CCN proteins in tumor development

JBUON 2016; 21(6): 1359-1367 ISSN: 1107-0625, online ISSN: 2241-6293 • www.jbuon.com E-mail: [email protected]

REVIEW ARTICLE Biological characteristics of CCN proteins in tumor development Stephany C. Barreto, Amitabha Ray, Page AG. Edgar Saint James School of Medicine, Anguilla, British West Indies

Summary

The (ECM) is no longer regarded as teins are capable of modulating a variety of biological pro- inert, rather it has multiple versatile physiologic functions. cesses in health as well as in disease conditions. In tumor Its diverse composition is implicated in each step of cancer development and in tumor microenvironment, CCN proteins progression including inflammation, , tumor can influence multiple facets of pathophysiological process- invasion and metastasis. In addition to structural proteins, es including cellular proliferation, invasion and metastasis. the ECM also contains a family of non-structural proteins This review has attempted a cohesive look at the CCN family called matricellular proteins. The six secreted CCN proteins, protein functions in a tumor-specific manner. which belong to the matricellular protein family, include the following: Cyr61 (CCN1), CTGF (CCN2), Nov (CCN3), WISP- Key words: cancer, CCN proteins, , extracel- 1 (CCN4), WISP-2 (CCN5) and WISP-3(CCN6). These pro- lular matrix, matricellular proteins

Introduction

The extracellular matrix (ECM) consists of or CCN1), connective tissue (CTGF diverse groups of proteins including matricellu- or CCN2), nephroblastoma overexpressed protein lar proteins, which are a family of non-structural (Nov or CCN3), Wnt-inducible secreted protein-1 matrix proteins capable of modulating a variety (WISP-1 or CCN4), WISP-2 (CCN5) and WISP- of biological processes. Members of this family 3 (CCN6). A growing body of evidence suggests include a large number of structurally unrelated that the CCN proteins are involved in different proteins such as thrombospondins, osteopontin, aspects of cancer development [2-5]. It has been and the CCN proteins. Overall, they play a high- shown that CCN proteins can modulate the sig- ly complex role in health and disease conditions nals of several proteins including integrins, Wnt, [1]. It is expected that these proteins are critical and transforming growth factor-β (TGF-β); many for the development of an appropriate tumor mi- of the functions of these proteins are also related croenvironment by establishing complex inter- to tumor growth [2,3]. actions/crosstalk among cancer cells and various Studies have revealed a link between CCN components of the surrounding stroma such as proteins and various cancer risk factors. One such different ECM constituents, inflammatory cells, important risk factor is chronic inflammation. Re- and numerous molecules of signaling pathways. cent reports documented that CCN proteins have The CCN (Cyr61-CTGF-Nov) family consists been strongly implicated in the inflammatory pro- of six members: cysteine-rich protein 61 (Cyr61 cess [6,7]. Expression of CCN has been shown to

Correspondence to: Page Edgar, MD. Faculty of Basic Sciences, Saint James School of Medicine, Albert Lake Drive, The Quarter, AI 2640 Anguilla, British West Indies. Tel: +1 264 235 4166, Fax: +773 897 3393, E-mail: [email protected] Received: 01/06/2016 ; Accepted: 17/06/2016 CCN proteins in tumor development

