Positional cloning identifies a novel cyclophilin as a candidate amplified oncogene in 1q21

Meza‐Zepeda, Leonardo A.; Forus, Anne; Lygren, Birgitte; Dahlberg, Anine B.; Godager, Linda H.; South, Andrew P.; Marenholz, Ingo; Lioumi, Maria; Flørenes, Viví Ann; Mælandsmo, Gunhild M.; Serra, Massimo; Mischke, Dietmar; Nižetić, Dean; Ragoussis, Jiannis; Tarkkanen, Maija; Nesland, Jahn M.; Knuutila, Sakari; Myklebost, Ola

doi:10.1038/sj.onc.1205339

Cited by 51 publications

(37 citation statements)

References 48 publications

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“…GOLPH3L is located at 1q21.3. It has been reported that 1q21 is amplified in several human malignancies, including rhabdomyosarcoma (16)(17)(18)(19)(20)(21)(22)(23)(24). An amplification of 5p13 has not yet been reported in rhabdomyosarcoma.…”

Section: Discussionmentioning

confidence: 99%

Role of GOLPH3 and GOLPH3L in the proliferation of human rhabdomyosarcoma

Kunigou

Nagao²,

Kawabata³

et al. 2011

Oncol Rep

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Abstract. GOLPH3 was originally identified by proteomic analyses of Golgi proteins localized in the trans-Golgi network. Recently, it was reported that GOLPH3 is up-regulated in various types of malignancies, including melanoma, colon cancer and lung cancer. However, the mechanism through which GOLPH3 is involved in the pathogenesis of rhabdomyosarcoma remains unidentified. In order to explore the function of GOLPH3 and its isoform, GOLPH3L, in the pathogenesis of rhabdomyosarcoma, we investigated the expression and knockdown effects of GOLPH3 and GOLPH3L in human rhabdomyosarcoma. Western blot analysis and real-time PCR revealed that human rhabdomyosarcoma cell lines and biopsy specimens exhibited an increased expression of GOLPH3 and GOLPH3L. GOLPH3 and GOLPH3L knockdown by siRNA prevented the proliferation of human rhabdomyosarcoma cell lines. In addition, double-knockdown of GOLPH3 and GOLPH3L also prevented the proliferation of rhabdomyosarcoma cell lines. Our findings improve the understanding of rhabdomyosarcoma pathogenesis and suggest that the knockdown of GOLPH3 or GOLPH3L may be an effective treatment for rhabdomyosarcoma. IntroductionRhabdomyosarcoma, which is the most common soft-tissue sarcoma in children, includes two major subtypes, alveolar rhabdomyosarcoma and embryonal rhabdomyosarcoma. Approximately 70% of rhabdomyosarcoma patients without metastatic tumors are cured, but the prognosis of patients with metastasis or relapse remains dismal. Although numerous clinical trials have been performed, little improvement has been made for high-risk rhabdomyosarcoma patients, who have a 3-year overall survival of approximately 30% (1,2). Thus, improvements in outcome and in the understanding of the molecular pathways of rhabdomyosarcoma pathogenesis are a priority.GOLPH3 (also known as GOPP1, GPP34, MIDAS or FLJ90675) was originally identified by proteomic analyses of Golgi proteins localized to the trans-Golgi network (3,4). It has been reported that GOLPH3 is dynamically associated with the trans-Golgi matrix, as it rapidly moves from the transGolgi network to the cytosol and localizes in endosomes and at the plasma membrane (5). Recently, it has been reported that GOLPH3 modulates solid tumors through mTOR signaling (6).GOLPH3L (also known as GPP34R, GMx33β or FLJ10687) is an isoform of GOLPH3; these proteins are very homologous to each other and are similarly localized (4). Although the two isoforms are highly homologous in their amino acid sequences, the function of GOLPH3L has not yet been examined.In the present study, we investigated the involvement of GOLPH3 and GOLPH3L in the pathogenesis of human rhabdomyosarcoma. We assessed the expression of GOLPH3 and GOLPH3L in rhabdomyosarcoma and the effect of GOLPH3 or GOLPH3L inhibition on the growth of rhabdomyosarcoma cells. We found that the knockdown of GOLPH3 or GOLPH3L inhibited human rhabdomyosarcoma cell proliferation. Materials and methodsCell culture. The human rhabdomyosarcoma cell lines, KYM-1 and RD, were provided by the Health Science R...

