Serglycin in tumor microenvironment promotes non-small cell lung cancer aggressiveness in a CD44-dependent manner

Guo, Jianbin; Hs, Hsu; Sw, Tyan; Fy, Li; Jy, Shew; Wh, Lee; Chen, Jy

doi:10.1038/onc.2016.404

Cited by 97 publications

(102 citation statements)

References 53 publications

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“…Recent studies have revealed elevated expression of SRGN in a variety of cancers, including hepatocellular carcinoma [3], non-small cell lung cancer [15], and nasopharyngeal squamous cell carcinoma [14]. SRGN is a small molecule glycoprotein predominantly distributed in the cell cytoplasm and cell membrane; however, it can also be secreted and integrated into the extracellular matrix [22].…”

Section: Discussionmentioning

confidence: 99%

“…Serglycin (SRGN) encoded by the SRGN is a hematopoietic cell granule proteoglycan, and aberrant expression of SRGN have been associated with tumor progression and metastasis, in breast cancer [13], nasopharyngeal carcinoma [14] and non-small cell lung cancer [15]. SRGN is constitutively secreted from the cells and integrated into the extracellular matrix [16].…”

Section: Introductionmentioning

confidence: 99%

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SRGN Promotes Colorectal Cancer Metastasis as a Critical Downstream Target of HIF-1α

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The chondroitin sulfate proteoglycan serglycin (SRGN), a hematopoietic cell granule proteoglycan, has been implicated in promoting tumor metastasis; however, the underlying mechanisms remain to be elucidated. The present study aimed to investigate the SRGN gene expression and its regulation as downstream signaling of hypoxia-inducible transcription factor 1 alpha (HIF-1α) in colorectal cancer (CRC) cells and tissues. Methods: The expression of SRGN was analyzed in CRC specimens for its correlation with progression and metastasis. Using chromatin-immunoprecipitation (ChIP), quantitative real-time PCR, Western blot, and transwell assay, the functional role and underlying mechanism of SRGN in CRC metastasis were elucidated. Thus, this study provides evidence of a critical role of SRGN in metastatic progression of CRC. Results: Our results indicated that SRGN overexpression was significantly associated with poor prognosis in CRC specimens. SRGN overexpression promoted CRC cell migration and invasion in vitro; however, SRGN depletion exhibited contrasting effects. Mechanistic investigations revealed that HIF-1α regulated SRGN transcription via physically binding to a hypoxia response element in its promoter region. Conclusions: In conclusion, we demonstrated that dysregulated HIF-1α/SRGN signaling promotes CRC progression and metastasis. SRGN may serve as a potential candidate therapeutic target for metastatic CRC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SRGN Promotes Colorectal Cancer Metastasis as a Critical Downstream Target of HIF-1α

Yang

et al. 2018

Cell Physiol Biochem

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“…A promising method to actively target cancer cells is the exploitation of the differential expression of Cluster Differentiation 44 (CD44). CD44 is a cell membrane bound surface receptor that mediates cell–cell and cell‐extracellular matrix (ECM) communication (Kingsmore et al, ; Mooney et al, ) and has been found to be overexpressed in numerous cancer types including breast (Cabuk et al, ), lung (Guo et al, ), colorectal (Xia & Xu, ) tumors compared to basal expression in equivalent healthy tissue (Rios de la Rosa, Tirella, Gennari, Stratford, & Tirelli, ). Hyaluronic acid (HA), a main component of the ECM, is a natural ligand to CD44 has been used as a targeting moiety for CD44 overexpressing cancers, facilitating preferential uptake, and potent therapeutic efficacy (Orian, ).…”

Section: Introductionmentioning

confidence: 99%

Novel nanohydrogel of hyaluronic acid loaded with quercetin alone and in combination with temozolomide as new therapeutic tool, CD44 targeted based, of glioblastoma multiforme

