TY - JOUR
T1 - Expression of Wnt and TGF-β pathway components and key adrenal transcription factors in adrenocortical tumors
T2 - Association to carcinoma aggressiveness
AU - Parviainen, Helka
AU - Schrade, Anja
AU - Kiiveri, Sanne
AU - Prunskaite-Hyyryläinen, Renata
AU - Haglund, Caj
AU - Vainio, Seppo
AU - Wilson, David B.
AU - Arola, Johanna
AU - Heikinheimo, Markku
N1 - Funding Information:
This work was financially supported by the Sigrid Jusélius Foundation, the Helsinki University Central Hospital Research Funds, the Clinical Graduate School in Pediatrics and Obstetrics/Gynecology, the US National Institutes of Health grant DK075618 and the German Academic Exchange Service. We thank Dr. Markku Kallio for valuable help with statistical analysis, and Taru Jokinen, Elina Aspiala and Eija Heiliö for expert technical assistance.
PY - 2013/8
Y1 - 2013/8
N2 - Factors controlling benign and malignant adrenocortical tumorigenesis are largely unknown, but several mouse models suggest an important role for inhibin-alpha (INHA). To show that findings in the mouse are relevant to human tumors and clinical outcome, we investigated the expression of signaling proteins and transcription factors involved in the regulation of INHA in human tumor samples. {dot operator} Thirty-one adrenocortical tumor samples, including 13 adrenocortical carcinomas (ACCs), were categorized according to Weiss score, hormonal profile, and patient survival data and analyzed using immunohistochemistry and RT-PCR.Expression of the TGF-β signaling mediator SMAD3 varied inversely with Weiss score, so that SMAD3 expression was lowest in the most malignant tumors. By contrast, SMAD2 expression was upregulated in most malignant tumors. Wnt pathway co-receptors LRP5 and LRP6 were predominantly expressed in benign adrenocortical tumors. In ACCs, expression of transcription factors GATA-6 and SF-1 correlated with that of their target gene INHA. Moreover, the diminished expression of GATA-6 and SF-1 in ACCs correlated with poor outcome.We conclude that the factors driving INHA expression are reduced in ACCs with poor outcome, implicating a role for INHA as a tumor suppressor in humans.
AB - Factors controlling benign and malignant adrenocortical tumorigenesis are largely unknown, but several mouse models suggest an important role for inhibin-alpha (INHA). To show that findings in the mouse are relevant to human tumors and clinical outcome, we investigated the expression of signaling proteins and transcription factors involved in the regulation of INHA in human tumor samples. {dot operator} Thirty-one adrenocortical tumor samples, including 13 adrenocortical carcinomas (ACCs), were categorized according to Weiss score, hormonal profile, and patient survival data and analyzed using immunohistochemistry and RT-PCR.Expression of the TGF-β signaling mediator SMAD3 varied inversely with Weiss score, so that SMAD3 expression was lowest in the most malignant tumors. By contrast, SMAD2 expression was upregulated in most malignant tumors. Wnt pathway co-receptors LRP5 and LRP6 were predominantly expressed in benign adrenocortical tumors. In ACCs, expression of transcription factors GATA-6 and SF-1 correlated with that of their target gene INHA. Moreover, the diminished expression of GATA-6 and SF-1 in ACCs correlated with poor outcome.We conclude that the factors driving INHA expression are reduced in ACCs with poor outcome, implicating a role for INHA as a tumor suppressor in humans.
KW - Adenoma
KW - Carcinoma
KW - Inhibin
KW - Signaling pathway
KW - Transcription factor
UR - http://www.scopus.com/inward/record.url?scp=84881557332&partnerID=8YFLogxK
U2 - 10.1016/j.prp.2013.06.002
DO - 10.1016/j.prp.2013.06.002
M3 - Article
C2 - 23866946
AN - SCOPUS:84881557332
SN - 0344-0338
VL - 209
SP - 503
EP - 509
JO - Pathology Research and Practice
JF - Pathology Research and Practice
IS - 8
ER -