Down-regulation of plasma membranous Annexin A1 protein expression in premalignant and malignant lesions of the oral cavity: correlation with epithelial differentiation

Nomura, Hitomi; Uzawa, Katsuhiro; Yamano, Y.; Fushimi, Kazuaki; Nakashima, Daisuke; Kouzu, Yukinao; Kasamatsu, Atsushi; Ogawara, Katsunori; Shiiba, Masashi; Bukawa, Hiroki; Yokoe, Hidetaka; Tanzawa, Hideki

doi:10.1007/s00432-008-0530-z

Cited by 21 publications

(18 citation statements)

References 30 publications

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“…Interestingly, a strong staining of ANXA1 is observed in the plasma membrane and nucleus of the primary cells, whereas only nuclear staining is observed in the immortalized cells. Loss of plasma membranous ANXA1 has been observed in premalignant lesions of the oral cavity (24), and nuclear localization has been correlated with shorter overall patient survival (25). Thus, we observe a correlation of expression levels and altered subcellular localization of ANXA1 during the early events of cancer development, which highlights that the role of ANXA1 in cancer should be further evaluated.…”

Section: Validation Of Differentially Expressed Genes On the Protein supporting

confidence: 52%

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Danielsson

Skogs

Huss

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The transformation of normal cells to malignant, metastatic tumor cells is a multistep process caused by the sequential acquirement of genetic changes. To identify these changes, we compared the transcriptomes and levels and distribution of proteins in a fourstage cell model of isogenically matched normal, immortalized, transformed, and metastatic human cells, using deep transcriptome sequencing and immunofluorescence microscopy. The data show that ∼6% (n = 1,357) of the human protein-coding genes are differentially expressed across the stages in the model. Interestingly, the majority of these genes are down-regulated, linking malignant transformation to dedifferentiation. The up-regulated genes are mainly components that control cellular proliferation, whereas the down-regulated genes consist of proteins exposed on or secreted from the cell surface. As many of the identified gene products control basic cellular functions that are defective in cancers, the data provide candidates for follow-up studies to investigate their functional roles in tumor formation. When we further compared the expression levels of four of the identified proteins in clinical cancer cohorts, similar differences were observed between benign and cancer cells, as in the cell model. This shows that this comprehensive demonstration of the molecular changes underlying malignant transformation is a relevant model to study the process of tumor formation.C ancer development is a multistep process where genetic changes are accumulated, thus progressively transforming cells into a cancerous phenotype (1, 2). Over the last decades, numerous investigators have studied the underlying molecular mechanisms for malignant transformation. This has resulted in many models that explain the development of a malignant phenotype of human cells, for instance the "hallmarks of cancer" by Hanahan and Weinberg (3,4).With new technologies for deep sequencing, novel opportunities to study the underlying molecular events leading to cancers have emerged. A large number of investigations have analyzed mutations occurring in tumors, such as the analysis of mRNA expression, microRNA expression, and DNA copy number in a large number of tumors in the Cancer Genome Atlas (5). Similarly, the Human Protein Atlas project (6) studies human cancers using a proteome-wide collection of antibodies, resulting in publicly available immunohistochemistry images covering 20 different human cancer types.An interesting approach to studying the molecular mechanisms underlying cancer is to use an isogenically matched cell model in which normal cells are progressively transformed into malignant cells. There are several studies where genetic elements such as oncogenes have been introduced to different types of cells in an accumulative order as an attempt to mimic the natural steps of transformation (7,8). One such cell model is the fourstage model based on BJ fibroblasts developed by the Weinberg group, in which primary fibroblast cells were immortalized with telomerase reverse transcriptase (...

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Section: Validation Of Differentially Expressed Genes On the Protein supporting

confidence: 52%

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Danielsson

Skogs

Huss

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…During EMT, epithelial cells lose their epithelial characteristics and gain invasive properties to become mesenchymal-like cells (29). ANXA1 has been demonstrated to be important for epithelial differentiation in OSCC (19). Nomura et al (19) found that loss of ANXA1 occurs frequently during oral carcinogenesis, and the loss of membranous ANXA1 is correlated with a poor differentiation status of OSCC cells.…”

Section: Discussionmentioning

confidence: 99%

“…ANXA1 has been demonstrated to be important for epithelial differentiation in OSCC (19). Nomura et al (19) found that loss of ANXA1 occurs frequently during oral carcinogenesis, and the loss of membranous ANXA1 is correlated with a poor differentiation status of OSCC cells. OSCC patients with nuclear localization of ANXA1 had poor overall survival (30).…”

Section: Discussionmentioning

confidence: 99%

“…A increasing number of studies suggested that the expression and the function of ANXA1 in tumors are tissue-and tumor-specific (9,10). Upregulation of ANXA1 was observed in human breast cancer (11), hepatocellular carcinoma (12) and melanoma (13,14), whereas downregulation of ANXA1 was observed in gastric cancer (15), prostate cancer (16,17) and oral cancer (18,19). The function of ANXA1 in tumors appears to be paradoxical.…”

