Abstract
Pheochromocytoma (Pheo) is a tumor derived from chromaffin cells. It can be studied using 18F-dihydroxyphenylalanine (DOPA)—positron emission tomography (PET) due to its overexpression of L-type amino acid transporters (LAT1 and LAT2). The oncogenic pathways involved are still poorly understood. This study examined the relationship between 18F-DOPA-PET uptake and LAT1 expression, and we explored the role of miR-375 and putative target genes. A consecutive series of 58 Pheo patients were retrospectively analyzed, performing 18F-DOPA-PET in 32/58 patients. Real-time quantitative PCR was used to assess the expression of LAT1, LAT2, phenylethanolamine N-methyltransferase (PNMT), miR-375, and the major components of the Hippo and Wingless/Integrated pathways. Principal germline mutations associated with hereditary Pheo were also studied. Pheo tissues had significantly higher LAT1, LAT2, and PNMT mRNA levels than normal adrenal tissues. MiR-375 was strongly overexpressed. Yes-associated protein 1 and tankyrase 1 were upregulated, while beta-catenin, axin2, monocarboxylate transporter 8, and Frizzled 8 were downregulated. A positive relationship was found between 18F-DOPA-PET SUV mean and LAT1 gene expression and for 24 h-urinary norepinephrine and LAT1. This is the first experimental evidence of 18F-DOPA uptake correlating with LAT1 overexpression. We also demonstrated miR-375 overexpression and downregulated (Wnt) signaling and identified the Hippo pathway as a new potentially oncogenic feature of Pheo.
Highlights
Pheochromocytoma (Pheo) is a tumor derived from adrenomedullary chromaffin cells, originating in adrenal medulla or extra-adrenal sites
We found miR-375 clearly upregulated in Pheo compared with normal adrenal tissues (p < 0.0001), with a median 55-fold overexpression (Figure 4)
The proportions of familial and sporadic forms of Pheo in our study sample are consistent with the literature, but there were slightly more benign cases than usually reported (95% vs. 90% in literature), and we found a prevalent norepinephrine production pattern, as confirmed by the 24-h urinary normetanephrine/metanephrine ratio of 2
Summary
Pheochromocytoma (Pheo) is a tumor derived from adrenomedullary chromaffin cells, originating in adrenal medulla or extra-adrenal sites (paraganglioma). 123I-metaiodobenzylguanidine (MIBG) scintigraphy, 18Fdihydroxyphenylalanine (DOPA)—positron emission tomography (PET), 68Ga-1,4,7,10tetra-azacyclododecane-1,4,7,10-tetraacetic acid-octreotate (DOTA-TATE)—PET, and 18Ffluorodeoxyglucose (FDG)—PET are useful functional imaging tools for confirming a diagnosis of Pheo and for detecting any metastatic disease [1,5,6,7]. In this scenario, the rationale for using the 18F-DOPA tracer is based on the fact that neuroendocrine tumors are capable of taking up, decarboxylating, and storing amino acids and their biogenic amines such as L-DOPA [8].
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