The role of relaxin in endometrial cancer

Kamat, Aparna A.; Feng, Shi Ting; Agoulnik, Irina U.; Kheradmand, Farrah; Bogatcheva, Natalia V.; Coffey, Donna; Sood, Anil K.; Agoulnik, Alexander I.

doi:10.4161/cbt.5.1.2289

Cited by 54 publications

(56 citation statements)

References 28 publications

(41 reference statements)

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“…This is in agreement with published evidence of stage-and grade-dependency of serum CA 125 [7]. The involvement of MMP-9, adiponectin, and FSH in endometrial cancer development was previously reported [27][28][29]. To our knowledge, this is the first report which describes an abnormal expression of serum MIP-1α, MIP-1β, TNFRI, IL-2R, IGFBP-I, MICA, SAA, TTR, Eotaxin, mesothelin, sVCAM-1, sICAM-1, tPAI-1, CD40L, MPO, ULBP-1,3, and MMP-2,3,8,9 in endometrial adenocarcinoma.…”

Section: Discussionsupporting

confidence: 82%

Development of multimarker panel for early detection of endometrial cancer. High diagnostic power of prolactin

Yurkovetsky

Ta’asan

Skates

et al. 2007

Gynecologic Oncology

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Objective-Endometrial carcinoma is the most common gynecologic cancer. Although the prognosis for endometrial cancer is generally good, cancers identified at late stages are associated with high levels of morbidity and mortality. Therefore, prevention and early detection may further reduce the burden of this challenging disease.Methods-A panel of 64 serum biomarkers was analyzed in sera of patients with stages I-III endometrial cancer and age-matched healthy women, utilizing a multiplex xMAP ™ bead-based immunoassay. For multivariate analysis, four different statistical classification methods were used: logistic regression (LR), separating hyperplane (SHP), k nearest neighbors (KNN), and Classification Tree (CART). For each of these classifiers a diagnostic model was created, based on the crossvalidation set consisting of sera from 115 patients with endometrial cancer and 135 healthy women.Results-Our data have demonstrated that patients with endometrial cancer have significantly different expression patterns of several serum biomarkers as compared to healthy controls. Prolactin was the strongest discriminative biomarker for endometrial cancer providing 98.3% sensitivity and 98.0% specificity alone. Our results have revealed that serum concentration of cancer antigens, including CA 125, CA 15-3, and CEA are higher in patients with Stage III endometrial cancer as compared to those with Stage I. In addition, we have shown that the expression of CA 125, AFP and ACTH is elevated in women with tumor grade 3 vs. grade 1. Furthermore, 5-biomarker panel Requests for reprints: Anna Lokshin, University of Pittsburgh Cancer Institute, Hillman Cancer Center, 5117 Centre Ave., Pittsburgh, PA 15213. Phone: 412-623-7706; Fax: 412-623-1415; E-mail: lokshina@pitt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (prolactin, GH, Eotaxin, E-selectin, and TSH) identified in this study, was able to discriminate endometrial cancer from ovarian and breast cancers with high sensitivity and specificity. NIH Public AccessConclusions-The ability of prolactin to accurately discriminate between cancer and control groups indicates that this biomarker could potentially be used for development of blood-based test for the early detection of endometrial cancer in high-risk populations. Combining the information on multiple serum markers using flexible statistical methods allows for achieving high cancer selectivity.

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Section: Discussionsupporting

confidence: 82%

Development of multimarker panel for early detection of endometrial cancer. High diagnostic power of prolactin

Yurkovetsky

Ta’asan

Skates

et al. 2007

Gynecologic Oncology

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“…30 Similar to a recent report on relaxin in endometrial cancer, 31 relaxin failed to act as a potent mitogen in thyroid carcinoma cells. Instead, increased cellular viability and enhanced tumor cell survival appeared to be important relaxinmediated actions on neoplastic thyrocytes as reflected by the large number of disseminated small-sized colonies during anchorage-independent growth of the FTC-133-RLN2 transfectants.…”

