Expression of HAb18G is associated with tumor progression and prognosis of breast carcinoma

Liu, Fangfang; Cui, Lifang; Zhang, Yang; Chen, Ling; Wang, Yahong; Fan, Yu; Lei, Ting; Gu, Feng; Lang, Ronggang; Pringle, Gordon A.; Zhang, Xinmin; Chen, Zhinan; Fu, Li

doi:10.1007/s10549-010-0790-6

Cited by 38 publications

(33 citation statements)

References 20 publications

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“…Our work showed that CD147 was more strongly upregulated in breast cancer tissues than in the adjacent tissues and that this overexpression correlated with tumor metastasis and advanced histologic grades. Combined with the previous results, CD147 might serve as a breast cancer biomarker detection (6,8,32,33). Elucidation of this transcriptional regulation mechanism could provide new targets for breast cancer clinical therapy.…”

Section: Discussionsupporting

confidence: 54%

“…Indeed, high CD147 expression levels have been reported in many tumors, including breast cancer, lymphoma, oral squamous cell carcinoma, glioma, melanoma, lung, bladder, liver, and kidney carcinomas (5)(6)(7). Accordingly, CD147 expression has been associated with known risk factors for breast cancer and with poor prognosis in patients with breast cancer (8)(9)(10). Nonetheless, although CD147 plays a critical role in breast cancer progression and prognosis, the mechanisms that underlie the upregulation of this molecule in breast cancer are not well elucidated.…”

Section: Introductionmentioning

confidence: 99%

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A Regulatory Loop Involving miR-22, Sp1, and c-Myc Modulates CD147 Expression in Breast Cancer Invasion and Metastasis

et al. 2014

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Breast cancer is the most common cancer in women for which the metastatic process is still poorly understood. CD147 is upregulated in breast cancer and has been associated with tumor progression, but little is known about its regulatory mechanisms. In this study, we demonstrated that CD147 was overexpressed in breast cancer tissues and cell lines, and the high expression correlated with tumor invasion and metastasis. We also found that the transcription factors Sp1 and c-Myc could bind to the CD147 promoter and enhance its expression. The CD147 mRNA has a 748-bp 3 0 -untranslated region (UTR) with many miRNA target sites, suggesting possible regulation by miRNAs. We discovered that miR-22 repressed CD147 expression by directly targeting the CD147 3 0 UTR. We also determined that miR-22 could indirectly participate in CD147 modulation by downregulating Sp1 expression. miR-22 could form an autoregulatory loop with Sp1, which repressed miR-22 transcription by binding to the miR-22 promoter. Together with the c-Myc-mediated inhibition of miR-22 expression, our investigation identified a miR-22/Sp1/c-Myc network that regulates CD147 gene transcription. In addition, miR-22 overexpression suppressed breast cancer cell invasion, metastasis, and proliferation by targeting CD147 in vitro and in vivo. Furthermore, we found that miR-22 was significantly downregulated in breast cancer tissues and that its expression was inversely correlated with the tumor-node-metastasis stage and lymphatic metastasis in patients. Our study provides the first evidence that an miR-22/Sp1/c-Myc network regulates CD147 upregulation in breast cancer and that miR-22 represses breast cancer invasive and metastatic capacities. Cancer Res; 74(14); 3764-78. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

A Regulatory Loop Involving miR-22, Sp1, and c-Myc Modulates CD147 Expression in Breast Cancer Invasion and Metastasis

et al. 2014

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“…Immunostaining was scored as positive and negative, as described previously. 15 Western blot analysis. Cells were lysed in 1% OG buffer (20 mM Tris-HCl, pH 8.0, 150 mM NaCl, 1% OG, 1 mM EDTA, 10 mg/ml leupeptin, 2 mg/ml aprotinin and 1 mM PMSF).…”

Section: Methodsmentioning

confidence: 99%

“…[12][13][14] The overexpression of Bip as a result of the three major transducers has been reported in malignant breast disease, colon cancer and gastric and esophageal adenocarcinomas. [15][16][17][18] It has also been reported that Bip overexpression is driven by a c-myb mutation in colon cancer. 19 These results confirmed that the complexity of UPR has increased from the three major UPR transducers that are involved in simple pathways to multimolecules, which are involved in a multibranching signal transduction cascade.…”

