative PCR and immunohistochemistry in bile duct epithelium biopsies collected from individuals with CCA, precancerous bile duct dysplasia and from disease-free controls. The functional impact of recombinant human (rh)TFF2 peptide treatment on proliferation and epidermal growth factor receptor (EGFR)/mitogenactivated protein kinase (MAPK) signaling was assessed in the CCA cell line, KMBC, by viable cell counting and immunoblotting, respectively. RESULTS: TFF1 , TFF2 and TFF3 mRNA expression was significantly increased in CCA tissue compared to disease-free controls, and was unrelated to gene copy number. TFF1 immunoreactivity was strongly increased in both dysplasia and CCA, whereas TFF2 immunoreactivity was increased only in CCA compared to diseasefree controls. By contrast, TFF3 immunoreactivity was moderately decreased in dysplasia and further decreased in CCA. Kaplan-Meier analysis found no association of TFF mRNA, protein and copy number with age, gender, histological subtype, and patient survival time. Treatment of KMBC cells with rhTFF2 stimulated proliferation, triggered phosphorylation of EGFR and downstream extracellular signal related kinase (ERK), whereas co-incubation with the EGFR tyrosine kinase inhibitor, PD153035, blocked rhTFF2-dependent proliferation and EGFR/ERK responses.CONCLUSION: TFF mRNA/protein expression is indicative of CCA tumor progression, but not predictive for histological sub-type or survival time. TFF2 is mitogenic in CCA via EGFR/MAPK activation.

Epigenetic Control of Trefoil Factor Family (TFF) Peptide Expression in Human Retinoblastoma Cell Lines

“…2C). A similar expression pattern for TFF1 and TFF3 was described for cholangiocarcinoma compared to disease-free control tissues [54]. …”

Trefoil factors: Gastrointestinal-specific proteins associated with gastric cancer

“…However, seemingly contradictory to its proposed role as a tumor suppressor, TFF1 is frequently ectopically expressed or overexpressed in many human cancers, including oesophagus, lung, breast, pancreas, biliary tract, large bowel, mucinous-subtype ovarian tumors, bladder and prostate as well as their associated metastases [68][69][70][71]. In all TFF1-positive cancers, the protein is expressed in the cytoplasm of the tumor epithelial cells, as it is in normal gastric mucosal cells [10,25,72] (Fig.…”

Gastrokines: stomach-specific proteins with putative homeostatic and tumor suppressor roles

“…Unlike the TFFs, which display altered expression in neoplasias within and outside the gastrointestinal tract (1,2,4,6,22,29,41,56,66), altered expression of GKNs is associated almost exclusively with gastric cancer. Exceptions have been noted.…”