Downregulation of connective tissue growth factor inhibits the growth and invasion of gastric cancer cells and attenuates peritoneal dissemination

Jiang, Chenggang; Lv, Ling; Liu, Furong; Wang, Zhenning; Liu, Funan; Li, Yanshu; Wang, Chunyu; Zhang, Hongyan; Sun, Zhe; Xu, Hui

doi:10.1186/1476-4598-10-122

Cited by 57 publications

(46 citation statements)

References 38 publications

(40 reference statements)

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“…Elevated expression of CTGF was observed in melanoma, papillary thyroid carcinoma, esophageal squamous cell carcinoma, gastric cancer, and cervical tumors, and so on, 17, 18, 19, 20, 21 in which CTGF was positively associated with tumor progression and poor prognosis. Conversely, in oral squamous cell carcinoma, ovarian cancer, and lung adenocarcinomas, 22, 23, 24 reduced CTGF expression was favorable for their progression and poor prognosis.…”

Section: Discussionmentioning

confidence: 98%

Loss of connective tissue growth factor as an unfavorable prognosis factor activates miR-18b by PI3K/AKT/C-Jun and C-Myc and promotes cell growth in nasopharyngeal carcinoma

Zhen

Yang

et al. 2013

Cell Death Dis

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Connective tissue growth factor (CTGF) has different roles in different types of cancer. However, the involvement and molecular basis of CTGF in tumor progression and prognosis of human nasopharyngeal carcinoma (NPC) have almost never been reported. In this study, we observed that downregulated CTGF expression was significantly associated with NPC progression and poor prognosis. Knockdown of CTGF markedly elevated the ability of cell proliferation in vivo and in vitro. Subsequently, we discovered that the reduction of CTGF increased the expression of miR-18b, an oncomir-promoting cell proliferation. Further, we discovered that attenuated CTGF-mediated upregulation of miR-18b was dependent on the increased binding of transcription factors Jun proto-oncogene (C-Jun) and v-Myc myelocytomatosis viral oncogene homolog (C-Myc) to miR-18b promoter region via phosphoinositide 3-kinase (PI3K)/AKT pathway. Finally, we further found that miR-18b directly suppressed the expression of CTGF in NPC. In clinical fresh specimens, miR-18b was widely overexpressed and inversely correlated with CTGF expression in NPC. Our studies are the first to demonstrate that reduced CTGF as an unfavorable prognosis factor mediates the activation of miR-18b, an oncomir directly suppresses CTGF expression, by PI3K/AKT/C-Jun and C-Myc and promotes cell growth of NPC.

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Section: Discussionmentioning

confidence: 98%

Loss of connective tissue growth factor as an unfavorable prognosis factor activates miR-18b by PI3K/AKT/C-Jun and C-Myc and promotes cell growth in nasopharyngeal carcinoma

Zhen

Yang

et al. 2013

Cell Death Dis

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“…Although previous studies have shown that blocking CTGF using antibodies has shown some promising results in inhibiting pancreatic tumor growth and metastasis in nude mice [28], it was found that the CTGF recombinant protein had a significantly therapeutic effect in advanced colorectal cancer [19]. However, previous studies have reported that CTGF may contribute positively to gastric cancer progression and attenuate adhesion of gastric cancer cells to cultured human peritoneal mesothelial cells [29][30][31]. The cells used were unavailable for further testing, and the differences in patient survival may due to genetic background variations between patient groups.…”

Section: Discussionmentioning

confidence: 98%

Connective tissue growth factor inhibits gastric cancer peritoneal metastasis by blocking integrin α3β1-dependent adhesion

et al. 2014

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Background Connective tissue growth factor (CTGF) plays important roles in normal and pathological conditions. The aim of this study was to investigate the role of CTGF in peritoneal metastasis as well as the underlying mechanism in gastric cancer progression. Methods CTGF expression levels for wild-type and stable overexpression clones were determined by Western blotting and quantitative polymerase chain reaction (Q-PCR). Univariate and multivariate analyses, immunohistochemistry, and survival probability analyses were performed on gastric cancer patients. The extracellular matrix components involved in CTGF-regulated adhesion were determined. Recombinant CTGF was added to cells or coinoculated with gastric cancer cells into mice to evaluate its therapeutic potential.Results CTGF overexpression and treatment with the recombinant protein significantly inhibited cell adhesion. In vivo peritoneal metastasis demonstrated that CTGFstable transfectants markedly decreased the number and size of tumor nodules in the mesentery. Statistical analysis of gastric cancer patient data showed that patients expressing higher CTGF levels had earlier TNM staging and a higher survival probability after the surgery. Integrin a3b1 was the cell adhesion molecule mediating gastric cancer cell adhesion to laminin, and blocking of integrin a3b1 prevented gastric cancer cell adhesion to recombinant CTGF. Coimmunoprecipitation results indicated that CTGF binds to integrin a3. Coinoculation of recombinant CTGF and gastric cancer cell lines in mice showed effective inhibition of peritoneal dissemination. Conclusions Our results suggested that gastric cancer peritoneal metastasis is mediated through integrin a3b1 binding to laminin, and CTGF effectively blocks the interaction by binding to integrin a3b1, thus demonstrating the therapeutic potential of recombinant CTGF in gastric cancer patients.

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“…Further, Yap1 functions as a transcription coactivator to regulate the expression of genes, including TEAD4 [24], CTGF [25], and CYR61 [26], which function as metastasispromoting genes in GC. The Hippo pathway plays an important role in tumorigenesis and tumor progression through the YAP-TEAD complex [27].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-506 inhibits gastric cancer proliferation and invasion by directly targeting Yap1

et al. 2015

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Increasing evidence indicates that microRNA (miR)-506 plays a vital role in tumorigenesis; however, the role of miR-506 in gastric cancer (GC) is unclear and needs further investigation. In the present study, we showed that the decrease in the expression of miR-506 is associated with tumor size, pathological tumor node metastasis (TNM) stage, and lymph node metastasis in 63 GC patient tumors. We found that patients with lower expression of miR-506 had a poor prognosis than that with the patients with high expression of miR-506. Notably, the ectopic expression of miR-506 was sufficient to inhibit cell proliferation, invasion, and epithelial-mesenchymal transition in the GC cells. Moreover, results from luciferase reporter assays identified miR-506 as a direct regulator of Yes-associated protein 1 (Yap1). Reintroduction of Yap1 rescues miR-506-induced effects on SGC-7901 cell proliferation and invasion. This function of miR-506/Yap1 axis is clinically significant, as the level of miR-506 is inversely correlated with Yap1 mRNA expression in matched tissues. Thus, our study demonstrates that miR-506 may act as a tumor suppressor in GC and that the miR-506/Yap1 axis may help us better understand the molecular mechanisms of GC progression.

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Downregulation of connective tissue growth factor inhibits the growth and invasion of gastric cancer cells and attenuates peritoneal dissemination

Cited by 57 publications

References 38 publications

Loss of connective tissue growth factor as an unfavorable prognosis factor activates miR-18b by PI3K/AKT/C-Jun and C-Myc and promotes cell growth in nasopharyngeal carcinoma

Loss of connective tissue growth factor as an unfavorable prognosis factor activates miR-18b by PI3K/AKT/C-Jun and C-Myc and promotes cell growth in nasopharyngeal carcinoma

Connective tissue growth factor inhibits gastric cancer peritoneal metastasis by blocking integrin α3β1-dependent adhesion

MicroRNA-506 inhibits gastric cancer proliferation and invasion by directly targeting Yap1

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