Altered expression of the tachykinins substance P/neurokinin A/hemokinin-1 and their preferred neurokinin 1/neurokinin 2 receptors in uterine leiomyomata

González-Santana, Ayoze; Marrero-Hernández, Sara; Dorta, I.; Hernández, Mariano; Pinto, Francisco M.; Báez, Delia; Bello, Aixa R.; Candenas, Luz; Almeida, Teresa

doi:10.1016/j.fertnstert.2016.07.007

Cited by 12 publications

(6 citation statements)

References 52 publications

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“…Further studies need to be conducted with a larger sample size focusing on longitudinal changes and any differences between various tendinopathy sites. Next, it is debatable that TAC1 gene expression was considered as representative of SP expression in our study, given that TAC1 not only codes for SP , but also encodes neurokinin A [50]. This was supported by the fact that SP is well known as the major neuropeptide synthesized from the TAC1 gene and found several studies that regarded TAC1 as representative of SP expression [51,52].…”

Section: Discussionmentioning

confidence: 82%

The Implication of Substance P in the Development of Tendinopathy: A Case Control Study

Han

Choi

Song

et al. 2017

IJMS

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It was reported that substance P had beneficial effects in the healing of acute tendon injury. However, the relationship between substance P and degenerative tendinopathy development remains unclear. The purpose of this study was to determine the role of substance P in the pathogenesis of tendinopathy. Healthy and tendinopathy tendon were harvested from human and tenocytes were cultured individually. The expression levels of genes associated with tendinopathy were compared. Next, substance P was exogenously administered to the healthy tenocyte and the effect was evaluated. The results showed that tendinopathy tenocytes had higher levels of COL3A1, MMP1, COX2, SCX, ACTA2, and substance P gene expression compared to healthy tenocytes. Next, substance P treatment on the healthy tenocyte displayed similar changes to that of the tendinopathy tenocytes. These differences between the two groups were also determined by Western blot. Additionally, cells with substance P had the tendinopathy change morphologically although cellular proliferation was significantly higher compared to that of the control group. In conclusion, substance P enhanced cellular proliferation, but concomitantly increased immature collagen (type 3 collagen). Substance P plays a crucial role in tendinopathy development and could be a future therapeutic target for treatment.

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Section: Discussionmentioning

confidence: 82%

The Implication of Substance P in the Development of Tendinopathy: A Case Control Study

Han

Choi

Song

et al. 2017

IJMS

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“…NK1R is expressed in human and rodent uterus 66–69 , so are CRLR and RAMP1 70 . The expression of NK1R and SP-coding gene TAC1 is reported to be upregulated by estrogen 68,71 and TNF-α 44 .…”

Section: Discussionmentioning

confidence: 99%

Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis

Yan

Liu

Guo

2019

Sci Rep

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Endometriotic lesions are known to be hyperinnervated, especially in lesions of deep endometriosis (DE), which are frequently in close proximity to various nerve plexuses. DE lesions typically have higher fibromuscular content than that of ovarian endometriomas (OE) lesions, but the underlying reason remains elusive. Aside from their traditional role of pain transduction, however, whether or not sensory nerves play any role in the development of endometriosis is unclear. Here, we show that, thorough their respective receptors neurokinin receptor 1 (NK1R), calcitonin receptor like receptor (CRLR), and receptor activity modifying protein 1 (RAMP-1), neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP) induce epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT) and further turn stromal cells into smooth muscle cells (SMCs) in endometriotic lesions, resulting ultimately in fibrosis. We show that SP and CGRP, or the rat dorsal root ganglia (DRG) supernatant, through the induction of NK1R and CGRP/CRLR/RAMP-1 signaling pathways, promoted EMT, FMT and SMM in endometriosis, resulting in increased migratory and invasive propensity, cell contractility, production of collagen, and eventually to fibrosis. Neutralization of NK1R and/or CGRP/CRLR/RAMP-1 abrogated these processes. Extended exposure of endometriotic stromal cells to SP and/or CGRP or the DRG supernatant induced increased expression of α-SMA, desmin, oxytocin receptor, and smooth muscle myosin heavy-chain. Finally, we show that DE lesions had significantly higher nerve fiber density, increased staining levels of α-SMA, NK1R, CRLR, and RAMP-1, concomitant with higher lesional fibrotic content than that of OE lesions. The extent of lesional fibrosis correlated positively with the staining levels of NK1R, CRLR, and RAMP-1, as well as the nerve fiber density in lesions. Thus, this study provides another piece of evidence that sensory nerves play an important role in promoting the development and fibrogenesis of endometriosis. It explains as why DE frequently have higher fibromuscular content than that of OE, highlights the importance of lesional microenvironment in shaping the lesional fate, gives more credence to the idea that ectopic endometrium is fundamentally wounds that go through repeated tissue injury and repair, and should shed much needed light into the pathophysiology of endometriosis.

