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Silencing Stmn1 Expression Decreases Aggressive Phenotype In Adrenocortical Carcinoma

Author
Aronova, Anna
Abstract
Background: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and few therapeutic options. Stathmin1 (STMN1) is a cytosolic protein involved in microtubule dynamics, which has been implicated in carcinogenesis and more aggressive behavior in multiple epithelial malignancies. Here we aimed to evaluate the expression of STMN1 in ACC and to elucidate how this may contribute to its malignant phenotype. Methods: STMN1 was identified as a highly differentially expressed gene in human samples of adrenocortical carcinoma submitted for high throughput RNA-sequencing compared to benign adrenal tumors. Expression was confirmed by qRT-PCR, Western blot, and immunohistochemical (IHC) staining of a tissue microarray (TMA) from two independent cohorts. The biologic relevance of this target was investigated in the NCI-H295R ACC cell line by lentivirus-mediated silencing of STMN1. In vitro phenotypic changes were assessed for cell viability, cell-cycle alterations, invasion, migration, and anchorage-independent growth. Results: Differential gene expression demonstrated over an eight-fold increase in STMN1 mRNA in malignant compared to benign adrenal tissue (p<2.4E-07). IHC showed significantly higher expression of STMN1 protein in ACC compared to normal and benign tissues (p<0.05, p<0.01, respectively). We achieved more than 70% reduction of STMN1 expression in NCI-H295R by lentivirus-mediated short hairpin RNA (shRNA) delivery. STMN1 knockdown resulted in decreased cell viability (p<0.01), cell-cycle arrest at G0/G1 (p<0.01), and increased apoptosis (p<0.01) in stressed, serum-starved conditions compared to scramble shRNA controls. STMN1 knockdown also decreased migration (p<0.05), invasion (p<0.05), and anchorage-independent growth (p<0.01) compared to controls. Conclusion: STMN1 is overexpressed in human ACC samples and knockdown of this target in vitro resulted in a less aggressive phenotype of ACC, particularly under serum-starved conditions. Further study is needed to investigate the feasibility of interfering with STMN1 as a potential therapeutic target.
Date Issued
2017Subject
adrenocortical carcinoma; cancer; endocrine surgery; microtubules; STMN1
Degree Discipline
Clinical & Translational Investigation
Degree Level
Master of Science
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Type
dissertation or thesis
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International