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J Pathol. 2019 Mar 18. doi: 10.1002/path.5264. [Epub ahead of print]

Increased expression of neurotensin in high grade serous ovarian carcinoma with evidence of serous tubal intraepithelial carcinoma.

Author information

1
Levine Cancer Institute, Atrium Health, 1021 Morehead Medical Drive, Charlotte, North Carolina, 28204, USA.
2
Q2 Solutions-EA Genomics, 5827 South Miami Boulevard, Morrisville, North Carolina, 27560, USA.
3
Carolinas Pathology Group, 2001 Vail Avenue, Charlotte, North Carolina, 28207, USA.

Abstract

High grade serous ovarian cancer (HGSC) without identifiable serous tubal intraepithelial carcinoma (STIC) within the Fallopian tube (FT) occurs in approximately 50% of patients. The objective of this study was to use a multi-site tumor sampling approach to study HGSC with and without STIC. RNAseq analysis of HGSC samples collected from multiple sites e.g. ovary, FT and peritoneum, revealed moderate levels of intra-patient heterogeneity in gene expression that could influence molecular profiles. Mixed-model ANOVA analysis of gene expression in tumor samples from patients with multiple tumor sites (N=13) and patients with a single site tumor sample (N=11) to compare HGSC-STIC to HGSC-NOSTIC identified neurotensin (NTS) as significantly higher (>2-fold change, FDR<0.10) in HGSC-STIC. This data was validated using publicly available RNA-Seq datasets. Concordance between higher NTS gene expression and NTS peptide levels in HGSC-STIC samples was demonstrated by immunohistochemistry. To determine the role of NTS in HGSC, five ovarian cancer (OvCa) cell lines were screened for expression of NTS and its receptors, NTSR1 and NTSR3. Increased expression of NTS and NSTR1 was observed in several of the OvCa cells, whereas the NTSR3 receptor was lower in all OvCa cells, compared to immortalized FT epithelial cells. Treatment with NTSR1 inhibitor (SR48692) decreased cell proliferation, but increased cell migration in OvCa cells. The effects of SR4862 were receptor mediated, since transient RNAi knockdown of NTSR1 mimicked the migratory effects and knockdown of NTSR3 mimicked the anti-proliferative effects. Further, knockdown of NTSR1 or NTSR3 was associated with acquisition of distinct morphological phenotypes, epithelial or mesenchymal, respectively. Taken together, our results reveal a difference in a biologically active pathway between HGSC with and without STIC. Furthermore, we identify neurotensin signaling as an important pathway involved in cell proliferation and epithelial-mesenchymal transition in HGSC-STIC which warrants further study as a potential therapeutic target.

KEYWORDS:

Fallopian tube; Neurotensin; Ovarian cancer; Serous tubal intraepithelial cancer

PMID:
30883751
DOI:
10.1002/path.5264

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