1360 CCN proteins in tumor development be regulated by diverse inflammatory mediators [23-25]. The available data on melanoma suggests including TGF-β, prostaglandins, and extracellu- that Cyr61 can act as a tumor-suppressor gene; lar matrix enzymes [8]. It has been hypothesized Dobroff et al. [26] found that Cyr61 reduced tu- that the CCN family proteins may play a central mor growth and metastases, decreased angiogen- role in signaling the tumor microenvironment of esis and matrix metalloproteinase-2 (MMP-2) ex- hepatocellular carcinoma (HCC) [9]. In general, pression, as well as stimulated in vivo. HCC takes place in inflammatory conditions that Cyr61 may also decrease the metastatic ability of could be associated, for example, with infection melanoma cells by altering vascular cell adhesion by hepatitis B virus (HBV) or hepatitis C virus molecule 1 (VCAM-1) activity [27]. (HCV). Other agents that have associated etiolog- Overexpressed Cyr61 has been associated ical roles in HCC are alcohol intake, obesity and with more invasive breast cancer phenotypes, cigarette smoking - all of which can generate a due to increased cell growth stimulated invasion chronic inflammatory environment [10]. Interest- and metastases, partly via up-regulated VEGF and ingly, CCN1 expression level was reported to be increased tumor vascularization in a VEGF-inde- correlated with smoking in non-small cell lung pendent manner [28-30]. Interestingly, Sarkissyan cancer (NSCLC) [11]. et al. [31] showed that IGF-1 can induce Cyr61 ex- Obesity-related inflammation has been linked pression, resulting in reduced E-cadherin expres- with a number of health problems such as cardio- sion in breast cancer. Zhang et al. [32] provided ev- vascular disorders, insulin resistance/type 2 dia- idence that 17β-estradiol exposure induced Cyr61 betes, and certain cancers. In different obesity-re- synthesis in MCF-7 breast cancer cells. Epidermal lated diseases, many components of matricellular growth factor (EGF) can also up-regulate Cyr61 in proteins including CCN have been shown to be MCF-7 cells, suggesting a synergistic regulation altered and influence the pathological processes. of Cyr61 in [33]. In addition, Cyr61 For instance, CCN1 can cause endothelial cell dys- can induce estrogen-independence and anti-estro- function in atherosclerosis [12]; CCN2 may play gen resistance to bring about an aggressive breast an important role in diabetic pathology [13,14]; cancer phenotype [28]. In concordance, Lin et al. and all CCN proteins probably affect breast cancer [34] observed that over-expressed Cyr61 in MCF- development [2,15]. Intriguingly, reports show a 7 cells had a remarkable resistance to apoptosis close connection between different CCN proteins against chemotherapeutic agents. and tumor-associated biochemical risk factors, Abnormal expression of Cyr61 has been e.g., estrogenic influence [16], pro-inflammatory demonstrated to be associated with osteosarco- such as alpha ma progression; Cyr61 can promote osteogene- (TNFα) and leptin [12,17], as well as enhanced ac- sis by increasing osteoblast differentiation and tivity of growth factors, for instance insulin-like impeding osteoclast formation [35]. Enticingly, growth factor-1 (IGF-1) and vascular endothelial Cyr61 levels correlated with a poor prognosis re- growth factor (VEGF) [5,16,18]. Obviously, high- gardless of metastasis [36]. In addition, Hou et al. er VEGF action promotes increased angiogenesis [35] showed that in osteosarcoma the abnormal and/or lymphangiogenesis, which is supportive expression of Cyr61 induced mesenchymal tran- for cell proliferation and tumor growth. In this re- sition and promoted lung metastases, via ανβ5 in- view article, an attempt has been made to focus tegrin, Raf-1, mitogen-activated protein kinase ki- on CCN proteins’ functions in the tumor microen- nase (MEK), extracellular signal-regulated kinase vironment. (ERK), and Elk-1 signal transduction pathways. They also demonstrated that the knockdown of CCN1: Cyr61 Cyr61 inhibited in vitro tumor cell invasion and migration, along with in vivo lung metastases. In certain cancers Cyr61 can induce tumori- genesis, cancer progression and/or invasion, such CCN2: CTGF as in gliomas, ovarian carcinoma, and prostate cancer [19-21]. In other cancers, including NSCLC, Increased levels of CTGF have been linked Cyr61 promoted apoptosis and impeded tumor with an advanced aggressive state of breast can- growth [22]. Astonishingly, elevated expressions cer, esophageal cancer, gastric cancer, osteosar- of Cyr61 have been found in colorectal cancer, coma, hepatocellular carcinoma and glioblasto- gastric cancer, and HCC; however its levels de- ma [37-42]. In a breast cancer cell line, Chien et clined when these cancers became more advanced al. [43] demonstrated that forced overexpression

