SFRP2 and Slug Contribute to Cellular Resistance to Apoptosis in Hypertrophic Scars

Han

Journal of Investigative Dermatology

et al. 2016

In this study, we found that secreted frizzled-related protein 2 (sFRP2) is overexpressed in the hyperpigmentary skins of melasma and solar lentigo and in the acutely UV-irradiated skin. To investigate the effect of sFRP2 on melanogenesis, normal human melanocytes were infected with sFRP2-lentivirus or sh-sFRP2. It was found that sFRP2 stimulates melanogenesis through MITF/tyrosinase upregulation via β-catenin signaling. The stimulatory action of sFRP2 in pigmentation was further confirmed in melanocytes co-cultured with fibroblasts and in ex vivo cultured skin. The findings suggest that sFRP2 functions as a melanogenic stimulator and that it plays a role in the development of UV-induced hyperpigmentary disorders.Journal of Investigative Dermatology accepted article preview online, 22 September 2015. doi:10.1038/jid.2015.365.

Section: Discussionsupporting

confidence: 53%

Secreted Frizzled-Related Protein 2 (sFRP2) Functions as a Melanogenic Stimulator; the Role of sFRP2 in UV-Induced Hyperpigmentary Disorders

Han

Journal of Investigative Dermatology

et al. 2016

“…Investigations into additional signaling cascades could provide novel insights into the direct role of sFRP2 and metastatic mechanisms for osteosarcoma. Besides the aforementioned PI3K-Akt pathway, additional candidate mechanisms include the possibility that sFRP2 could positively regulate the expression of the stem cell transcription factor Slug [32], which is involved promoting the metastatic phenotypes of carcinomas [33]. Studies into if sFRP2 could alter the differentiation or stemness of osteosarcoma cells would also be interesting to investigate.…”

Section: Discussionmentioning

confidence: 99%

Secreted Frizzled-Related Protein 2 (sFRP2) promotes osteosarcoma invasion and metastatic potential

et al. 2016

BackgroundOsteosarcoma (OS), which has a high potential for developing metastatic disease, is the most frequent malignant bone tumor in children and adolescents. Molecular analysis of a metastatic genetically engineered mouse model of osteosarcoma identified enhanced expression of Secreted Frizzled-Related Protein 2 (sFRP2), a putative regulator of Wnt signaling within metastatic tumors. Subsequent analysis correlated increased expression in the human disease, and within highly metastatic OS cells. However, the role of sFRP2 in osteosarcoma development and progression has not been well elucidated.MethodsStudies using stable gain or loss-of-function alterations of sFRP2 within human and mouse OS cells were performed to assess changes in cell proliferation, migration, and invasive ability in vitro, via both transwell and 3D matrigel assays. In additional, xenograft studies using overexpression of sFRP2 were used to assess effects on in vivo metastatic potential. ResultsFunctional studies revealed stable overexpression of sFRP2 within localized human and mouse OS cells significantly increased cell migration and invasive ability in vitro and enhanced metastatic potential in vivo. Additional studies exploiting knockdown of sFRP2 within metastatic human and mouse OS cells demonstrated decreased cell migration and invasion ability in vitro, thus corroborating a critical biological phenotype carried out by sFRP2. Interestingly, alterations in sFRP2 expression did not alter OS proliferation rates or primary tumor development.ConclusionsWhile future studies further investigating the molecular mechanisms contributing towards this sFRP2-dependent phenotype are needed, our studies clearly provide evidence that aberrant expression of sFRP2 can contribute to the invasive and metastatic potential for osteosarcoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2909-6) contains supplementary material, which is available to authorized users.

“…SFRP2 prevented cell death and local administration of exogenous SFRP2 reduced fibrosis and improved heart function . These antifibrotic of SFRP2 effects are not restricted to myocardiac tissue, but have also been implicated in wound repair of skin tissue . The reduced regenerative ability of aged HSCs have been attributed to accumulated replication stress, characterized by accumulation of the DNA damage response marker γH2A.X and activation of Cdc42, which, amongst others, reduces the polarized expression of the H4K16 acetylated marker .…”

Section: Discussionmentioning

confidence: 99%

“…Sfrp2 has been reported to be upregulated in situations of physiological stress. In particular, SFRP2 has been shown to regulate fibrotic responses in scarring of cardiac, and skin tissues and to play a major role in myocardial repair . SFRP2 is highly secreted by mineralized osteoblasts in the endosteal niche and SFRP2 has been suggested to inhibit differentiation of HSCs by enhancing self‐renewal .…”

Section: Introductionmentioning

confidence: 99%

Loss of Sfrp2 in the Niche Amplifies Stress-Induced Cellular Responses, and Impairs the In Vivo Regeneration of the Hematopoietic Stem Cell Pool

et al. 2016

Sfrp2 is overexpressed in stromal cells which maintain hematopoietic stem cells (HSCs) during in vitro culture. We here showed, that coculture of hematopoetic cells with stromal cells with reduced expression of Sfrp2 increases the number lineage-negative Kit 1 Sca-1 1 (LSK) and progenitor cells in vitro. The LSK cells from these cocultures showed activation of canonical Wnt signaling, higher levels of Ki-67, BrdU incorporation, and the number of cH2A.X positive foci. Total repopulating activity of these cultures was, however, diminished, indicating loss of HSC. To extend these in vitro data, we modelled stress in vivo, i.e., by aging, or 5-FU treatment in Sfrp2 2/2 mice, or replicative stress in regeneration of HSCs in Sfrp2 2/2 recipients. In all three in vivo stress situations, we noted an increase of LSK cells, characterized by increased levels of b-catenin and cyclin D1. In the transplantation experiments, the increase in LSK cells in primary recipients was subsequently associated with a progressive loss of HSCs in serial transplantations. Similar to the in vitro coculture stress, in vivo genotoxic stress in 5-FU-treated Sfrp2 2/2 mice increased cell cycle activity of LSK cells with higher levels of BrdU incorporation, increased expression of Ki-67, and canonical Wnt signaling. Importantly, as noted in vitro, increased cycling of LSKs in vivo was accompanied by a defective cH2A.X-dependent DNA damage response and depolarized localization of acetylated H4K16. Our experiments support the view that Sfrp2 expression in the niche is required to maintain the HSC pool by limiting stressinduced DNA damage and attenuating canonical Wnt-mediated HSC activation. STEM CELLS 2016;34:2381-2392 SIGNIFICANCE STATEMENTHematopoietic stress (coculture, regeneration, genotoxicity, and aging) results in reduced hematopoietic stem cell (HSC) numbers and quality. Here, we show that stromal Sfrp2 dampens the response of HSC to different forms of stress in vitro and in vivo. Without Sfrp2, the niche's ability to limit the stress response is diminished. As a result, HSC show an increased DNA damage response, do not efficiently self-renew, resulting in a defective regeneration of the HSC pool. Thus, SFRP2 secreted by the niche preserves the number of HSCs, a finding which may help to identify new ways to prevent the loss of stem cells under stress conditions.