TY - JOUR
T1 - Insulin-Like Growth Factor and SLC12A7 Dysregulation
T2 - A Novel Signaling Hallmark of Non-Functional Adrenocortical Carcinoma
AU - Brown, Taylor C.
AU - Nicolson, Norman G.
AU - Stenman, Adam
AU - Juhlin, C. Christofer
AU - Gibson, Courtney E.
AU - Callender, Glenda G.
AU - Korah, Reju
AU - Carling, Tobias
N1 - Publisher Copyright:
© 2019
PY - 2019/9
Y1 - 2019/9
N2 - 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 studied previously. In addition, 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, suggest a potential IGF-SLC12A7 signaling circuitry in ACC. Here we investigate the potential complicity of IGF-SLC12A7 signaling in ACC. Study Design: Insulin-like growth factor CNVs were determined by whole-exome sequencing analysis in an exploratory cohort of ACC. Quantitative polymerase chain reaction methods determined IGF1 and IGF2 expression levels and were evaluated for correlation with SLC12A7 expression and tumor characteristics. Insulin-like growth factor CNVs and expression patterns were compared with The Cancer Genome Atlas. In vitro studies determined the relationship of IGF and SLC12A7 co-expression in 2 ACC cell lines, SW-13 and NCI-H295R. Immunohistochemistry assessed IGF1 receptor (IGF1R) activation. Results: The IGF1 gene was amplified in 9 of 19 ACC samples, similar to findings in The Cancer Genome Atlas database. The 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, and endogenous overexpression and silencing of SLC12A7 significantly altered IGF1 and IGF1R expression without impacting other IGFs. The IGF1R activation was associated with IGF1 overexpression in ACC tumor samples. Conclusions: 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.
AB - 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 studied previously. In addition, 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, suggest a potential IGF-SLC12A7 signaling circuitry in ACC. Here we investigate the potential complicity of IGF-SLC12A7 signaling in ACC. Study Design: Insulin-like growth factor CNVs were determined by whole-exome sequencing analysis in an exploratory cohort of ACC. Quantitative polymerase chain reaction methods determined IGF1 and IGF2 expression levels and were evaluated for correlation with SLC12A7 expression and tumor characteristics. Insulin-like growth factor CNVs and expression patterns were compared with The Cancer Genome Atlas. In vitro studies determined the relationship of IGF and SLC12A7 co-expression in 2 ACC cell lines, SW-13 and NCI-H295R. Immunohistochemistry assessed IGF1 receptor (IGF1R) activation. Results: The IGF1 gene was amplified in 9 of 19 ACC samples, similar to findings in The Cancer Genome Atlas database. The 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, and endogenous overexpression and silencing of SLC12A7 significantly altered IGF1 and IGF1R expression without impacting other IGFs. The IGF1R activation was associated with IGF1 overexpression in ACC tumor samples. Conclusions: 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.
UR - http://www.scopus.com/inward/record.url?scp=85065882782&partnerID=8YFLogxK
U2 - 10.1016/j.jamcollsurg.2019.04.018
DO - 10.1016/j.jamcollsurg.2019.04.018
M3 - Article
C2 - 31034883
AN - SCOPUS:85065882782
SN - 1072-7515
VL - 229
SP - 305
EP - 315
JO - Journal of the American College of Surgeons
JF - Journal of the American College of Surgeons
IS - 3
ER -