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“…Neuropeptide signaling through the receptors is well known to regulate various physiological functions such as induction of pain response, relaxation of smooth muscle, dilation of blood vessels, and vascular permeability. It has been demonstrated that tachykinins and their receptors are expressed in several non‐neuronal cells, which connect the nervous and peripheral organ systems to control respiratory, cardiovascular, endocrine, and gastrointestinal activity 2,4 . Furthermore, recent studies revealed that neuropeptide receptors are expressed in various cancer cells in the tumor microenvironment, therefore tachykinin signaling through these receptors possibly regulates pathological functions related to the development of cancer and tumor malignancy 5,6 …”

Section: Introductionmentioning

confidence: 99%

IFN‐α/β‐mediated NK2R expression is related to the malignancy of colon cancer cells

et al. 2022

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Neurokinin 2 receptor (NK2R), a G protein‐coupled receptor for neurokinin A (NKA), a tachykinin family member, regulates various physiological functions including pain response, relaxation of smooth muscle, dilation of blood vessels, and vascular permeability. However, the precise role and regulation of NK2R expression in cancer cells have not been fully elucidated. In this study, we found that high NK2R gene expression was correlated with the poor survival of colorectal cancer patients, and Interferon (IFN‐α/β) stimulation significantly enhanced NK2R gene expression level of colon cancer cells in a Janus kinas 1/2 (JAK 1/2)‐dependent manner. NKA stimulation augmented viability/proliferation and phosphorylation of Extracellular‐signal‐regulated kinase 1/2 (ERK1/2) levels of IFN‐α/β‐treated colon cancer cells and NK2R blockade by using a selective antagonist reduced the proliferation in vitro. Administration of an NK2R antagonist alone or combined with polyinosinic‐polycytidylic acid, a synthetic analog of double‐stranded RNA, to CT26‐bearing mice significantly suppressed tumorigenesis. NK2R‐overexpressing CT26 cells showed enhanced tumorigenesis and metastatic colonization in both lung and liver after the inoculation into mice . These findings indicate that IFN‐α/β‐mediated NK2R expression is related to the malignancy of colon cancer cells, suggesting that NK2R blockade may be a promising strategy for colon cancers.

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Altered expression of the tachykinins substance P/neurokinin A/hemokinin-1 and their preferred neurokinin 1/neurokinin 2 receptors in uterine leiomyomata

Abstract: These and our previous data demonstrate that the whole tachykinin system is differentially regulated in leiomyomas. The increased expression of NK1R-Tr might stimulate leiomyoma growth in a similar way to that observed in other steroid-dependent tumors.

Cited by 12 publications

References 52 publications

The Implication of Substance P in the Development of Tendinopathy: A Case Control Study

The Implication of Substance P in the Development of Tendinopathy: A Case Control Study

Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis

IFN‐α/β‐mediated NK2R expression is related to the malignancy of colon cancer cells

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