Research Papers:

TWIST1/miR-584/TUSC2 pathway induces resistance to apoptosis in thyroid cancer cells

Francesca Maria Orlandella, Gennaro Di Maro, Clara Ugolini, Fulvio Basolo and Giuliana Salvatore _

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Oncotarget. 2016; 7:70575-70588. https://doi.org/10.18632/oncotarget.12129

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Francesca Maria Orlandella1, Gennaro Di Maro1, Clara Ugolini2, Fulvio Basolo3, Giuliana Salvatore1,4

1IRCCS SDN Spa, 80121 Napoli, Italy

2Dipartimento di Area Medica, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy

3Dipartimento di Patologia Chirugica, Medica, Molecolare e dell'Area Critica dell' Università di Pisa, 56126 Pisa, Italy

4Dipartimento di Scienze Motorie e del Benessere, Universita’ “Parthenope”, 80133 Napoli, Italy

Correspondence to:

Giuliana Salvatore, email: [email protected]

Keywords: miR-584, TWIST1, TUSC2, anaplastic thyroid carcinoma, apoptosis

Received: February 23, 2016     Accepted: September 02, 2016     Published: September 20, 2016


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.

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