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confidence: 96%

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

Tang

Zhang

et al. 2012

Cell Death Differ

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The unfolded protein response (UPR) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. However, tumor-specific UPR transducers are largely unknown. In the present study, we identified CD147, a cancer biomarker, as an UPR inducer in hepatocellular carcinoma (HCC). The expression of the major UPR target, Bip, was found to be positively associated with CD147 in human hepatoma tissues. By phosphorylating FAK and Src, CD147-enhanced TFII-I tyrosine phosphorylation at Tyr248. CD147 also induced p-TFII-I nuclear localization and binding to the Bip promoter where endoplasmic reticulum (ER) stress response element 1 (ERSE1) ( À 82/ À 50) is the most efficient target of the three ERSEs, thus increasing transcription of Bip. Furthermore, by inducing UPR, CD147 inhibited HCC cell apoptosis and decreased cell Adriamycin chemosensitivity, thus decreasing the survival rate of hepatoma-bearing nude mice. Together, these results reveal pivotal roles for CD147 in modulating the UPR in HCC and raise the possibility that CD147 is a target that promotes HCC cell apoptosis and increases the sensitivity of tumors to anti-cancer drugs. Therefore, CD147 inhibition provides an opportunity to enhance the efficacy of existing agents and represents a novel target for HCC treatment. The uncontrolled growth and insufficient vascularization of a tumor mass lead to a stressed state in the tumor microenvironment, which includes low oxygen supply, nutrient deprivation and pH changes. Microenvironment stresses directly impinge on the luminal milieu of the endoplasmic reticulum (ER) and might be sufficiently severe to cause ER stress (ERS). 1 These ERS conditions activate a range of cellular stress response pathways, including the unfolded protein response (UPR). 2,3 UPR activation has profound consequences for tumor growth and resistance to radiotherapy and chemotherapy. [4][5][6] Therefore, the UPR might be responsible for the failure of some patients to respond to treatment and is associated with a poor prognosis. 7 Given the observation that UPR is correlated with certain types of aggressive tumors, drug resistance, recurrence and poor survival, 8-11 the inhibition of the UPR pathway may yield more efficient treatments for cancer.Although there is sufficient evidence to indicate that the UPR is generally activated in solid tumors, the UPR remains poorly characterized in cancers. The three major UPR transducers are inositol-requiring enzyme 1 (IRE1), pancreatic kinase-like ER kinase (PERK) and the UPR-specific transcription factor, activating transcription factor 6 (ATF6).These factors all sense the presence of unfolded proteins in the ER lumen and transduce signals to the nucleus that activate the transcription of UPR target genes, such as Bip (also called glucose-regulated protein 78). 12-14 The overexpression of Bip as a result of the three major transducers has been reported in malignant breast disease, colon cancer and gastric and esophageal adenocarcinomas. [15][16][17][18] It has also been...

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“…CD147 is involved in embryonic development, and little is known about its regulation (Iacono et al, 2007). However, CD147 is overexpressed in a number of epithelial cell-derived carcinomas and is associated with tumor progression (Liu et al, 2010). Immunohistochemistry has shown that HAb18G/ CD147 expression is significantly higher in human HCC tissues than in normal adult and fetal tissues .…”

Section: Introductionmentioning

confidence: 99%

HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug

et al. 2011

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Epithelial-mesenchymal transition (EMT) induced by transforming growth factor-b (TGF-b) is implicated in hepatocarcinogenesis and hepatocellular carcinoma (HCC) metastasis. HAb18G/CD147, which belongs to the CD147 family, is an HCC-associated antigen that has a crucial role in tumor invasion and metastasis. The goal of this study was to investigate the role of HAb18G/ CD147 during EMT in hepatocarcinogenesis. Human normal hepatic cell lines QZG and L02, primary mouse hepatocytes and nude mouse models were used to determine the role of HAb18G/CD147 in EMT, and the involvement of the TGF-b-driven pathway. A dualluciferase reporter assay and ChIP were used to investigate the transcriptional regulation of the CD147 gene. Samples from patients with liver disease were assessed to determine the relationship between HAb18G/CD147 and typical markers for EMT. Our results show that upregulation of HAb18G/CD147 is induced by TGF-b coupled with downregulation of E-cadherin and upregulation of N-cadherin and vimentin. The expression of HAb18G/CD147 is controlled by the cell survival PI3K/ Akt/GSK3b signaling pathway, and is directly regulated by the transcription factor Slug. Transfection of CD147 also induces an elevated expression of TGF-b. CD147-transfected hepatocytes have mesenchymal phenotypes that accelerate tumor formation and tumor metastasis in vivo. Immunohistochemistry analysis shows a negative correlation between HAb18G/CD147 and E-cadherin expression (r s ¼ À0.3622, P ¼ 0.0105), and a positive correlation between HAb18G/CD147 and Slug expression (r s ¼ 0.3064, P ¼ 0.0323) in human HCC tissues. Our study uncovers a novel role of HAb18G/CD147 in mediating EMT in the process of HCC progression and showed that CD147 is a Slug target gene in the signaling cascade TGF-b-PI3K/Akt-GSK3b-Snail-Slug-CD147. Our results suggest that CD147 may be a potential target for the treatment and prevention of HCC.

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Expression of HAb18G is associated with tumor progression and prognosis of breast carcinoma

Cited by 38 publications

References 20 publications

A Regulatory Loop Involving miR-22, Sp1, and c-Myc Modulates CD147 Expression in Breast Cancer Invasion and Metastasis

A Regulatory Loop Involving miR-22, Sp1, and c-Myc Modulates CD147 Expression in Breast Cancer Invasion and Metastasis

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug

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