CCN: core regulatory proteins in the microenvironment that affect the metastasis of hepatocellular carcinoma?

Jia, Qingan; Dong, Qiongzhu; Qin, Lun–Xiu

doi:10.18632/oncotarget.6209

Cited by 38 publications

(35 citation statements)

References 109 publications

(121 reference statements)

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“…In clinical samples whereas CCN2 and CCN3 are positively correlated with HCC development, CCN1 is both negatively and positively correlated with HCC development while no differences were noted for CCN5 (Jia et al 2016). They did not have data for CCN6 in HCC.…”

Section: Ccn Proteins and Cancermentioning

confidence: 85%

CCN family of proteins: critical modulators of the tumor cell microenvironment

Yeger

Perbal

2016

J. Cell Commun. Signal.

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The CCN family of proteins consisting of CCN1 (Cyr61), CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2) and CCN6 (WISP-3) are considered matricellular proteins operating essentially in the extracellular microenvironment between cells. Evidence has also been gradually building since their first discovery of additional intracellular roles although the major activity is triggered at the cell membrane. The proteins consist of 4 motifs, a signal peptide (for secretion} followed consecutively by the IGFBP, VWC, TSP1 and CT (C-terminal cysteine knot domain) motifs, which signify their potential binding partners and functional connections to a variety of key regulators of physiological processes. With respect to cancer it is now clear that, whereas certain members can facilitate tumor behavior and progression, others can competitively counter the process. It is therefore clear that the net outcome of biological interactions in the matrix and what gets signaled or inhibited can be a function of the interplay of these CCN 1-6 proteins. Because the CCN proteins further interact with other key proteins, like growth factors in the matrix, the balance is not only important but can vary dynamically with the physiological states of tumor cells and the surrounding normal cells. The tumor niche with its many cell players has surfaced as a critical determinant of tumor behavior, invasiveness, and metastasis. It is in this context that CCN proteins should be investigated with the potential of being recognized and validated for future therapeutic approaches.

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Section: Ccn Proteins and Cancermentioning

confidence: 85%

CCN family of proteins: critical modulators of the tumor cell microenvironment

Yeger

Perbal

2016

J. Cell Commun. Signal.

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“…The CCN family, first described by P. Bork in 1993, is a small, six-member family of cysteine-rich regulatory proteins found in humans. Members of this secreted protein family comprise a secretory signal peptide followed by four structural domains; namely, insulin-like growth factor binding proteins (IGFBP), von Willebrand factor type C repeat (VWC), thrombospondin type I repeat (TSP-1), and carboxy-terminal domain (CT) [3]. Because the four unique globular modules share homology with functional domains of various extracellular proteins, CCN proteins have emerged as localized multitasking signal integrators in the inflammatory microenvironment [12].…”

Section: Discussionmentioning

confidence: 99%

“…While, the precise mechanism associated with HSCs trending, infiltration and remodeling are still vague in HCC, which orchestrated the stroma-derived resistance to oxaliplatin in HCC [2]. www.impactjournals.com/oncotarget CCN3 (Nephroblastoma Overexpressed proteins, NOV) is one of the six-member family of cysteine-rich secretory proteins found in humans that emerged as localized multitasking signal integrators in the microenvironment, and play an important role in modifying the cellular phenotype [3]. Thus far, the expression of CCN3 in HCC, and the precise physiological function and mechanism of action of CCN3 remain elusive.…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Hepatic stellate cells transmigration and remodeling are related to CCN3 in oxaliplatin-resistant hepatocellular carcinoma

