Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting SYT13 to Treat Peritoneal Metastasis of Gastric Cancer

Kanda, Mitsuro; Kasahara, Yuuya; Shimizu, Dai; Miwa, Takashi; Umeda, Shinichi; Sawaki, Koichi; Nakamura, Shunsuke; Kodera, Yasuhiro; Obika, Satoshi

doi:10.1016/j.omtn.2020.10.001

Cited by 36 publications

(17 citation statements)

References 43 publications

(25 reference statements)

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“…Patients with peritoneal metastasis of gastric cancer exhibit dismal survival outcomes 24 . In our cohort, ADAR1 up-regulation displayed a significant correlation to depth of invasion, TNM stage as well as peritoneal metastasis, as previously reported 14 .…”

Section: Discussionmentioning

confidence: 99%

Targeting ADAR1 suppresses progression and peritoneal metastasis of gastric cancer through Wnt / β-catenin pathway

Li¹,

Huang²,

Xu³

et al. 2021

J. Cancer

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Objective: Peritoneal metastasis frequently occurs in advanced gastric cancer, which is typically not eligible for radical surgery. Here, this study observed the function and regulatory mechanism of ADAR1 in peritoneal metastasis of gastric cancer. Methods: ADAR1, CALR and β-catenin proteins were detected in normal mucosa, primary gastric cancer, metastatic lymph node and metastatic omentum tissues by immunohistochemistry, western blot, and immunofluorescence. After silencing ADAR1 by siADAR1, the effect and mechanism of ADAR1 on gastric cancer metastasis were observed in nude mouse models of gastric cancer with peritoneal metastasis as well as HGC-27 and AGS gastric cancer cells. Result: Our results showed that ADAR1 was significantly up-regulated in gastric cancer, metastatic lymph node and metastatic omentum tissues. Its up-regulation was significantly correlated to lymph node metastasis and peritoneal metastasis. Silencing ADAR1 significantly reduced the volume of peritoneal metastatic tumors and weakened oncogene CALR expression, Wnt / β-catenin pathway and epithelial-mesenchymal transition (EMT) process in vivo . Furthermore, ADAR1 knockdown distinctly suppressed cell viability, colony formation and migration of HGC-27 and AGS cells and ameliorated the effects of Wnt pathway activator on tumor progression. The similar findings were investigated when treated with ADAR1 inhibitor 8-Azaadenosine. Conclusion: Collectively, this study identified a novel oncogenic function of ADAR1 in peritoneal metastasis of gastric cancer via Wnt / β-catenin pathway. Hence, ADAR1 could be a novel marker and therapeutic target against gastric cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

Targeting ADAR1 suppresses progression and peritoneal metastasis of gastric cancer through Wnt / β-catenin pathway

Li¹,

Huang²,

Xu³

et al. 2021

J. Cancer

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“…As the Syt13-VF mRNA utilizes the Syt13 UTR, it might be possible to use the fusion protein as a sensor to study Syt13 miRNA or antisense oligonucleotide function in silencing Syt13. This is important when aiming to target Syt13 for therapeutic purposes as it has been previously reported [27]. Finally, this novel tool will aid in monitoring Syt13-expressing cells under physiological and pathological conditions in vivo.…”

Section: Pancreatic Endocrine But Not Exocrine Cells Specifically Express Syt13 Proteinmentioning

confidence: 79%

Synaptotagmin-13 Is a Neuroendocrine Marker in Brain, Intestine and Pancreas

Tarquis-Medina

Scheibner

González-García

et al. 2021

IJMS

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Synaptotagmin-13 (Syt13) is an atypical member of the vesicle trafficking synaptotagmin protein family. The expression pattern and the biological function of this Ca2+-independent protein are not well resolved. Here, we have generated a novel Syt13-Venus fusion (Syt13-VF) fluorescence reporter allele to track and isolate tissues and cells expressing Syt13 protein. The reporter allele is regulated by endogenous cis-regulatory elements of Syt13 and the fusion protein follows an identical expression pattern of the endogenous Syt13 protein. The homozygous reporter mice are viable and fertile. We identify the expression of the Syt13-VF reporter in different regions of the brain with high expression in tyrosine hydroxylase (TH)-expressing and oxytocin-producing neuroendocrine cells. Moreover, Syt13-VF is highly restricted to all enteroendocrine cells in the adult intestine that can be traced in live imaging. Finally, Syt13-VF protein is expressed in the pancreatic endocrine lineage, allowing their specific isolation by flow sorting. These findings demonstrate high expression levels of Syt13 in the endocrine lineages in three major organs harboring these secretory cells. Collectively, the Syt13-VF reporter mouse line provides a unique and reliable tool to dissect the spatio-temporal expression pattern of Syt13 and enables isolation of Syt13-expressing cells that will aid in deciphering the molecular functions of this protein in the neuroendocrine system.

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“…In lung adenocarcinoma, SYT13 contributes to cellular proliferation, clonality, and anti-apoptotic effects [11], and in colorectal cancer, silencing SYT13 inhibits tumor growth in mouse models [10]. Our group previously found that intraperitoneal injection of SYT13 siRNA inhibited the peritoneal dissemination of gastric cancer in mouse models, and that SYT13 expression was an independent risk factor for peritoneal recurrence in patients with gastric cancer [9,14]. Despite these previous findings, the significance of SYT13 in BC remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Synaptotagmin 13 Is Highly Expressed in Estrogen Receptor-Positive Breast Cancer

et al. 2021

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Background: Accumulating evidence indicates tumor-promoting roles of synaptotagmin 13 (SYT13) in several cancers; however, no studies have investigated its expression in breast cancer (BC). This study aimed to clarify the significance of SYT13 in BC. Methods: SYT13 mRNA expression levels were evaluated in BC cell lines. Polymerase chain reaction (PCR) array analysis was conducted to determine the correlation between expression levels of SYT13 and other tumor-associated genes. Then, the association of SYT13 expression levels in the clinical BC specimens with patients’ clinicopathological factors was evaluated. These findings were subsequently validated using The Cancer Genome Atlas (TCGA) database. Results: Among 13 BC cell lines, estrogen receptor (ER)-positive cells showed higher SYT13 mRNA levels than ER-negative cells. PCR array analysis revealed positive correlations between SYT13 and several oncogenes predominantly expressed in ER-positive BC, such as estrogen receptor 1, AKT serine/threonine kinase 1, and cyclin-dependent kinases 4. In 165 patients, ER-positive specimens exhibited higher SYT13 mRNA expression levels than ER-negative specimens. The TCGA database analysis confirmed that patients with ER-positive BC expressed higher SYT13 levels than ER-negative patients. Conclusion: This study suggests that SYT13 is highly expressed in ER-positive BC cells and clinical specimens, and there is a positive association of SYT13 with the ER signaling pathways.

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Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting SYT13 to Treat Peritoneal Metastasis of Gastric Cancer

Cited by 36 publications

References 43 publications

Targeting ADAR1 suppresses progression and peritoneal metastasis of gastric cancer through Wnt / β-catenin pathway

Targeting ADAR1 suppresses progression and peritoneal metastasis of gastric cancer through Wnt / β-catenin pathway

Synaptotagmin-13 Is a Neuroendocrine Marker in Brain, Intestine and Pancreas

Synaptotagmin 13 Is Highly Expressed in Estrogen Receptor-Positive Breast Cancer

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