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Upregulation of PCP4 in human aldosterone-producing adenomas fosters human adrenocortical tumor cell growth via AKT and AMPK pathway.

ABSTRACT: Primary aldosteronism (PA) is characterized by aldosterone hypersecretion and adrenal hyperplasia and ranks as one of the most common causes of secondary hypertension. However, the molecular mechanism involved in adrenal hyperplasia and tumorigenesis is largely unknown. Dysregulation of Purkinji cell protein 4 (PCP4) is involved in the development and progression of neoplasia and aldosterone secretion, but little is known about the effect of PCP4 on human adrenocortical tumorigenesis. We investigated the expression pattern of PCP4 in different adrenal tissues and studied whether PCP4 is involved in cell growth in human adrenal cell lines. The mRNA levels of PCP4 were measured by real-time PCR in tissues from aldosterone-producing adenomas (APAs), idiopathic hyperaldosteronism (IHA) tissues, and normal adrenal (NA) tissues. In vitro siRNA knockdown of PCP4 in NCI-H295R and SW13 cell lines was used to determine the effect of PCP4 on cellular growth. Our results show that the mRNA level of PCP4 is upregulated in APAs and IHA compared with that in NA. The PCP4 mRNA expression level was positively correlated with tumor size in APAs. Knockdown of PCP4 decreased cell proliferation. Flow cytometry analysis showed that PCP4 knockdown fosters apoptosis. Finally, PCP4 knockdown inhibited phosphorylation of AKT308 and AMPKThr172. Our data suggest that PCP4 may represent a key player in the development and pathophysiology of PA via targeting the AKT and AMPK signaling pathways and thus may be a promising therapeutic target for PA.

SUBMITTER: Aji G

PROVIDER: S-EPMC6958178 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Upregulation of PCP4 in human aldosterone-producing adenomas fosters human adrenocortical tumor cell growth via AKT and AMPK pathway.

Aji Gulibositan G Li Fang F Chen Jiachao J Leng Fei F Hu Ke K Cheng Ziyun Z Luo Yu Y Xu Xi X Zhang Jing J Lu Zhiqiang Z

International journal of clinical and experimental pathology 20180301 3

Primary aldosteronism (PA) is characterized by aldosterone hypersecretion and adrenal hyperplasia and ranks as one of the most common causes of secondary hypertension. However, the molecular mechanism involved in adrenal hyperplasia and tumorigenesis is largely unknown. Dysregulation of Purkinji cell protein 4 (PCP4) is involved in the development and progression of neoplasia and aldosterone secretion, but little is known about the effect of PCP4 on human adrenocortical tumorigenesis. We investi ...[more]

PMID: 31938214

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Project description:ContextThe use of next-generation sequencing has resulted in the identification of recurrent somatic mutations underlying primary aldosteronism (PA). However, significant gaps remain in our understanding of the relationship between tumor aldosterone synthase (CYP11B2) expression and somatic mutation status.ObjectiveThe objective of the study was to investigate tumor CYP11B2 expression and somatic aldosterone-driver gene mutation heterogeneity.MethodsFifty-one adrenals from 51 PA patients were studied. Immunohistochemistry for CYP11B2 was performed. Aldosterone-producing adenomas with intratumor CYP11B2 heterogeneity were analyzed for mutation status using targeted next-generation sequencing. DNA was isolated from CYP11B2-positive, CYP11B2-negative, and adjacent normal areas from formalin-fixed, paraffin-embedded sections.ResultsOf 51 adrenals, seven (14 %) showed distinct heterogeneity in CYP11B2 by immunohistochemistry, including six adenomas with intratumor heterogeneity and one multinodular hyperplastic adrenal with both CYP11B2-positive and -negative nodules. Of the six adrenocortical adenomas with CYP11B2 heterogeneity, three had aldosterone-regulating mutations (CACNA1D p.F747C, KCNJ5 p.L168R, ATP1A1 p.L104R) only in CYP11B2-positive regions, and one had two different mutations localized to two histologically distinct CYP11B2-positive regions (ATP2B3 p.L424_V425del, KCNJ5 p.G151R). Lastly, one adrenal with multiple CYP11B2-expressing nodules showed different mutations in each (CACNA1D p.F747V and ATP1A1 p.L104R), and no mutations were identified in CYP11B2-negative nodule or adjacent normal adrenal.ConclusionsAdrenal tumors in patients with PA can demonstrate clear heterogeneity in CYP11B2 expression and somatic mutations in driver genes for aldosterone production. These findings suggest that aldosterone-producing adenoma tumorigenesis can occur within preexisting nodules through the acquisition of somatic mutations that drive aldosterone production.

Dataset Information

Upregulation of PCP4 in human aldosterone-producing adenomas fosters human adrenocortical tumor cell growth via AKT and AMPK pathway.

Publications

Upregulation of PCP4 in human aldosterone-producing adenomas fosters human adrenocortical tumor cell growth via AKT and AMPK pathway.

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