Genetic Targeting of Relaxin and Insulin-Like Factor 3 Receptors in Mice

Kamat, Aparna A.; Feng, Shi Ting; Bogatcheva, Natalia V.; Truong, Anne; Bishop, Colin E.; Agoulnik, Alexander I.

doi:10.1210/en.2004-0515

Cited by 126 publications

(154 citation statements)

References 29 publications

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“…The closely related insulin-like 3 peptide receptor RXFP2 also responds to higher doses of RLN by cAMP increase in cells transfected with RXFP2 (Feng et al 2007), however, such crossreactivity was not detected in vivo (Kamat et al 2004. Despite significant variations in the amino acid sequence of different mammalian RLN peptides, they all efficiently cross-activate human RXFP1 (Sherwood 2004, Bathgate et al 2006.…”

Section: Discussionmentioning

confidence: 99%

Suppression of relaxin receptor RXFP1 decreases prostate cancer growth and metastasis

Feng

Agoulnik

Truong

et al. 2010

Endocrine-Related Cancer

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Relaxin (RLN) is a small peptide hormone expressed in several cancers of reproductive and endocrine organs. Increased expression of RLN in prostate cancer correlates with aggressive cancer. RLN G-protein-coupled receptor (RLN family peptide receptor 1, RXFP1) is expressed in both androgen receptor (AR)-positive and -negative prostate cancers as well as in prostate cancer cell lines. RLN behaves as a cell growth factor and increases invasiveness and proliferation of cancer cells in vitro and in vivo. The objective of this study is to determine whether downregulation of RXFP1 expression using small interfering RNA (siRNA) reduces cancer growth and metastasis in a xenograft model of prostate cancer. We used two well-characterized prostate adenocarcinoma cell lines, AR-positive LNCaP cells and AR-negative PC3 cells. The tumors were established in nude male mice by s.c. injections. Intratumoral injections of siRNAs loaded on biodegradable chitosan nanoparticles led to a downregulation of RXFP1 receptor expression and a dramatic reduction in tumor growth. In LNCaP tumors, the siRNA treatment led to an extensive necrosis. In PC3 xenografts treated with siRNA against RXFP1, the smaller tumor size was associated with the decreased cell proliferation and increased apoptosis. The downregulation of RXFP1 resulted in significant decrease in metastasis rate in PC3 tumors. Global transcriptional profiling of PC3 cells treated with RXFP1 siRNA revealed genes with significantly altered expression profiles previously shown to promote tumorigenesis, including the downregulation of MCAM, MUC1, ANGPTL4, GPI, and TSPAN8. Thus, the suppression of RLN/RXFP1 may have potential therapeutic benefits in prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Suppression of relaxin receptor RXFP1 decreases prostate cancer growth and metastasis

Feng

Agoulnik

Truong

et al. 2010

Endocrine-Related Cancer

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“…13 The differences in thyroidal expression pattern between relaxin and INSL3 implicate distinct functional roles for each of the relaxin-like members in the human thyroid and evidence in mice suggests that relaxin and INSL3 appear to activate distinct LGR7-and LGR8-mediated signaling pathways, respectively. 26 Stable transfectants of the relaxin-responsive human follicular thyroid carcinoma cell lines FTC-133 and FTC-238 were used to analyze functional roles of RLN2 in human neoplastic thyrocytes. These transfectants produced a single proRLN2 immunoprotein indicating incomplete processing of RLN2 hormone in these thyroid carcinoma cells likely reflecting their limited capacity to process constitutively produced relaxin proform.…”

Section: Discussionmentioning

confidence: 99%

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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“…Relaxin (RLN) was initially described as a hormone of pregnancy that is best known for its role during parturition in various species, but it has also been implicated in regulation of testicular function, although testicular source of the hormone in mammalian males still remains largely unknown (Sherwood 1994, 2004, Kohsaka et al 2003. Recent studies in adult male mice with knockout of the gene encoding either RLN or its distinct receptor, now known to be RLN family peptide receptor 1 (RXFP1; originally called LGR7, leucine-rich repeat-containing G-protein-coupled receptor 7) (Hsu et al 2002), have demonstrated a decrease in sperm maturation, an increase of apoptosis in the testis and a reduction in the fertility of such mice (Samuel et al 2003, Krajnc-Franken et al 2004, although another study indicated normal male fertility in Rxfp1 knockout mice (Kamat et al 2004). …”

Section: Introductionmentioning

confidence: 99%

Evidence for expression of relaxin hormone-receptor system in the boar testis

Kato¹,

Siqin²,

Minagawa³

et al. 2010

Journal of Endocrinology

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Although the physiological role of relaxin (RLN) in males remains largely unknown, there is limited evidence that the testis might be a candidate source and target of RLN in boars, as RLN transcripts are detected in the boar testis and it contains RLN-binding sites. To determine whether the boar testis acts as a source and target tissue of RLN, we characterised the expression pattern and cellular localisation of both RLN and its own receptor LGR7 (RXFP1) in boar testes during postnatal development by molecular and immunological approaches. Testes were collected from Duroc boars, and partial cDNA sequences of the boar homologue of human RXFP1 were identified. RLN expression increased through puberty onwards, while RXFP1 expression changed little during development.RLN mRNA and protein expression were restricted to the Leydig cells, whereas both Leydig cells and seminiferous epithelial cells expressed RXFP1 mRNA and protein.Interestingly, RLN was expressed in the testis as an 18 kDa form (the expected size of proRLN), but not as the 6 kDa mature form, during development because of a lack of the enzyme required for proRLN processing. In contrast, RXFP1 was detected at all stages as specific bands of 75 and 91-95 kDa (likely non-glycosylated and glycosylated RXFP1 respectively). Thus, we provide evidence for expression of RLN-RXFP1 ligand-receptor system in the boar testis, suggesting that the testis act as a source and possible target tissue of RLN.

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Genetic Targeting of Relaxin and Insulin-Like Factor 3 Receptors in Mice

Cited by 126 publications

References 29 publications

Suppression of relaxin receptor RXFP1 decreases prostate cancer growth and metastasis

Suppression of relaxin receptor RXFP1 decreases prostate cancer growth and metastasis

Relaxin Enhances the Oncogenic Potential of Human Thyroid Carcinoma Cells

Evidence for expression of relaxin hormone-receptor system in the boar testis

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