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Figure 1. General structure of CCN proteins. The general structure of the CCN proteins consists of the signal peptide (SP), insulin-like growth factor binding domain (IGFBP), von Willebrand factor type C domain (vWF-C), thrombospondin type-1 repeat (TSP-1), and a carboxy-terminal domain (CT) which contains a cysteine knot (not depicted). CCN5 (WISP-2) lacks CT domain. Listed above each domain, are some of the corresponding known binding partners. Underneath each domain are the corresponding known or suspected roles. Thought-provoking- ly, more than one domain can bind to the same protein, thus the interactions of the full-length protein may be needed to bring about certain functions. A hinge region exists, which is susceptible to cleavage by matrix metal- loproteases -1, -2, -3, -7, -9, -13, as well as by elastase and plasmin. IGFs: Insulin like growth factors, BMP: bone morphogenic protein, TGF: transforming growth factor, LRP-1: LDL receptor protein-1, GAGs: glycosaminogly- cans, VEGF: vascular endothelial growth factor, HSPGs: heparin sulphated proteoglycans, PDGF: platelet-derived growth factor, Rbp 7: Retinol Binding Protein 7, JNK: c-Jun Kinase.

of CTGF led to stimulation of angiogenesis and osteosarcoma with poor prognosis [46,49]. CCN3 migration, and suggested that the CT domain of can promote cell motility and invasion in certain CTGF (Figure 1) was critically important for the cancers, and has been implicated in the progres- migratory ability. sion of chondrosarcoma and Ewing’s sarcoma [50]. The expression of CTGF has also been seen While increased levels of CCN3 have been in murine melanoma cells; Sha and Leask [44] linked to higher metastatic rates in melanoma, demonstrated that CTGF was expressed in B16 decreased CCN3 expression has also been ob- (F10) melanoma cells and was downstream of the served in melanomas to promote cancer progres- oncogenic MEK/ERK pathway. Finger et al. [45] sion, revealing the complexity in the role of CCN3 reported that hypoxia was a key factor in up-reg- [51,52]. In melanocytes, CCN3 can regulate cell ulating CTGF expression, promoting melanoma adhesion and maintain correct spatial localization progression and metastases. In addition, they re- to the basement membrane. Therefore, in ear- vealed the effectiveness of an antibody against ly tumorigenesis down-regulation of CCN3 may CTGF to impede metastatic melanoma tumor pro- be needed for the tumor cells to locally invade. gression in vivo. Subsequently with progression and visceral me- tastases of melanoma, CCN3 levels are then over- CCN3: NOV expressed [51-53]. Of note, two different isoforms have been identified in melanoma cells, which can CCN3 has tumor suppressive and oncogen- further account for the diverse functions [53]. ic properties, dependent on tumor type [46-48]. Chen et al. [54] showed that increased CCN3 Bohlig et al. [47] reported that the CCN3 gene expression stimulated cell migration, by up-reg- could be transcriptionally up-regulated by the tu- ulating the intracellular adhesion molecule-1 mor suppressor p53. Nevertheless, elevated levels (ICAM-1) levels in a prostate cancer cell line. They of CCN3 have been demonstrated to be associat- showed that the knockdown of CCN3 resulted in a ed with prostate cancer with bone metastasis and decrease in both cell migration in vitro and me-