Wei¹,

Wang²,

Zhang³

et al. 2018

Oncotarget

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Background: Hepatic stellate cells (HSCs) have a key role in fibrogenesis and in the filtrates of the hepatocellular carcinoma (HCC) stroma, in which they are remodeled and play a critical role in HCC progression. While, the precise mechanism associated with HSCs trending, infiltration and remodeling is still vague in HCC, especially in Oxaliplatin-resistant HCC.Materials and Methods: The chemoresistant cell and mouse model, and the HCC clinical samples were collected and were established. We explored the relationship between secretory CCN3 from Oxaliplatin-resistant HCC and the infiltration of HSCs in Oxaliplatin-resistant HCC microenvironment. We also evaluated the associated mechanism of HSCs infiltration and HSCs remodeling in HCC with high expression of CCN3.Results: We constructed oxaliplatin-resistant HCC models and found the increased infiltration of HSCs into the microenvironment. We reanalyzed the cDNA profiles of the oxaliplatin-resistant HCC and found CCN3 was one of the significantly increased genes. In HCC clinical samples, the levels of CCN3 and α-SMA are positively correlated, and high expression of CCN3 and α-SMA are positively associated with malignant phenotype and poor prognosis. Then we proved that CCN3 could enhance the migration and proliferation of HSC, and induce the remodeling of HSC with elevation of cytokines relating to HCC malignancy, which was related to ERK signaling pathway activation. Finally, we confirmed that the role of CCN3 enhanced the transmigration of HSCs using the xenograft tumor model. Conclusions: HSCs transmigration and remodeling are positively related to CCN3 paracrine in hepatocellular carcinoma, which orchestrated the stroma-derived resistance to chemotherapy in HCC.

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“…CCN proteins are emerging as a unique group of extracellular signaling modulators involved in establishment, growth, and metastases in liver cancer via interaction of cancer cells with the intratumor stroma [24]. The majority of CCN family members are induced by growth factors, cytokines, and cellular stress such as inflammation.…”

Section: Discussionmentioning

confidence: 99%

Members of the Cyr61/CTGF/NOV Protein Family: Emerging Players in Hepatic Progenitor Cell Activation and Intrahepatic Cholangiocarcinoma

Jorgensen

Song

et al. 2016

Gastroenterology Research and Practice

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Hepatic stem/progenitor cells (HPC) reside quiescently in normal biliary trees and are activated in the form of ductular reactions during severe liver damage when the replicative ability of hepatocytes is inhibited. HPC niches are full of profibrotic stimuli favoring scarring and hepatocarcinogenesis. The Cyr61/CTGF/NOV (CCN) protein family consists of six members, CCN1/CYR61, CCN2/CTGF, CCN3/NOV, CCN4/WISP1, CCN5/WISP2, and CCN6/WISP3, which function as extracellular signaling modulators to mediate cell-matrix interaction during angiogenesis, wound healing, fibrosis, and tumorigenesis. This study investigated expression patterns of CCN proteins in HPC and cholangiocarcinoma (CCA). Mouse HPC were induced by the biliary toxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Differential expression patterns of CCN proteins were found in HPC from DDC damaged mice and in human CCA tumors. In addition, we utilized reporter mice that carried Ccn2/Ctgf promoter driven GFP and detected strong Ccn2/Ctgf expression in epithelial cell adhesion molecule (EpCAM)+ HPC under normal conditions and in DDC-induced liver damage. Abundant CCN2/CTGF protein was also found in cytokeratin 19 (CK19)+ human HPC that were surrounded by α-smooth muscle actin (α-SMA)+ myofibroblast cells in intrahepatic CCA tumors. These results suggest that CCN proteins, particularly CCN2/CTGF, function in HPC activation and CCA development.

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CCN: core regulatory proteins in the microenvironment that affect the metastasis of hepatocellular carcinoma?

Cited by 38 publications

References 109 publications

CCN family of proteins: critical modulators of the tumor cell microenvironment

CCN family of proteins: critical modulators of the tumor cell microenvironment

WITHDRAWN: Hepatic stellate cells transmigration and remodeling are related to CCN3 in oxaliplatin-resistant hepatocellular carcinoma

Members of the Cyr61/CTGF/NOV Protein Family: Emerging Players in Hepatic Progenitor Cell Activation and Intrahepatic Cholangiocarcinoma

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