Nectin-4 expression contributes to tumor proliferation, angiogenesis and patient prognosis in human pancreatic cancer

Nishiwada, Satoshi; Sho, Masayuki; Yasuda, Satoshi; Shimada, Kaoru; Yamato, Ichiro; Akahori, Toshikazu; Kinoshita, Shoichi; Nagai, Minako; Konishi, Noboru; Nakajima, Yoshiyuki

doi:10.1186/s13046-015-0144-7

Cited by 120 publications

(115 citation statements)

References 43 publications

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“…Nectin-4 plays a role in the formation and maintenance of adherens junctions in cooperation with cadherins [24][25][26][27] . Other scholars have revealed that nectin-4 is re-expressed as a tumourassociated antigen with pro-oncogenic properties in various carcinomas [28][29][30]. In our previous study [31] , Nectin-4 is critical for GBC proliferation and invasion via activating PI3K/AKT pathway.…”

Section: Discussion 10mentioning

confidence: 69%

ERRα promotes gallbladder cancer development via activating PI3K/AKT signaling pathway mediated by Nectin-4

Wang

Guo

Yang

et al. 2019

Preprint

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Background: Gallbladder cancer (GBC) is the most common malignant tumour of the bile duct with a poor prognosis. The estrogen-related receptor alpha (ERRα) is a nuclear receptor that has been associated with metabolic processes and cancer progression. Increased ERRα has been shown in endocrine-related cancer and non-endocrine-related cancer. Nevertheless, its role in GBC remains unknown. Methods: ERRα expression was analyzed by immunohistochemistry in 59 GBC samples. Its association with clinicopathologic characteristics was evaluated. The effect of ERRα on GBC cell proliferation and invasion was evaluated by loss- or gain-of-function assays in vitro and in vivo. The influence of ERRα on EMT biomarkers, Nectin-4 and PI3K/AKT signaling pathway was detected by western blotting. Inhibition of Nectin-4 was conducted to explore the potential mechanism of ERRα in GBC. Results: Our study reveals increased ERRα expression in GBC tissues vs. non-tumour adjacent tissues. ERRα expression is significantly positively correlated with high TNM stage, high invasion depth and lymph node metastasis, while negatively associated with prognosis. Targeted depletion of ERRα by lentivirus-mediated shRNA decreased cell proliferation in vitro and in vivo. ERRα promoted cancer cell migration and epithelial-mesenchymal transition by regulating the expression of EMT relevant genes. Ectopic expression of ERRα promoted GBC cell growth and invasion in vitro, while inhibiton of Nectin-4 attenuated cell growth and invasion induced by ERRα. Moreover, ERRα overexpression activated the PI3K/AKT signaling pathway while this effect can be blocked by Nectin-4 depletion. Nectin-4 was involved in the oncogenic function of ERRα to activate PI3K/AKT signaling pathway in GBC. Conclusions: ERRα promotes GBC progression via activating PI3K/AKT signaling pathway mediated by Nectin-4. ERRα may be a potential prognostic factor and molecular therapeutic target for GBC.

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Section: Discussion 10mentioning

confidence: 69%

ERRα promotes gallbladder cancer development via activating PI3K/AKT signaling pathway mediated by Nectin-4

Wang

Guo

Yang

et al. 2019

Preprint

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“…It has been reported that nectin‐4 expression correlated significantly with levels of both ki67 and vascular endothelial growth factor expression, which suggests that nectin‐4 expression contributes to tumor proliferation and angiogenesis . Actually, patients with a high nectin‐4 expression level had a poorer postoperative prognosis than those with low expression in human pancreatic cancer . Therefore, rMV‐SLAMblind is expected to contribute to treatment of malignant cancer.…”

Section: Discussionmentioning

confidence: 99%

“…a). Conversely, it has been reported that nectin‐4 was strongly expressed in 69/123 clinical samples from pancreatic cancer patients . Therefore, rMV‐SLAMblind has the potential to be therapeutically applicable to approximately half of pancreatic cancers.…”

Section: Discussionmentioning

confidence: 99%

“… We examined lung and colon cancer cells, and rMV‐SLAMblind showed an efficient oncolytic activity for those cells expressing nectin‐4 in vitro and in xenografted models . It was also reported that nectin‐4 was overexpressed in pancreatic cancer cells, and that this in turn might contribute to tumor proliferation, angiogenesis, and poor prognosis . From these reports, nectin‐4 is expected to be a potential therapeutic target for intractable cancers as well as being a new cancer cell marker.…”

