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ETV5, an Ets Family Transcription Factor, is a Marker for RAS‐Dependent Papillary Thyroid Cancer
Author(s) -
Hoang Nguyet Minh,
Puli Oorvashi Roy,
Danysh Brian,
Hofmann Marie Claude
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1119.1
Subject(s) - cancer research , vemurafenib , papillary thyroid cancer , thyroid cancer , v600e , epithelial–mesenchymal transition , cancer , medicine , thyroid carcinoma , thyroid , transcription factor , biology , metastasis , melanoma , mutation , gene , biochemistry , metastatic melanoma
BRAF V600E mutation has a significant association with recurrence in patients with papillary thyroid cancer, reducing survival rate from 98% to 40%. Patients treated with BRAF V600E inhibitors such as vemurafenib acquire resistance to the drug over time (6 months) and tumor cells metastasize to distant organs, leading to patient death. Within the group of patients with BRAF V600E tumors, there are no reliable biomarkers to predict local or distant recurrences, especially when tumors acquire clonal resistance due to the effects of targeted therapies. PTC (Papillary Thyroid Cancer) patients with the BRAF V600E and RAS mutations show an elevated ETV5 (Ets‐transcript variant 5) expression. ETV5, a transcription factor, is known to promote epithelial to mesenchymal transition (EMT) in endometrial carcinomas and ovarian cancer by up‐regulating ZEB1, a repressor of E‐Cadherin, causing cell detachment and invasion. ETV5 also induces the expression of matrix metalloproteinase 2 (MMP‐2) in human endometrial carcinomas, causing invasion. Hypothesis We hypothesize that ETV5 drives cell proliferation and EMT (Epithelial to Mesenchymal Transition) in advanced papillary thyroid cancer. Methods We used the cell line KTC1 ( BRAF V600E mutant thyroid cancer cell line) as a model. ETV5 and BRAF V600E were knocked‐down using Silencer Select siRNA. Alternatively, cells were treated with standard pharmacological inhibitors (i.e. PI3Ki, AKTi, vemurafenib, ERKi, TGFBR1i). ETV5 expression was quantified using Quantitative PCR and Western Blots. Proliferation/growth assays were performed for 5 days and the cell numbers were counted using the IN Cell 6000 confocal system and Image Analysis software post‐transfection/treatment. Results Knockdown of ETV5 and/or BRAF decreased KTC1 cell proliferation. Cell growth was reduced upon treatment with vemurafenib, or PI3K‐AKT and ERK inhibitors, but not with TGFBR1 inhibitors. In comparison to DMSO treatment (control), ETV5 levels were down‐regulated upon ERK inhibitor treatment but were increased when treated with PI3K inhibitors. Short‐term vemurafenib treatment (48h) showed a reduction in ETV5, N‐Cadherin, and CXCR4 expression suggesting its role in EMT. Conclusion ETV5 acts downstream of the RAS‐MAPK (ERK1/2) pathway. ETV5 is crucial for KTC1 cell proliferation and may also play a role in EMT in PTC. Support or Funding Information This project is sponsored by a DRP grant, which is part of NIH P50 CA168505