Barbarisi

Iaffaioli

Armenia

et al. 2018

Journal Cellular Physiology

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Glioblastoma multiforme is the most common and aggressive primary brain cancer with only ∼3% of patients surviving more than 3 years from diagnosis. Several mechanisms are involved in drug and radiation resistance to anticancer treatments and among them one of the most important factors is the tumor microenvironment status, characterized by cancer cell hypersecretion of interleukins and cytokines. The aim of our research was the synthesis of a nanocarrier of quercetin combined with temozolomide, to enhance the specificity and efficacy of this anticancer drug commonly used in glioblastoma treatment. The nanohydrogel increased the internalization and cytotoxicity of quercetin in human glioblastoma cells and, when co-delivered with temozolomide, contribute to an improved anticancer effect. The nanohydrogel loaded with quercetin had the ability to recognize CD44 receptor, a brain cancer cell marker, through an energy and caveolae dependent mechanism of internalization. Moreover, nanohydrogel of quercetin was able to reduce significantly IL-8, IL-6, and VEGF production in pro-inflammatory conditions with interesting implications on the mechanism of glioblastoma cells drug resistance. In summary, novel CD44 targeted polymeric based nanocarriers appear to be proficient in mediating site-specific delivery of quercetin via CD44 receptor in glioblastoma cells. This targeted therapy lead to an improved therapeutic efficacy of temozolomide by modulating the brain tumor microenvironment.

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“…Additionally, microenvironment is known to be a major player in maintaining CSC properties in different cancers . Factors released from cancer associated fibroblasts (CAF), such as chondroitin‐sulfate, proteoglycan‐serglycin, promotes tumor growth, invasion, migration and colonisation in breast and lung cancers in CD44‐dependent manner . Co‐culture of stromal cells such as omental adipose derived and/or bone‐marrow mesenchymal stem cells with tumor associated macrophages have been correlated with aberrant expression of stem cell profile in ovarian, myeloma, breast, and gastric cancer cells .…”

Section: Introductionmentioning

confidence: 99%

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

Kulsum

Raju²,

Raghavan³

et al. 2019

Molecular Carcinogenesis

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Understanding the cellular interactions during oral carcinogenesis has the potential to identify novel prognostic and therapeutic targets. This study aimed at investigating the cancer stem cell (CSC)‐fibroblast niche interactions using in‐vitro dysplastic cell line models developed from different stages of 4NQO‐induced oral carcinogenic mice model. The spontaneously transformed epithelial cells (DysMSCTR6, 14 and 16) were developed from three time points (mild/moderate/severe), while two fibroblast cell lines (FibroMSCTR12, 16) were developed from moderate and severe dysplastic tissue. The epithelial (Epcam+/Ck+) and the fibroblast cell lines (Vimentin+/α‐SMA+/Ck‐) were authenticated and assessment of cells representing progressive grades of dysplastic severity indicated a significant increase in dysplastic marker profile (P < 0.05). Evaluation of the CSC characteristics showed that an increase in expression of Cd133, Cd44, Aldh1a1, Notch1, and Sox2 was accompanied by an increase in migratory (P > 0.05) and colony formation capacity (P > 0.005). Targeting Notch1 (GSI inhibitor PZ0187; 30 μM), showed a significant reduction in cell proliferation capacity (P < 0.05) and in the dysplastic marker profile. Further, Notch1 inhibition resulted in down regulation of Cd133 and Aldh1a 1 (P < 0.05) and a complete abrogation of colony formation ability (P < 0.0001). The effect of niche interactions evaluated using FibroMSCTR12‐conditioned media studies, revealed an enrichment of ALDH1A1+ cells (P < 0.05), induction of spheroid formation ability (P < 0.0001) and increased proliferation capacity (3.7 fold; P < 0.005). Although PZ0187 reduced cell viability by ∼40%, was unable to abrogate the conditioned‐media induced increase in proliferation capacity completely. This study reports a Notch‐1 dependent enrichment of CSC properties during dysplastic progression and a Notch‐1 independent dysplastic cell‐fibroblast interaction during oral carcinogenesis.

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Serglycin in tumor microenvironment promotes non-small cell lung cancer aggressiveness in a CD44-dependent manner

Cited by 97 publications

References 53 publications

SRGN Promotes Colorectal Cancer Metastasis as a Critical Downstream Target of HIF-1α

SRGN Promotes Colorectal Cancer Metastasis as a Critical Downstream Target of HIF-1α

Novel nanohydrogel of hyaluronic acid loaded with quercetin alone and in combination with temozolomide as new therapeutic tool, CD44 targeted based, of glioblastoma multiforme

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

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