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Insulin-Like Growth Factor and SLC12A7 Dysregulation: A Novel Signaling Hallmark of Non-Functional Adrenocortical Carcinomas.
Journal of the American College of Surgeons 2019 April 27
BACKGROUND: Insulin-like growth factor (IGF) dysregulation and gene copy number variations (CNV) are hallmarks of adrenocortical carcinoma (ACC). The contribution of IGF CNVs in adrenal carcinogenesis has not been previously studied. Moreover, studies demonstrating an association between SLC12A7 gene amplifications and enhanced metastatic behavior in ACC, as well as reported IGF-SLC12A7 signaling interactions in other cancers, suggests a potential IGF-SLC12A7 signaling circuitry in ACC. Here we investigate the potential complicity of IGF-SLC12A7 signaling in ACC.
STUDY DESIGN: IGF CNVs were determined by whole-exome sequencing analysis in an exploratory cohort of ACC. Quantitative PCR methods determined IGF1 and IGF2 expression levels and were evaluated for correlation with SLC12A7 expression and tumor characteristics. IGF CNVs and expression patterns were compared to The Cancer Genome Atlas (TCGA). In vitro studies determined the relationship of IGF and SLC12A7 co-expression in two ACC cell lines, SW-13 and NCI-H295R. Immunohistochemistry assessed IGF1 receptor (IGFR) activation.
RESULTS: The IGF1 gene was amplified in 9 of 19 ACC samples, similar to findings in the TCGA database. IGF1 overexpression was observed in 5 samples and was associated with SLC12A7 overexpression and non-functional, early stage tumors (p<0.05). In contrast, IGF2 overexpression was associated with larger tumors (p<0.05). In vitro IGF treatment of ACC cell lines did not stimulate SLC12A7 expression, while endogenous overexpression and silencing of SLC12A7 significantly altered IGF1 and IGF1R expression without impacting other IGFs. IGF1R activation was associated with IGF1 overexpression in ACC tumor samples.
CONCLUSION: These findings indicate that IGF1 overexpression caused, in part, by gene amplifications, is correlated with SLC12A7 overexpression in non-functional, early stage ACCs, suggesting a potentially targeted IGF1-SLC12A7 therapeutic opportunity for these tumors.
STUDY DESIGN: IGF CNVs were determined by whole-exome sequencing analysis in an exploratory cohort of ACC. Quantitative PCR methods determined IGF1 and IGF2 expression levels and were evaluated for correlation with SLC12A7 expression and tumor characteristics. IGF CNVs and expression patterns were compared to The Cancer Genome Atlas (TCGA). In vitro studies determined the relationship of IGF and SLC12A7 co-expression in two ACC cell lines, SW-13 and NCI-H295R. Immunohistochemistry assessed IGF1 receptor (IGFR) activation.
RESULTS: The IGF1 gene was amplified in 9 of 19 ACC samples, similar to findings in the TCGA database. IGF1 overexpression was observed in 5 samples and was associated with SLC12A7 overexpression and non-functional, early stage tumors (p<0.05). In contrast, IGF2 overexpression was associated with larger tumors (p<0.05). In vitro IGF treatment of ACC cell lines did not stimulate SLC12A7 expression, while endogenous overexpression and silencing of SLC12A7 significantly altered IGF1 and IGF1R expression without impacting other IGFs. IGF1R activation was associated with IGF1 overexpression in ACC tumor samples.
CONCLUSION: These findings indicate that IGF1 overexpression caused, in part, by gene amplifications, is correlated with SLC12A7 overexpression in non-functional, early stage ACCs, suggesting a potentially targeted IGF1-SLC12A7 therapeutic opportunity for these tumors.
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