Section: Discussionsupporting

confidence: 55%

Relaxin Enhances the Oncogenic Potential of Human Thyroid Carcinoma Cells

Hombach‐Klonisch

Białek

Trojanowicz

et al. 2006

The American Journal of Pathology

102

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The role of members of the insulin-like superfamily in human thyroid carcinoma is primarily unknown. Here we demonstrate the presence of RLN2 relaxin and relaxin receptor LGR7 in human papillary, follicular, and undifferentiated anaplastic thyroid carcinoma suggesting a specific involvement of relaxin-LGR7 signaling in thyroid carcinoma. Stable transfectants of the LGR7-positive human follicular thyroid carcinoma cell lines FTC-133 and FTC-238 that secrete bioactive proRLN2 revealed this hormone to act as a multifunctional endocrine factor in thyroid carcinoma cells. Although RLN2 did not act as a mitogen, it acted as an autocrine/paracrine factor and significantly increased anchorage-independent growth and thyroid carcinoma cell motility and invasiveness through elastin matrices. In recent years, the multifunctional peptide hormone relaxin has been identified as an important endocrine player in the reproductive tract, cardiovascular/neural systems, and oncology.1,2 The thyroid was once considered to be a relaxin target tissue with relaxin reported to increase thyroid weight, radioactive iodine uptake, and protein-bound iodination in rats.3,4 Likely because of the crude relaxin preparations used at the time, these results could not be confirmed. 5 No further investigations were reported thereafter using highly purified relaxin preparations to validate a potential role of relaxin in thyroid tissues and thyroid cell lines. Some 40 years later, the discovery of the G-protein-coupled relaxin-like receptors LGR7 and LGR8 revealed the presence of transcripts for both LGR7 (relaxin receptor) and LGR8 (INSL3/relaxin receptor) in the thyroid gland. 6 -8 Relaxin and the relaxin-like INSL3 have been shown to activate cAMP-dependent signaling pathways by binding to either LGR7 or LGR8. 8 -12 We recently demonstrated the expression and regulation of INSL3 and LGR8 transcripts in human thyroid carcinoma cell lines, identifying hyper-and neoplastic human thyrocytes as a new source and target of the actions of INSL3 and a novel INSL3 splice variant. 8,13 Although still primarily undefined, relaxin appears to have oncogenic potential in various organs and tissues, including the human thyroid.14 -17 Relaxin affects proliferation and differentiation of MCF-7 human carcinoma cells in a concentration-dependent manner 18 and can modify the extracellular matrix by affecting the expresSupported by the Deutsche Forschungsgemeinschaft (grants KL1249/5-1

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“…Additionally, it was shown that relaxin increases vascularization and angiogenesis either directly or indirectly through the stimulation of VEGF or other cell signals. An increased relaxin expression in cancer samples was associated with the more aggressive disease and a decline in survival of the patients (13,24). Several attempts have been made to evaluate the effects of relaxin and relaxin receptor suppression as a potential therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

Expression of LDL-A module of relaxin receptor in prostate cancer cells inhibits tumorigenesis

Feng

Agoulnik

2011

Int J Oncol

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Abstract. Peptide hormone relaxin produced in normal and cancer prostate cells can stimulate prostate cancer progression. Suppression of relaxin or relaxin receptor RXFP1 expression inhibited prostate cancer both in vitro and in vivo. RXFP1 is a G protein-coupled receptor with the extracellular low density lipoprotein A (LDL-A) module located at the N-terminus. The LDL-A module exhibits a competitive inhibition effect on the RXFP1 function and might be used to suppress relaxin signaling. In this study, we investigated the effect of LDL-A overexpression on prostate cancer cells. PC3 cells expressing the RXFP1-LDL-A module had a decreased proliferation, soft agar colony formation, adhesion, invasion in vitro, and grew at a slower rate than control cells as tumors in xenograft models in mice. Expression analysis revealed that the RXFP1-LDL-A expression in PC3 cells inhibited Akt phosphorylation and MMP2 activation, and led to the down-regulation of several genes previously implicated in tumorigenesis, such as MMP28, S100P, IGFBP2, MUC1 and S100A4. These results indicate that the inhibition of RXFP1 by peptide based on the LDL-A module of this receptor may be a potential approach for prostate cancer suppression.

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The role of relaxin in endometrial cancer

Cited by 54 publications

References 28 publications

Development of multimarker panel for early detection of endometrial cancer. High diagnostic power of prolactin

Development of multimarker panel for early detection of endometrial cancer. High diagnostic power of prolactin

Relaxin Enhances the Oncogenic Potential of Human Thyroid Carcinoma Cells

Expression of LDL-A module of relaxin receptor in prostate cancer cells inhibits tumorigenesis

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