Neurotensin and Neurotensin Receptor 1 Expression in Human Myometrium and Uterine Leiomyomas1

Abstract

Leiomyomas or fibroids are the most frequently diagnosed tumors of the female genital tract, and their growth seems to be steroid-hormone dependent by a yet undetermined cellular and molecular mechanism. Sexual hormones induce the secretion of growth factor peptides and the expression of their receptors, stimulating cell proliferation. One of these factors is neurotensin, and increasing evidence suggests that it can promote growth of different cancer cells. Since there are no data on neurotensin expression in normal and tumoral uterine tissue, we have analyzed the expression of NTS and NTSR1 receptor using immunohistochemistry for protein detection, in situ hybridization to detect cells expressing NTS mRNA, and RT-PCR to detect NTSR1 transcript as well as any of the alternative splice variants recently described for this receptor. We found that NTS and NTSR1 are expressed in connective cells of normal myometrium. In leiomyomas, immunoreactivity for NTS and NTSR1 receptor is colocalized in the smooth muscle cells that are also transcribing NTS. Women receiving high doses of steroids for in vitro fertilization showed tumor growth and increased immunoreactivity for neurotensin and NTSR1 receptor. Interestingly, alternative splice variants of NTSR1 receptor were detected only in tumoral tissue. These findings suggest a role of steroid hormones inducing neurotensin expression in leiomyoma smooth muscle cells. In these cells, NTS could act autocrinally through NTSR1 receptor, promoting their proliferation.

Differentially regulated expression of neurokinin B (NKB)/NK3 receptor system in uterine leiomyomata

“…Ovarian steroids play a key role in the pathophysiology of uterine leiomyomas and high levels of estrogen and progesterone receptors are found in leiomyomas, compared with adjacent myometrium (Brandon et al, 1993;Rodríguez et al, 2011). In this sense, our data argue for differential regulation or reprogramming of the effects of E 2 on NKB and NK 3 R expression, such as occurs with other estrogenresponsive genes expressed in uterine leiomyomas (Rodríguez et al, 2010(Rodríguez et al, , 2011.…”

“…In order to obtain reliable data, 5 mg of RNA from 20 tumours and 18 matched leiomyomas (n ¼ 38) were needed to obtain enough cDNA suitable for quantification. Regarding TAC3 and in order to compare this sample set with a previous one of 10 leiomyomas and 10 matched myometrium (Rodríguez et al, 2010), retrotranscription was carried out using 2 mg of RNA (n ¼ 58). First-strand cDNA was synthesized from the total RNA using Moloney murine leukaemia virus reverse transcriptase, RNase H Minus, Point Mutant (Promega) and a 1:1 mix of oligo(dT)23 primer (Sigma-Aldrich Co.) and Random Hexamers (Roche, Basel, Switzerland) according to manufacturer's instructions (Promega).…”

Effects of Progesterone Treatment on Expression of Genes Involved in Uterine Quiescence

“…110 Neurotensin and neurotensin receptor 1 are expressed in connective tissue cells of the human myometrium. 111 However, both hormone and receptor are expressed in smooth muscle cells of leiomyomas. 111 In the present studies, estradiol increased the level of neurotensin expression over 7-fold and progesterone was found to cause about a 5-fold reduction in neurotensin mRNA levels in the human myometrial cells (Supplement Table 1).…”

Molecular characterization of central neurocytomas: Potential markers for tumor typing and progression

“…NTS encodes a common precursor for two peptides, neuromedin N and neurotensin. Neurotensin is found in the CNS and the gastrointestinal tract 32 and there is evidence that it can promote the growth of different cancer cells 33,34 and is associated with the tumorigenesis of functioning adenomas 35 . Among the other genes overexpressed in CNs, some have already been shown to be upregulated in other tumors.…”