Connective tissue growth factor induces c-fos gene activation and cell proliferation through p44/42 MAP kinase in primary rat hepatic stellate cells

Gao, Runping; Ball, DeAnna K.; Perbal, Bernard; Brigstock, David R.

doi:10.1016/j.jhep.2003.11.012

Cited by 62 publications

(54 citation statements)

References 55 publications

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“…Studies using these inhibitors therefore have suggested that the proliferative effect of CCN2 on neoplastic ECL cells occurs via MAPK pathway activation (ERK1/2) and not via the PI3K pathway. The results in ECL cells with PD-98059 were similar to studies in hepatic stellate cells, where CCN2-stimulated DNA synthesis was associated with phosphorylation of ERK1/2 and an induction of c-fos expression (7), effects that could be blocked by inhibiting ERK1/2 with PD-98059 (7). The principal pathway that regulated CCN2-mediated proliferation in the chondrocyte (HCS-2/8) cell line was phosphorylation of ERK1/2 and could be inhibited by PD-98059 (39).…”

Section: Discussionsupporting

confidence: 79%

Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development

Kidd¹,

Modlin²,

Eick³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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cell proliferation is initially gastrin driven, but once neoplasia develops, cells become gastrin autonomous. We hypothesized that CCN2 (CTGF), a mitogenic growth factor, may regulate ECL cell proliferation. A Mastomys GeneChip database was examined (dCHIP) to identify CCN2 expression levels. CCN2 in normal and tumor ECL cell preparations obtained using FACS (100 nM acridine orange) was examined by real-time PCR. CCN2 protein was identified in mucosal and ECL cell preparations by immunohistochemistry. Short-term cultured cells were stimulated with either CCN2 or CCN2 ϩ EGF, and proliferation was measured (MTT assay). The ERK1/2 inhibitor PD-98059 (0.1-100 M) was assessed in terms of CCN2 (1 ng/ml)-mediated proliferation and ERK1/2 phosphorylation. CCN2 transcript and protein was then examined in clinical gastric carcinoids. The ccn2 transcript was upregulated in tumor samples compared with the normal mucosa (ϩ2.36-fold, P Ͻ 0.01). PCR demonstrated that ccn2 was not expressed in FACS-prepared (Ͼ98% pure) normal ECL cells but was elevated in tumor ECL cell fractions (41.3 Ϯ 10.7-fold). Immunostaining of the Mastomys gastric mucosa and FACS preparations confirmed that CCN2 protein was present in ECL tumors but not in normal ECL cells. Neither CCN2 nor CCN2 ϩ EGF stimulated normal ECL cell proliferation. CCN2 stimulated tumor proliferation (EC 50 ϳ0.01 ng/ml); EGF significantly augmented (P Ͻ 0.01) CCN2-induced tumor cell proliferation (EC50 ϭ 20 pg/ml). PD-98059 inhibited CCN2-induced proliferation (Ϫ12 Ϯ 3%, P Ͻ 0.05) and ERK1/2 phosphorylation (Ϫ34 Ϯ 5%, P Ͻ 0.05) in tumor cells. In clinical samples, both CCN2 transcript and protein were elevated in gastrin-autonomous carcinoids (P Ͻ 0.02) compared with the normal mucosa. In conclusion, CCN2 may be a proliferative regulator of Mastomys ECL neoplastic proliferation once these cells become autonomous of gastrin regulation. Identification of CCN2 in gastric carcinoid tissue may be useful both as an indicator of ECL cell transformation and may define gastrin autonomy, a criteria of gastric carcinoid malignancy.connective tissue growth factor; epithelial growth factor AGENTS involved in regulating cell proliferation during the development of carcinoids and neuroendocrine (NE) tumors remain an elusive issue. Little information in this area is available since few models and NE cell lines exist to evaluate the problem. The rodent Mastomys develops gastric carcinoids both spontaneously (12-18 mo) and very rapidly (8 -12 wk) when acid suppression and hypergastrinemia are engendered (26, 34). In the stomach, the enterochromaffin-like (ECL) cell, which regulates acid secretion under the effect of both gastrin and PACAP (31, 40), transforms into a neoplastic phenotype when exposed to hypergastrinemia (34). Gastrin itself has no proliferative effect on ECL cells once neoplastic transformation has occurred and the ECL cells become gastrin autonomous (34). Nevertheless, proliferation continues even if the gastrin stimulus is withdrawn, indicating that an alternative proliferativ...

