CD147 silencing via RNA interference reduces tumor cell invasion, metastasis and increases chemosensitivity in pancreatic cancer cells

Pan, Yuqin; He, Bangshun; Song, Guoqi; Bao, Qiyu; Tang, Zhipeng; Tian, Fei; Wang, Shukui

doi:10.3892/or.2012.1729

Cited by 22 publications

(14 citation statements)

References 33 publications

(43 reference statements)

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“…Further, MCT1 and MCT4 require expression of the plasma membrane glycoprotein CD147 for proper cell membrane insertion (17). Support for the importance of these processes has recently come from preclinical data demonstrating that inhibition or reduction of MCTs holds promise for cancer therapeutics (10, 18, 25, 39, 40). For example, MCT1 inhibition with α-cyano-4-hydroxycinnamate delays tumor growth, induces tumor core necrosis, and decreases tumor hypoxia in Lewis Lung carcinoma and WiDr human colorectal adenocarcinoma xenographs.…”

Section: Discussionmentioning

confidence: 99%

Cell Surface Lactate Receptor GPR81 Is Crucial for Cancer Cell Survival

et al. 2014

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The mechanisms which allow cancer cells to adapt to the typical tumor microenvironment of low oxygen and glucose and high lactate are not well understood. GPR81 is a lactate receptor recently identified in adipose and muscle cells that has not been investigated in cancer. In the current study, we examined GPR81 expression and function in cancer cells. We found that GPR81 was present in colon, breast, lung, hepatocellular, salivary gland, cervical and pancreatic carcinoma cell lines. Examination of tumors resected from pancreatic cancer patients indicated that 94% (148/158) expressed high levels of GPR81. Functionally, we observed that the reduction of GPR81 levels using shRNA mediated silencing had little effect on pancreatic cancer cells cultured in high glucose, but led to the rapid death of cancer cells cultured in conditions of low glucose supplemented with lactate. We also observed that lactate addition to culture media induced the expression of genes involved in lactate metabolism including monocarboxylase transporters in control, but not in GPR81 silenced cells. In vivo, GPR81 expression levels correlated with the rate of pancreatic cancer tumor growth and metastasis. Cells in which GPR81 was silenced showed a dramatic decrease in growth and metastasis. Implantation of cancer cells in vivo was also observed to lead to greatly elevate levels of GPR81. These data support that GPR81 is important for cancer cell regulation of lactate transport mechanisms. Furthermore, lactate transport is important for the survival of cancer cells in the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Cell Surface Lactate Receptor GPR81 Is Crucial for Cancer Cell Survival

et al. 2014

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“…Degradation of the ECM at both the primary tumor site and at the secondary colonization site is critical for tumor invasion and metastasis [12]. Recently, the role of CD147 in tumor invasiveness was confirmed in several human malignancies, including gastric cancer [14]–[16]. Inhibition of CD147 expression by RNA interference reduced tumor cell invasion and tumorigenicity, as well as increased chemosensitivity to paclitaxel [17].…”

Section: Introductionmentioning

confidence: 99%

CD147 Expression in Human Gastric Cancer Is Associated with Tumor Recurrence and Prognosis

Chu

Zhu

et al. 2014

PLoS ONE

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CD147 is correlated with tumor aggressiveness in various human malignancies. Here, we investigated CD147 protein expression in 223 patients with gastric cancer by immunohistochemistry and analyzed its association with disease-free and overall survival. CD147 was increased in gastric cancer compared to normal tissues. Additionally, CD147 expression was associated with gastric cancer invasion, metastasis and TNM stage, whereas it was not related to age, sex, differentiation status, tumor site or Lauren classification. Kaplan-Meier analysis confirmed that CD147 was associated with disease-free and overall survival in patients with gastric cancer; i.e., patients with positive CD147 staining tend to have worse disease-free and overall survival. Moreover, Cox's proportional hazards analysis demonstrated that CD147 was an independent marker of disease-free and overall survival for patients with gastric cancer. These results confirm the association of CD147 with gastric cancer invasion and metastasis and prove that CD147 might be an indicator of tumor recurrence and prognosis in gastric cancer.

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“…We also showed that HAb18G/CD147 was highly expressed in breast carcinomas and sarcomas (17), but its expression in pancreatic cancers were not included in that analysis. Although targeting CD147 by siRNA (27, 28) or monoclonal antibody (29, 30) can reduce cell growth and invasion in vitro and inhibits tumor growth and metastasis in a xenograft model, the role of HAb18G/CD147 in the early promotion of PDCA, especially in STAT3-involved PDCA initiation, remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

HAb18G/CD147 Promotes pSTAT3-Mediated Pancreatic Cancer Development via CD44s

Tang

et al. 2013

Clinical Cancer Research

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Purpose STAT3 plays a critical role in initiation and progression of pancreatic cancer. However, therapeutically targeting STAT3 is failure in clinic. We previously identified HAb18G/CD147 as an effective target for cancer treatment. In this study, we aimed to investigate potential role of HAb18G/CD147 in STAT3-involved pancreatic tumorigenesis in vitro and in vivo. Experimental Design The expression of HAb18G/CD147, pSTAT3 and CD44s were determined in tissue microarrays. The tumorigenic function and molecular signaling mechanism of HAb18G/CD147 was assessed by in vitro cellular and clonogenic growth, reporter assay, immunoblot, immunofluorescence staining, immunoprecipitation, and in vivo tumor formationusing loss or gain-of-function strategies. Results Highly expressed HAb18G/CD147 promoted cellular and clonogenic growth in vitro and tumorigenicity in vivo. CyPA, a ligand of CD147, stimulated STAT3 phosphorylation and its downstream genes cyclin D1/survivin through HAb18G/CD147 dependent mechanisms. HAb18G/CD147 was associated and co-localized with cancer stem cell marker CD44s in lipid rafts. The inhibitors of STAT3 and survivin, as well as CD44s neutralizing antibodies suppressed the HAb18G/CD147-induced cell growth. High HAb18G/CD147 expression in pancreatic cancer was significantly correlated with the poor tumor differentiation, and the high co-expression of HAb18G/CD147-CD44s-STAT3 associated with poor survival of patients with pancreatic cancer. Conclusions We identified HAb18G/CD147 as a novel upstream activator of STAT3 via interacts with CD44s and plays a critical role in the development of pancreatic cancer. The data suggest HAb18G/CD147 could be a promising therapeutic target for highly aggressive pancreatic cancer and a surrogate marker in the STAT3-targeted molecular therapies.

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CD147 silencing via RNA interference reduces tumor cell invasion, metastasis and increases chemosensitivity in pancreatic cancer cells

Cited by 22 publications

References 33 publications

Cell Surface Lactate Receptor GPR81 Is Crucial for Cancer Cell Survival

Cell Surface Lactate Receptor GPR81 Is Crucial for Cancer Cell Survival

CD147 Expression in Human Gastric Cancer Is Associated with Tumor Recurrence and Prognosis

HAb18G/CD147 Promotes pSTAT3-Mediated Pancreatic Cancer Development via CD44s

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