Histidine Decarboxylase, DOPA Decarboxylase, and Vesicular Monoamine Transporter 2 Expression in Neuroendocrine Tumors: Immunohistochemical Study and Gene Expression Analysis

Silvia Uccella ^1*, Roberta Cerutti ¹, Davide Vigetti ¹, Daniela Furlan ¹, Rita Oldrini ¹, Ileana Carnevali ¹, Giuseppe Pelosi ¹, Stefano La Rosa ¹, Alberto Passi ¹ and Carlo Capella ¹

¹ Department of Human Morphology, Section of Anatomic Pathology, University of Insubria and Ospedale di Circolo, Varese, Italy (SU,RC,DF,RO,IC,SL,CC); Department of Biochemical, Experimental and Clinical Sciences, University of Insubria, Varese, Italy (DV,AP); and Section of Anatomic Pathology, European Institute of Oncology, Milan, Italy (GP)

^* To whom correspondence should be addressed. E-mail: silvia.uccella{at}uninsubria.it.

Submitted on June 23, 2005
Accepted on 22 February 2006

	Abstract

Histidine decarboxylase (HDC) and vesicular monoamine transporter 2 (v-MAT2) are involved in the biosynthesis and the storage of histamine and their expression is a feature of histamine-handling cells. DOPA decarboxylase (DDC) is involved in the biosynthesis of a variety of amines and shares a high degree of homology with HDC. HDC and v-MAT2 immunoneactivities (IR) have recently been detected in well differentiated neuroendocrine tumors (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs) of various sites and have been proposed as general endcrine markers. We evaluated HDC and v-MAT2 IR in a series of 117 WDNETs and PDNECs from different sites and a Western blotting analysis was performed to verify the specificity of anti-DDC and anti-HDC antibodies. Real-time RT-PCR was performed using specific probes and primers for HDC and DDC on 42 cases, in which DDC IR was also evaluated. HDC and v-MAT2 IR were observed in the majority of WDNETs and PDNECs of all sites. However, the comparison between the gene expression analysis and the immunohistochemistry for HDC and DDC in a sample of cases showed conflicting results. In fact, all the cases analyzed were both HDC- and DDC-IR, while high levels of HDC m-RNA were detected only in the gastroenteropancreatic WDNETs, which did not show increased DDC m-RNA levels. In contrast, bronchial carcinoids and lung PDNECs showed high DDC m-RNA levels, but HDC m-RNA was nearly undetectable in these tumors. The Western blotting analysis confirmed a cross-reaction between the anti-HDC and the anti-DDC antibodies. In conclusion, HDC should not be considered as a general endocrine marker and HDC IR in bronchial carcinoids and PDNECs of the lung is probably to be attributed to a cross-reaction with DDC.

Key Words: histidine decarboxylase, vesicular monoamine transporter 2, DOPA decarboxylase, real time RT-PCR, neuroendocrine tumors, small cell lung cancer

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