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Published on: August 23, 2019
TWIST1/miR-584/TUSC2 pathway induces resistance to apoptosis in thyroid cancer cells
Francesca Maria Orlandella1, Gennaro Di Maro1, Clara Ugolini2
1IRCCS SDN Spa, 80121 Napoli, Italy.
Abstract:
TWIST1, a transcription factor, plays a pivotal role in cancer initiation and progression. Anaplastic thyroid carcinoma (ATC) is one of the deadliest human malignancies; TWIST1 is overexpressed in ATC and increases thyroid cancer cell survival, migration and invasion. The molecular mechanisms underlying the effects of TWIST1 are partially known. Here, using miRNome profiling of papillary thyroid cancer cells (TPC-1) ectopically expressing TWIST1, we identified miR-584. We showed that TWIST1 directly binds miR-584 using chromatin immunoprecipitation. Importantly, miR-584 was up-regulated in human ATC compared to papillary thyroid carcinoma (PTC) and normal thyroid samples. Overexpression of miR-584 in TPC cells induced resistance to apoptosis, whereas stable transfection of anti-miR-584 in TPC-TWIST1 and 8505C cells increased the sensitivity to apoptosis. Using bioinformatics programs, we identified TUSC2 (tumor suppressor candidate 2) as a novel target of miR-584. TUSC2 mRNA and protein levels were decreased in TPC miR-584 and increased in TPC-TWIST1 anti-miR-584 cells. Luciferase assays demonstrated direct targeting. Restored expression of TUSC2 rescued the inhibition of apoptosis induced by miR-584. Finally, qRT-PCR and immunohistochemical analysis showed that TUSC2 was down-regulated in ATC and PTC samples compared to normal thyroids. In conclusion, our study identified a novel TWIST1/miR-584/TUSC2 pathway that plays a role in resistance to apoptosis of thyroid cancer cells.
Insights
The transcription factor TWIST1 promotes thyroid cancer by upregulating miR-584, which suppresses the tumor suppressor TUSC2, leading to apoptosis resistance. This TWIST1/miR-584/TUSC2 pathway is crucial in anaplastic thyroid carcinoma progression.
Area of Science:
- Molecular Oncology
- Cancer Biology
- Gene Regulation
Background:
- TWIST1 is a key transcription factor in cancer development, notably overexpressed in deadly anaplastic thyroid carcinoma (ATC).
- TWIST1 promotes thyroid cancer cell survival, migration, and invasion, but its precise molecular mechanisms remain incompletely understood.
- Understanding TWIST1's role is critical for developing targeted therapies against aggressive thyroid cancers.
Purpose of the Study:
- To elucidate the molecular mechanisms by which TWIST1 contributes to thyroid cancer progression.
- To identify novel microRNAs (miRNAs) regulated by TWIST1 in thyroid cancer cells.
- To investigate the functional role of identified miRNAs and their downstream targets in apoptosis resistance.
Main Methods:
- miRNome profiling of papillary thyroid cancer cells (TPC-1) expressing TWIST1.
- Chromatin immunoprecipitation (ChIP) to confirm direct TWIST1 binding to miR-584.
- Quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry (IHC) to assess gene and protein expression.
- Bioinformatic analysis and luciferase assays to identify and validate miR-584 targets.
- Apoptosis assays and rescue experiments to evaluate functional significance.
Main Results:
- TWIST1 directly upregulates miR-584 expression in thyroid cancer cells.
- miR-584 is significantly elevated in human ATC and papillary thyroid carcinoma (PTC) compared to normal thyroid tissues.
- Overexpression of miR-584 confers apoptosis resistance, while its inhibition increases apoptosis sensitivity.
- TUSC2 (tumor suppressor candidate 2) was identified as a direct target of miR-584, with its expression inversely correlated to miR-584 levels.
- Restoring TUSC2 expression abrogated the apoptosis-inhibitory effects of miR-584.
- TUSC2 is downregulated in both ATC and PTC samples, suggesting its role as a tumor suppressor.
Conclusions:
- A novel TWIST1/miR-584/TUSC2 signaling axis was identified in thyroid cancer.
- This pathway contributes significantly to apoptosis resistance in thyroid cancer cells.
- Targeting this pathway may offer a therapeutic strategy for aggressive thyroid malignancies like ATC.
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