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Section: Discussionmentioning

confidence: 99%

Role of GOLPH3 and GOLPH3L in the proliferation of human rhabdomyosarcoma

Kunigou

Nagao²,

Kawabata³

et al. 2011

Oncol Rep

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“…A novel cyclophilin, which is similar to CypA, has been associated with metastasis and is overexpressed in bladder cancer, hepatocellular carcinoma, sarcoma, and breast carcinoma. 10 However, there are no reports of CypA correlation with pancreatic cancer.…”

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confidence: 99%

Cyclophilin A is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147

Li¹,

Zhai

Bharadwaj³

et al. 2006

Cancer

141

127

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BACKGROUNDAlthough overexpression of cyclophilin A (CypA) is associated with several types of cancer, its role in pancreatic cancer has not been studied. In this study the expression of CypA and its receptor CD147 on pancreatic cancer was determined as well as the effect of exogenous CypA on pancreatic cancer cell proliferation.METHODSThe expression of CypA and CD147 in human pancreatic cancer cell lines and tissues was determined with real‐time reverse transcriptase polymerase chain reaction (RT‐PCR), Western blot, and immunostaining. Cell proliferation in response to CypA was performed by [3H]thymidine incorporation assay. Phosphorylation of MAPK and cytokine secretion profiles in pancreatic cancer cells were determined by using the Bio‐Plex phosphoprotein assay and cytokine assay.RESULTSPancreatic cancer cell lines expressed significantly higher levels of CypA and CD147 than normal human pancreatic ductal epithelium (HPDE) cells. Expression of CypA and CD147 was also substantially higher in human pancreatic adenocarcinoma tissues than those in normal pancreatic tissues. Addition of exogenous CypA significantly stimulated pancreatic cancer cell proliferation in a dose‐dependent manner and this effect was effectively blocked by pretreatment with anti‐CD147 antibody. In addition, CypA activated ERK1/2 and p38 MAPK signaling pathways and increased the secretion of 2 key cytokines IL‐5 and IL‐17 in Panc‐1 cells.CONCLUSIONSThe expression of CypA and CD147 was significantly increased in both pancreatic cancer cell lines and tissues. Exogenous CypA promotes pancreatic cancer cell growth, which may be mediated through the interaction with CD147 and the activation of ERK1/2 and p38 MAPKs. Cancer 2006. © 2006 American Cancer Society.

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“…Reflecting these biological potentials, the role of CypA has been studied in many types of malignant tumors, such as non-small cell lung carcinoma, pancreatic cancer, bladder cancer, hepatocellular carcinoma, sarcoma and breast cancer (20)(21)(22). These studies showed that CypA expression is up-regulated in tumor tissues and that CypA induces cancer cell proliferation and MMP expression, resulting in a poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the homophilic binding of EMMPRIN, recent studies reported that cyclophilin A (CypA) acts as a ligand for EMMPRIN (17,18). The importance of the CypA-EMMPRIN interaction has been reported in rheumatoid arthritis (19), foam cell formation (17) and also in several solid tumors (20)(21)(22). However, the role of CypA and its interaction with EMMPRIN in HNSCC has not yet been evaluated.…”

Section: Introductionmentioning

confidence: 99%

Cyclophilin A-EMMPRIN interaction induces invasion of head and neck squamous cell carcinoma

Takahashi

Suzuki

Ishikawa³

2011

Oncol Rep

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Abstract. Extracellular matrix remodeling crucial to tumorigenesis involves proteolytic enzymes, primarily matrix metalloproteinases (MMPs). MMP production is stimulated by multiple factors, including the extracellular matrix metalloproteinase inducer EMMPRIN/CD147. Overexpression of EMMPRIN, a member of the immunoglobulin superfamily, promotes invasion, metastasis, growth and survival of malignant cells. Cyclophilin A (CypA) is a multifunctional protein that promotes cancer progression in various cancer types. CypA can interact with and activate EMMPRIN; however, the role of CypA-EMMPRIN interaction in oncogenicity is not completely understood. To investigate tumorigenicity induced by the CypA-EMMPRIN interaction, we stimulated EMMPRINexpressing head and neck squamous cell carcinoma (HNSCC) cells with CypA. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye assay revealed that HNSCC cell proliferation increased upon stimulation of the cells with CypA, whereas cisplatin-induced cell death decreased after stimulation. Gelatin zymography showed that CypA also induced MMP-9 up-regulation. Moreover, HNSCC cell invasion through Matrigel™-coated membranes was increased upon stimulation of cells with CypA. This elevated invasive potential was abrogated by an EMMPRIN function-blocking antibody. These findings suggest that CypA, through its interaction with EMMPRIN, contributes to HNSCC tumorigenesis.

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Positional cloning identifies a novel cyclophilin as a candidate amplified oncogene in 1q21

Cited by 51 publications

References 48 publications

Role of GOLPH3 and GOLPH3L in the proliferation of human rhabdomyosarcoma

Role of GOLPH3 and GOLPH3L in the proliferation of human rhabdomyosarcoma

Cyclophilin A is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147

Cyclophilin A-EMMPRIN interaction induces invasion of head and neck squamous cell carcinoma

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