Section: Introductionmentioning

confidence: 99%

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ANXA1 affects cell proliferation, invasion and epithelial‑mesenchymal transition of oral squamous cell carcinoma

et al. 2017

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Abstract. Annexin A1 (ANXA1) acts either as a tumor suppressor or an oncogene in different tumor types. Several clinical studies revealed that the expression of ANXA1 is associated with the pathologic differentiation grade in oral squamous cell carcinoma (OSCC) patients. However, the direct function of ANXA1 in OSCC progression has remained to be fully clarified. The present study was designed to investigate the role of ANXA1 in OSCC cell proliferation and invasion in vitro. Furthermore, whether ANXA1 was involved in transforming growth factor β1 (TGFβ1)/epidermal growth factor (EGF)-induced epithelial-mesenchymal transition (EMT) in OSCC was explored. Tca-8113 and SCC-9 cells were transfected with ANXA1-pcDNA3.1 plasmid to overexpress ANXA1. Subsequently, cell proliferation and invasion were examined using MTT and Transwell-Matrigel invasion assays. TGFβ1 and EGF were used to induce EMT in Tca-8113 and SCC-9 cells, and the expression of epithelial (E)-cadherin, neural (N)-cadherin and vimentin was determined by western blot analysis. The results demonstrated that ANXA1 overexpression induced a significant decrease of cell growth and invasiveness in Tca-8113 and SCC-9 cells. The expression of E-cadherin was significantly increased, while the expression of vimentin and N-cadherin was significantly decreased in ANXA1-overexpressing Tca-8113 and SCC-9 cells. ANXA1 expression was significantly decreased in TGFβ1/EGF-treated cells. Furthermore TGFβ1/EGF-induced EMT in OSCC cell lines was attenuated by ANXA1 overexpression. In conclusion, to the best of our knowledge, the present study was the first to evidence that ANXA1 inhibits OSCC cell proliferation and invasion in vitro. TGFβ1/EGF-induced EMT was reversed by ANXA1 in OSCC. ANXA1 was suggested to be a potential marker for OSCC as well as a novel treatment.

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“…Evidence for this lies in the clear observations that its expression is in a tumor-specific manner. It has been reported that annexin A1 is up-regulated in hepatocellular carcinoma (de Coupade et al, 2000), bladder cancer (Cui et al, 2007), larynx cancer (Silistino-Souza et al, 2007), human breast cancer (Kang et al, 2012) and pituitary adenoma (Mulla et al, 2004), while it is absent or down-regulated in human esophageal squamous cell carcinoma (Liu et al, 2003), oral squamous-cell carcinoma (Nomura et al, 2009), prostate cancers (Silistino-Souza et al, 2007) head and neck cancers (Garcia Pedrero et al, 2004), intestinal-type sinonasal adenocarcinoma (Rodrigo et al, 2011), B-cell non-Hodgkin's lymphomas (Vishwanatha et al, 2004), thyroid cancers (Petrella et al, 2006) and endometrial carcinoma (Da et al, 2001). In our study, we found that annexin A1 was significantly overexpressed in PDAC tissues by real-time RT-PCR, Western blot and immunohistochemistry, which was consistent with the early study of annexin A1 expression in pancreatic cancer (Bai et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance of Annexin A1 Expression in Pancreatic Ductal Adenocarcinoma

Chen¹,

Shen²,

Wang³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Annexin A1 is a 37-kDa calcium-and phospholipid-binding protein of the annexin superfamily considered to play an important role in tumorigenesis. However, associations with clinicopathological features in pancreatic ductal adenocarcinoma (PDAC) cases have yet to be fully defined. We therefore investigated the prognostic value of annexin A1 protein as a PDAC biomarker in 83 tumor and matched non-cancerous tissues or normal pancreas tissues. Expression was analyzed using real-time RT-PCR, Western blotting and immunohistochemistry. In non-tumor tissue, myoepithelial cells showed no or weak expression of annexin A1 while expression was strong and sometimes even located in the nuclei of endothelial cells in tumor tissue. High expression was significantly associated with advanced stage (P <0.05) and a worse overall survival (P <0.05). These results provide new insights to better understand the role of annexin A1 in PDAC survival, and might be relevant to prediction of prognosis and development of more effective therapeutic strategies aimed at improving survival.

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Down-regulation of plasma membranous Annexin A1 protein expression in premalignant and malignant lesions of the oral cavity: correlation with epithelial differentiation

Abstract: Our findings suggest that loss of ANXA1 is frequent and early event during oral carcinogenesis and that ANXA1 could contribute to maintaining epithelial differentiation in OSCC.

Cited by 21 publications

References 30 publications

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

ANXA1 affects cell proliferation, invasion and epithelial‑mesenchymal transition of oral squamous cell carcinoma

Prognostic Significance of Annexin A1 Expression in Pancreatic Ductal Adenocarcinoma

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