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1362 CCN proteins in tumor development tastases to bone in vivo. However, divergent data CCN5: WISP-2 appear to exist in regards to breast cancer. Elevat- ed CCN3 levels were demonstrated to be associat- WISP-2 (CCN5) can suppress proliferation ed with breast cancer cells that metastasized and and attenuate invasive phenotypes in certain caused osteolysis of bone [55]. Recently, Dobson cancers [64,65]; it can also act as a tumor sup- et al. [48] provided evidence that CCN3 prevented pressor [66]. Differing data exist in regards to invasion by metastatic breast cancer cells and that WISP-2 in breast cancer, which must be correlat- silencing CCN3 in MDA-MB-231 cells resulted in ed to the phenotype of the cancer. Studies have less migratory and more invasive cells. shown WISP-2 expression to be predominately in pre-neoplastic disorders, i.e., atypical ductal hyperplasia and non-invasive ductal carcinoma CCN4: WISP-1 in situ (DCIS) [65,67]. The mRNA transcript of Conflicting findings have been reported in WISP-2 was undetectable in normal mammary WISP-1 (CCN4), which possesses oncogenic and cells as well as in poorly differentiated highly tumor suppressive roles in different cancers. In aggressive breast cancer cell lines, while ele- breast cancer, it was documented that WISP-1 vated levels were observed in non-invasive and levels were decreased in tumor cells compared to more differentiated breast cancer cell pheno- normal breast tissue and that the expression was types [68]. Fritah et al. showed that the knock- less in the more aggressive tumor types [56]. On down of WISP-2 in the MCF-7 breast cancer cell the contrary, Klinke [57] focused on a larger sam- line induced an estradiol-independent growth, ple size and on invasive breast cancer to reveal which was found to be associated with loss of es- that an increased WISP-1 gene expression was as- trogen receptor-α (ERα) expression and promot- sociated with oncogenic transformation. ed epithelial-to-mesenchymal transition (EMT) In murine models, up-regulated WISP-1 lev- [68]. Importantly, the loss of WISP-2 expression has also been seen to result in a triple negative els were demonstrated in highly metastatic D122 (ER‒/PR‒/HER2‒) breast cancer cell line [67]. Fer- Lewis lung carcinoma pulmonary metastasis and rand et al. successfully demonstrated a glucocor- B16-F10.9 melanoma cell lines, as compared to ticoid-induced up-regulation of WISP-2 in estro- the primary tumors [58]. However, Soon et al. [59] gen receptor-negative breast cancer, which led to found that WISP-1 overexpression in H460 lung a reduction in cellular proliferation and invasive cancer cells prevented lung metastases as well as phenotype [67]. in vitro cell invasion and mortality. In melanoma cells, Kulkarni et al. [60] showed that up-regulat- ed tumor-derived WISP-1 inhibited the cells’ re- CCN6: WISP-3 sponse to anti-tumor immunity enhancer inter- WISP-3 (CCN6) can function in a tumor-sup- leukin-12. Shao et al. [61] provided evidence that pressor manner in certain cancers. WISP-3 has the Notch1 pathway increased WISP-1 secretion, been shown to be expressed in normal breast ep- inhibiting melanoma growth and tumor angio- ithelium but down-regulated or lost in many in- genesis. Taken altogether, perhaps WISP-1 is not vasive carcinomas [69]. A study revealed that its needed for tumor growth in melanoma, but is cru- levels were dramatically reduced in aggressive cial for progression and cancer metastases. breast cancer, particularly breast cancer with ax- Ono et al. [62] found elevated WISP-1 levels in illary lymph node metastases and in inflammato- early stage prostate cancer in mice and humans. ry breast cancer [70]. WISP-3 may be crucial in Antibodies against WISP-1 led to a decrease in maintaining normal epithelial morphology and both growth of the tumor xenograft cell line and regulating anoikis in breast cancer cells. Huang et metastases to bone. Additionally, the study ob- al. [71] showed that in human mammary epitheli- served that Cyr61 expression in prostate cancer al cells, WISP-3 knockdown led to a resistance to was consistent with a lower recurrence risk and anoikis and an increased anchorage-independent an inverse relationship with p53 levels. WISP-1 growth. Pal et al. [72] demonstrated that WISP-3 has been shown to activate the anti-apoptotic Akt/ overexpression reduced invasion and distant me- PKB signaling pathway, rendering cells resistant tastases of breast cancer cells, while decreased to apoptosis following DNA damage by prevent- levels led to disruption of acinar morphogenesis ing the mitochondrial release of cytochrome C and and promoted mammary epithelial cell invasion. the up-regulation of anti-apoptotic Bcl-xL, which Moreover, the loss of WISP-3 has been seen as a protects cells from p53-dependent cell death [63]. trigger for EMT [73].

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Table 1. Association of different CCN proteins with three important groups of the intracellular signaling system Family Integrins Transforming growth Wnt signaling members factor-β

CCN1 Via ανβ3, CCN1 promotes tumor growth; CCN1 sequesters TGF-β Wnt3a stimulation induces CCN1 ex- stimulates proliferation, EMT and leading to decreased pression in mesenchymal stem cells; migration in pancreatic cancer cells, TGF-β signaling and fibro- β-catenin activation increases CCN1 and induces VEGF secretion in breast genesis in primary portal expression in HCC cells. cancer cells. myofibroblasts. Elevated CCN1 levels activate β-caten-

Interaction with α6β1 inhibits tumor In macrophages, CCN1 in signaling in gastric epithelial cells growth and induces apoptosis. downregulates the TGF-β1 promoting wound healing; in glioma

As a to α4β1, reduces metastases gene. cells enhancing tumorigenicity; in in melanoma cells. However, TGF-β increas- NSCLC cells suppressing growth; in es CCN1 expression in ESCC promoting oncogenesis. osteoblasts.