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Section: Discussionsupporting

confidence: 79%

Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development

Kidd¹,

Modlin²,

Eick³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…It has a vital role in chondrogenesis, angiogenesis and skeletal system development during embryonic period [3]. Also it plays a crucial role in some important cellular functions as cell proliferation and differentiation [4,5], extracellular matrix synthesis [6], cell adhesion to extracellular matrix [7,8] and cell migration [7]. It has been shown that CTFG induces the production of extracellular matrix by stimulating transcription of type 1 collagen [8].…”

Section: Introductionmentioning

confidence: 99%

Concentrations of Connective Tissue Growth Factor in Patients with Nonalcoholic Fatty Liver Disease: Association with Liver Fibrosis

et al. 2012

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Aim:In this study, we aimed to investigate the relationship between the histological fibrosis stage of nonalcoholic fatty liver disease (NAFLD) and serum connective tissue growth factor (CTGF) to determine the usefulness of this relationship in clinical practice.Methods:Serum samples were collected from 51 patients with biopsy-proven NAFLD and 28 healthy controls, and serum levels of CTGF were assayed by ELISA.Results:Levels of CTGF were significantly higher in patients with NAFLD compared with controls (P= 0.001). The serum CTGF levels were significantly increased, that correlated with histological fibrosis stage, in patients with NAFLD [in patients with no fibrosis (stage 0) 308.2 ± 142.9, with mild fibrosis (stage 1–2) 519.9±375.2 and with advanced fibrosis (stage 3–4) 1353.2 ± 610 ng/l,P< 0.001]. Also serum level of CTGF was found as an independent predictor of histological fibrosis stage in patients with NAFLD (β= 0.662,t= 5.6,P< 0.001). The area under the ROC curve was estimated 0.931 to separate patients with severe fibrosis from patients with other fibrotic stages.Conclusion:Serum levels of CTGF may be a clinical utility for distinguishing NAFLD patients with and without advanced fibrosis.

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“…We have shown further that CCN2 promoter activity is enhanced in a Smad7-dependent fashion by TGF-b in primary rat HSCs transfected with the CCN2 promoter, luciferase reporter constr uct [10] , and that CCN2 production in the HSCs is stimulated by TGF-b1 [6] . We recently showed that TGF-b-induced CCN2 promoter activity in activated mouse HSCs requires Smad and Ets-1 elements in the CCN2 promoter [16] , as described for normal fibroblasts or mesangial cells [17][18][19][20] .…”

Section: Introductionmentioning

confidence: 60%

“…CCN2 is recognized increasingly as a central player in hepatic fibrosis and may offer new options for prognosis, diagnosis and therapy [7] . Previously, we have shown that exposure of HSCs to CCN2 induces cell adhesion, migration and proliferation, the latter of which is associated with transient induction of c-fos and activation of the extracellular signal-regulated kinase 1/2 signaling pathway [8][9][10] . In addition, CCN2 induces expression of a-SMA and type Ⅰ collagen in HSCs, consistent with a role in activation and fibrogenesis [8] .…”

Section: Introductionmentioning

confidence: 98%

Connective tissue growth factor hammerhead ribozyme attenuates human hepatic stellate cell function

Gao¹,

Brigstock²

2009

WJG

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AIM:To determine the effect of hammerhead ribozyme targeting connective tissue growth factor (CCN2) on human hepatic stellate cell (HSC) function. METHODS:CCN2 hammerhead ribozyme cDNA plus two self-cleaving sequences were inserted into pTriEx2 to produce pTriCCN2-Rz. Each vector was individually transfected into cultured LX-2 human HSCs, which were then stimulated by addition of transforming growth factor (TGF)-b1 to the culture medium. Semiquantitative RT-PCR was used to determine mRNA levels for CCN2 or collagen Ⅰ, while protein levels of each molecule in cell lysates and conditioned medium were measured by ELISA. Cell-cycle progression of the transfected cells was assessed by flow cytometry. RESULTS:In pTriEx2-transfected LX-2 cells, TGF-β1 treatment caused an increase in the mRNA level for CCN2 or collagen Ⅰ, and an increase in produced and secreted CCN2 or extracellular collagen Ⅰ protein levels. pTriCCN2-Rz-transfected LX-2 cells showed decreased basal CCN2 or collagen mRNA levels, as well as produced and secreted CCN2 or collagen Ⅰ protein. Furthermore, the TGF-b1-induced increase in mRNA or protein for CCN2 or collagen Ⅰ was inhibited partially in pTriCCN2-Rz-transfected LX-2 cells. Inhibition of CCN2 using hammerhead ribozyme cDNA resulted in fewer of the cells transitioning into S phase.CONCLUSION: Endogenous CCN2 is a mediator of basal or TGF-b1-induced collagen Ⅰ production in human HSCs and regulates entry of the cells into S phase.

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Connective tissue growth factor induces c-fos gene activation and cell proliferation through p44/42 MAP kinase in primary rat hepatic stellate cells

Cited by 62 publications

References 55 publications

Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development

Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development

Concentrations of Connective Tissue Growth Factor in Patients with Nonalcoholic Fatty Liver Disease: Association with Liver Fibrosis

Connective tissue growth factor hammerhead ribozyme attenuates human hepatic stellate cell function

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