A novel liver metastasis-correlated protein of pancreatic neuroendocrine neoplasm (PanNEN) discovered by proteomic analysis

Shimura, Muneaki; Mizuma, Masamichi; Takadate, Tatsuyuki; Katoh, Yohei; Suzuki, Takashi; Iseki, Masahiro; Hata, Tatsuo; Aoki, Shuichi; Suzuki, Yoshihisa; Sakata, Naoaki; Ohtsuka, Hideo; Hayashi, Hiroki; Morikawa, Takanori; Nakagawa, Kazuhiko; Motoi, Fuyuhiko; Naitoh, Takeshi; Igarashi, Kazuhiko; Sasano, Hironobu; Unno, Michiaki

doi:10.18632/oncotarget.25110

Cited by 11 publications

(7 citation statements)

References 42 publications

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“…Lower expression of CNPY2 also activates the p53 pathway and impairs colorectal tumor growth . This is consistent with observations that CNPY2 expression provides a poor prognosis in several cancers including pancreatic neuroendocrine neoplasm, renal cancer, and colorectal cancer …”

Section: Introductionsupporting

confidence: 90%

Characterization of CNPY5 and its family members

et al. 2019

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The Canopy (CNPY) family consists of four members predicted to be soluble proteins localized to the endoplasmic reticulum (ER). They are involved in a wide array of processes, including angiogenesis, cell adhesion, and host defense. CNPYs are thought to do so via regulation of secretory transport of a diverse group of proteins, such as immunoglobulin M, growth factor receptors, toll‐like receptors, and the low‐density lipoprotein receptor. Thus far, a comparative analysis of the mammalian CNPY family is missing. Bioinformatic analysis shows that mammalian CNPYs, except the CNPY1 homolog, have N‐terminal signal sequences and C‐terminal ER‐retention signals and that mammals have an additional member CNPY5, also known as plasma cell‐induced ER protein 1/marginal zone B cell‐specific protein 1. Canopy proteins are particularly homologous in four hydrophobic alpha‐helical regions and contain three conserved disulfide bonds. This sequence signature is characteristic for the saposin‐like superfamily and strongly argues that CNPYs share this common saposin fold. We showed that CNPY2, 3, 4, and 5 (termed CNPYs) localize to the ER. In radioactive pulse‐chase experiments, we found that CNPYs rapidly form disulfide bonds and fold within minutes into their native forms. Disulfide bonds in native CNPYs remain sensitive to low concentrations of dithiothreitol (DTT) suggesting that the cysteine residues forming them are relatively accessible to solutes. Possible roles of CNPYs in the folding of secretory proteins in the ER are discussed.

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Section: Introductionsupporting

confidence: 90%

Characterization of CNPY5 and its family members

et al. 2019

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“…7 Lower expression of CNPY2 also activates the p53 pathway and impairs colorectal tumor growth. 8 This is consistent with observations that CNPY2 expression provides a poor prognosis in several cancers including pancreatic neuroendocrine neoplasm, 9 renal cancer, 10 and colorectal cancer. 11 CNPY3 protein is widely expressed, with highest levels in neurons, the gastrointestinal (GI) tract, and other glandular epithelia.…”

Section: Introductionsupporting

confidence: 90%

Erratum

2020

Protein Science

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The Canopy (CNPY) family consists of four members predicted to be soluble proteins localized to the endoplasmic reticulum (ER). They are involved in a wide array of processes, including angiogenesis, cell adhesion, and host defense. CNPYs are thought to do so via regulation of secretory transport of a diverse group of proteins, such as immunoglobulin M, growth factor receptors, toll-like receptors, and the low-density lipoprotein receptor. Thus far, a comparative analysis of the mammalian CNPY family is missing. Bioinformatic analysis shows that mammalian CNPYs, except the CNPY1 homolog, have N-terminal signal sequences and C-terminal ER-retention signals and that mammals have an additional member CNPY5, also known as plasma cell-induced ER protein 1/marginal zone B cell-specific protein 1. Canopy proteins are particularly homologous in four hydrophobic alpha-helical regions and contain three conserved disulfide bonds. This sequence signature is characteristic for the saposin-like superfamily and strongly argues that CNPYs share this common saposin fold. We showed that CNPY2, 3, 4, and 5 (termed CNPYs) localize to the ER. In radioactive pulse-chase experiments, we found that CNPYs rapidly form disulfide bonds and fold within minutes into their native forms. Disulfide bonds in native CNPYs remain sensitive to low concentrations of dithiothreitol (DTT) suggesting that the cysteine residues forming them are relatively accessible to solutes. Possible roles of CNPYs in the folding of secretory proteins in the ER are discussed.

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“…CNYP2 contributes to angiogenesis and the prevention of hypertrophic cardiomyopathy (7,8). In addition, it modulates DNA replication, cellular invasion, blood vessel development, and metastasis of several malignancies including human prostate cancer, colorectal cancer, and renal cell carcinoma (9)(10)(11)(12). In a recent study, an elevated CNPY2 expression level in NSCLC patients was correlated with poor survival (13).…”

Section: Introductionmentioning

confidence: 99%

miR‑30a‑3p suppresses the proliferation and migration of lung adenocarcinoma cells by downregulating CNPY2

Wang

Kanmangne

et al. 2019

Oncol Rep

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Lung cancer is a leading cause of cancer-related morbidity and mortality worldwide. Although there are currently various therapeutic strategies including surgery, chemotherapy and radiotherapy, lung cancer still results in high mortality with a 5-year survival rate of less than 20%. The increasing need for new therapeutic targets and diagnostic/prognostic tools for lung cancer has promoted the demand for a better molecular and mechanistic understanding of its pathobiology. microRNA-30a-3p (miR-30a-3p) was recently recognized to be closely involved in the regulation of cancer cell invasion, migration and proliferation. However, the mechanistic role of miR-30a-3p in regulating the biological behavior of lung cancer, especially lung adenocarcinoma (LADC), is unknown. In the present study, we aimed to confirm the downregulation of miR-30a-3p in LADC tissues, and validate its functional impact on the pathogenesis of LADC via its molecular target, canopy fibroblast growth factor signaling regulator 2 (CNPY2), a known oncogene. Our data confirmed that CNPY2 was upregulated in LADC tissues, and the expression level of CNPY2 was correlated with the clinical outcomes of lung cancer patients. miR-30a-3p was confirmed as a key negative regulator of CNPY2 and reduced miR-30a-3p expression resulted in CNPY2 upregulation in LADC tissues. We then validated the functional outcome of miR-30a-3p in cancer pathobiology by the overexpression of miR-30a-3p in the LADC EKVX cell line. miR-30a-3p overexpression inhibited cancer cell proliferation, invasion and migration, by suppressing CNPY2 expression. In addition, miR-30a-3p inhibited epithelial-mesenchymal transition, a key feature of LADC, via CNPY2 suppression. Taken together, these findings suggest that miR-30a-3p exerts a novel inhibitory role in the pathogenesis of LADC via CNPY2 downregulation, and the miR-30a-3p/CNPY2 pathway is a potential therapeutic target for human LADC.

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A novel liver metastasis-correlated protein of pancreatic neuroendocrine neoplasm (PanNEN) discovered by proteomic analysis

Cited by 11 publications

References 42 publications

Characterization of CNPY5 and its family members

Characterization of CNPY5 and its family members

Erratum

miR‑30a‑3p suppresses the proliferation and migration of lung adenocarcinoma cells by downregulating CNPY2

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