CCN2 Participates in cytoskeleton rearrange- A cofactor of TGF-β, to Canonical Wnt signaling activates the ment and migration of breast cancer undergo active cell adhe- CCN2 promoter in NIH3T3 fibroblasts;

cells through ανβ3. sion; TGF-β induces CCN2 in mesenchymal cells Wnt3a induces

Interactions with integrin α5β1, pro- synthesis and CCN2 could CCN2 expression in early stages of mote keratinocyte adhesion to fibronec- be a downstream mediator osteogenic differentiation. tin and migration. of TGF-β1 actions. CCN2 activates the canonical Wnt Other known ligands of CCN2 include: In mesangial cells, CCN2 pathway, stimulates β-catenin nuclear

αMβ2 associated with cell adhesion to enhances TGF-β/Smad translocation in mesangial cells. monocytes and macrophages; signaling pathway and In chondrocytes, β-catenin induces

αIIbβ3 contributes to the adhesion of represses inhibitors. CCN2 expression. activated platelets.

CCN3 CCN3 stimulated COX-2 expression en- TGF-β suppresses CCN3 Overexpressed CCN3 antagonizes Wnt hances migration in osteosarcoma via expression in adrenocorti- 3 activity in cells of the osteoblastic

ανβ5. Interaction with ανβ3 induces cell cal, glial, mesangial cells, lineage. migration and has been associated with osteoblasts and nucleus In NIH3T3 fibroblasts, CCN3 mRNA ICAM-1 expression in prostate cancer pulposus cells; TGF-β sig- is only modestly induced by Wnt3a. cells. Increases MMP-13 to stimulate naling induces the CCN3 Fibroblasts treated with Wnt3a and

migration via ανβ3/ανβ5 receptor in promoter via Smad3 and TGF-β, show a synergistic effect to chondrosarcoma cells and can also in- enhances its repression elevate CCN3 expression.

teract with α5β1 and α6β1 on endothelial through MAPK signaling. cells to stimulate cell adhesion.

CCN4 Acts as a ligand for ανβ5 and α6β1, and TGF-β increases CCN4 Both Wnt-1 and β-catenin signaling increases VCAM-1 expression. expression in osteoblasts induce WISP-1 gene expression.

Interaction with ανβ3 induces migra- and in a hepatic stellate Wnt-11 induces WISP-1 expression in tion in oral squamous cell carcinoma cell line. In lung fibro- fibroblasts. and promotes VEGF-A expression to blasts, TGF-β1 induces In Wnt-1-expressing tumor cells, regulate angiogenesis. Mediates VSMC CCN4 expression, which CCN4 is predominately in the stromal adhesion, migration and proliferation can be reversed by miR- fibroblasts; CCN4 expression is in-

through α5β1. 30a and miR-92a. duced by Wnt-1-expressing mammary glands.

CCN5 It has been shown to bind to integrin TGF-β induces CCN5 CCN5 is downstream of Wnt-1 signal-

ανβ3 in VSMCs and in podosomes to mRNA. CCN5 inhibits ing. Secreted CCN5 activates canoni- regulate matrix degradation. TGF-β signaling prevent- cal WNT in mesenchymal precursor ing EMT in cancer cells. cells.

CCN6 Interaction with ανβ3 and ανβ5 is associ- CCN6 antagonizes BMP4, CCN6 may be downstream of Wnt-1 ated with increased ICAM-1 expression a TGF-β superfamily signaling. Silenced CCN6 in gastric enhancing migration in chondrosarco- ligand and attenuates cancer cells attenuates Wnt/β-catenin ma cells. invasion in breast cancer signaling. cells. EMT:epithelial-to-mesenchymal transition, VEGF:vascular endothelial growth factor, HCC:hepatocellular carcinoma, NSCLC:non-small cell lung cancer, ESCC:esophageal squamous cell carcinoma, COX:cyclooxygenase, ICAM:intercellular adhesion molecule, MMP:matrix metalloproteinase, VCAM:vascular cell adhesion molecule, VSMC:vascular smooth muscle cell, miR-30a and miR-92a:Small non-cod- ing RNA/microRNA precursor

