KCC4/IGF1 Dysregulation: A Novel Signaling Hallmark of Non-functional Adrenocortical Carcinomas
*Taylor C. Brown1, *Norman G. Nicolson1, *Adam Stenman2, *Christofer C. Juhlin2, *Courtney E. Gibson1, Glenda G. Callender1, Tobias Carling1
1Yale University School of Medicine, Department of Surgery, New Haven, CT; 2Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Objective: K-Cl Co-transporter 4 (KCC4) dysregulation promotes tumor metastases and was recently implicated in fostering the aggressive behavior of adrenocortical carcinoma (ACC). A role for aberrant insulin growth factor (IGF) signaling, a hallmark of ACC, in mediating KCC4-induced dedifferentiation of ACC, has not been previously studied. Here, we investigate the potential complicity of KCC4 and IGF signaling in ACC.
Design: Retrospective and in vitro analyses.
Setting: Tertiary academic referral centers.
Patients (or Other Participants): Thirty-three patients who underwent adrenalectomy for ACC.
Interventions: Real-time quantitative PCR determined IGF1 and IGF2 expression levels in tumor samples compared to normal adrenal tissue in 33 ACC tumors whose KCC4 expression has been previously determined. Tumor IGF expression levels were evaluated for correlation with KCC4 expression levels and tumor characteristics. In vitro studies determined the relationship of IGF signaling and KCC4 co-expression in the ACC cell line SW-13.
Main Outcome Measures: Tumor expression levels of IGF1 and IGF2, their association with KCC4 expression and tumor characteristics, and their potential role in KCC4 overexpression in vitro.
Results: Increased IGF1 expression was associated with KCC4 overexpression and non-functional and early stage tumors (p<0.05). In contrast, IGF2 overexpression was associated with larger tumors (diameter, p=0.07; weight, p<0.05), but was not associated with increased KCC4 expression. In vitro treatment of SW-13 cells with recombinant IGFs did not stimulate KCC4 expression while enforced overexpression of KCC4 resulted in a 4-fold increase in IGF1 expression without significantly impacting other IGF signaling components including IGF2.
Conclusions: Increased IGF1 stimulation is associated with KCC4 overexpression in non-functional, early stage ACCs, suggesting a targeted KCC4/IGF1 therapeutic opportunity for these tumors.