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confidence: 92%

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Measles virus selectively blind to signaling lymphocyte activity molecule has oncolytic efficacy against nectin‐4‐expressing pancreatic cancer cells

et al. 2016

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Pancreatic cancer is one of the most intractable cancers and has a devastating prognosis; over the past three decades the 5‐year survival rate has been <10%. Therefore, development of a novel anticancer treatment for pancreatic cancer is a matter of urgency. We previously developed an oncolytic recombinant measles virus (MV), rMV‐SLAMblind, that had lost the ability to bind to its principal receptor, signaling lymphocyte activity molecule (SLAM), but which selectively infected and efficiently killed nectin‐4‐expressing breast and lung cancer cells. In this study, we analyzed the antitumor effect of this virus against pancreatic cancer. Nectin‐4 was expressed on the surface of 4/16 tested pancreatic cancer cell lines, which were efficiently infected and killed by rMV‐SLAMblind in vitro. The intratumoral inoculation of rMV‐SLAMblind suppressed the growth of KLM1 and Capan‐2 cells xenografted in SCID mice. The sequence analysis of MV isolated from the tumor revealed that the designed mutation in the H protein of rMV‐SLAMblind had been stably maintained for 47 days after the last inoculation. These results suggest that rMV‐SLAMblind is a promising candidate for the novel treatment of pancreatic cancer.

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“…On the other hand, the expression of nectin-3 is upregulated in lung adenocarcinoma (Maniwa et al 2012) and ovarian, colorectal, and peritoneal endometriotic tissues (Ballester et al 2012). The expression of nectin-4 is upregulated in breast carcinoma tissues (Athanassiadou et al 2011;Fabre-Lafay et al 2005;Pavlova et al 2013), non-small-cell lung cancer tissues (Takano et al 2009), ovarian cancer tissues (Derycke et al 2010), pancreatic cancer tissues (Izumi et al 2015;Nishiwada et al 2015), and eutopic endometrium tissues with endometriosis (Ballester et al 2012). Nectin-2 is involved in cancer immunity by modulating the signaling cascade in certain T cells and NK cells (Pende et al 2005;Stanietsky et al 2009).…”

Section: Cancermentioning

confidence: 99%

Cooperative Roles of Nectins with Cadherins in Physiological and Pathological Processes

Fujiwara

Mizoguchi

Takai

2016

The Cadherin Superfamily

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Mammalian tissues and organs are composed of cells of different types and these cells adhere to one another to form societies of cells including the mesenchyme and the epithelium. Cell-cell adhesion in the mesenchyme is weak whereas cells are organized into closely adherent barrier-forming sheets by cellcell adhesions in the epithelium. Cell-cell adhesion is organized to allow the release or incorporation of individual cells during various physiological or pathological processes, for example, organ development and growth, maintenance and repair of tissues, or tumorigenesis. One prominent cell-cell adhesion apparatus is adherens junctions (AJs). The central structural components of AJs are transmembrane cellcell adhesion molecules, cadherins and nectins. Nectins recruit cadherins to the cell-cell contact sites and mediate cell-cell adhesions that control local membrane dynamics for cell polarization and coordinate shape change at the cellular level. Nectins are engaged in calcium-independent homophilic and heterophilic transinteractions between opposing cells in numerous tissues and cell types to form homotypic and heterotypic cell-cell adhesion, whereas cadherins are primarily involved in calcium-dependent homophilic trans-interactions between opposing cells to form homotypic cell-cell adhesion. Nectins function cooperatively with or independently of cadherins to control physiological processes and cooperative ones include the formation of AJs and apico-basal polarity, apical constriction, contact inhibition of cell movement and proliferation, formation of synapse, formation of checkerboard-like cell arrangement, ciliary epithelium and lens, and

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Nectin-4 expression contributes to tumor proliferation, angiogenesis and patient prognosis in human pancreatic cancer

Cited by 120 publications

References 43 publications

ERRα promotes gallbladder cancer development via activating PI3K/AKT signaling pathway mediated by Nectin-4

ERRα promotes gallbladder cancer development via activating PI3K/AKT signaling pathway mediated by Nectin-4

Measles virus selectively blind to signaling lymphocyte activity molecule has oncolytic efficacy against nectin‐4‐expressing pancreatic cancer cells

Cooperative Roles of Nectins with Cadherins in Physiological and Pathological Processes

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