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CCN Proteins Intertwined been shown to increase invasion in vitro and pro- mote lung metastases in vivo [83]. In general, the promotion of cell prolifer- ation and tumor growth have been associated Conclusions with CCN1, CCN2, and CCN4, while the suppres- sion of cell proliferation and tumor growth have The ECM is composed of diverse components been linked to CCN3, CCN5 and CCN6; however, including glycosaminoglycans, hyaluronic acid, exceptions exist [74]. Perhaps, these perplexing collagen, laminin, fibronectin etc. and thus ac- features of the different CCN proteins indicate complishes a myriad of functions. The interaction their connection with a number of diverse sig- between the CCN proteins themselves, as well as naling components such as the various members other environmental components, is an intricately of integrins and TGF-β family (Table 1), and their complex process that, if precisely understood, could involvement in cellular processes where malig- provide invaluable insight into various pathologi- nant cells may exploit like tissue invasion and cal conditions. The interactions among ECM pro- the organization of tumor microenvironment. teins and their pathways are tissue-specific and Nevertheless, it is of great value to examine phenotype-specific. Therefore, no single member the CCN family members as a whole in cancers. of the CCN family can be generally considered as Ohgawara et al. [75] evaluated all six of the CCN oncogenic or tumor suppressive. Even within the proteins in a breast cancer cell line and record- same tissues, the same CCN protein may carry out ed that the CCN2/CCN3 ratio was a parameter different functions during the formation, mainte- associated with a highly metastatic phenotype nance and/or progression of cancers. to bone, while a higher ratio of CCN1/CCN3 was Precisely examining the entire CCN protein noted in highly invasive MDA-MB-231 cells. ER family in various stages of different cancers could status has been shown to be a valuable predictor lead to a clearer understanding of the proteins’ of Cyr61 expression, whereas the HER-2/neu sta- functions and to decreased discrepancies. Poten- tus was an important factor for WISP-1 expres- tially, this understanding would provide a basis sion [76]. In addition, Cyr61 along with CTGF, for the creation of new biomarkers to improve have exhibited a drug resistance role in breast earlier detection of disease, improve prediction cancer. Lai et al. [77] demonstrated that resis- of disease severity, and assist in therapeutic as- tance to paclitaxel in breast cancer treatment sessments and interventions. On the other hand, was completely reversed when both Cyr61 and there are other matricellular proteins that sig- CTGF were blocked. nificantly influence various pathologic process- The expressions of Cyr61, CTGF and WISP- es. Understanding the crucial role of the ECM 1 have been observed in esophageal squamous and its proteins may lead to the development of cell carcinoma (ESCC) in association with high interventions to cease and hopefully reverse in- tumor grade, metastases and/or poor prognosis flammation, in order to prevent the progression [38,78,79]. The silencing of the Cyr61 gene in an to carcinogenesis. The microenvironment media- ESCC cell line led to an inhibition of cell growth, tors continue to provide us abundant opportuni- adhesion and invasion [80]. Bartel et al. [81] re- ties for study. As our understanding of the ECM in ported an inverse expression between Cyr61 and disease becomes clearer, it will continue to open CTGF in both borderline and invasive ovarian doors towards important clinical implications to cancer (IOC). The highest levels of Cyr61 were better combat human diseases. seen in IOC, and the study demonstrated that the independent loss of CTGF was a poor prognostic Acknowledgements marker in IOC [81]. In gastrointestinal tract can- cers WISP-3 has been reported to be up-regulat- The authors would like to sincerely thank ed and acting in an oncogenic fashion, whereas Dr. Claude-Bernard Iliou, Dean of Basic Sciences, WISP-2 behaved as a tumor suppressor [82,83]. Saint James School of Medicine, Anguilla Cam- WISP-1 may promote colorectal cancer (CRC) pus, British West Indies, for his support. progression, with elevated levels associated with poorly differentiated, high grade tumors and a Conflict of interests worse prognosis [84]. While CTGF can inhibit CRC metastasis, the overexpression of Cyr61 has The authors declare no confict of interests.

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