Chemically Modified Antisense Oligonucleotide Against ARL4C Inhibits Primary and Metastatic Liver Tumor Growth

Harada, Taishi; Matsumoto, Shinji; Hirota, Suguru; Kimura, Hiroyuki; Fujii, Shinsuke; Kasahara, Yuuya; Gon, Hidetoshi; Yoshida, Toshihiko; Itoh, Tomoo; Haraguchi, Naotsugu; Noda, Takehiro; Eguchi, Hidetoshi; Nojima, Satoshi; Morii, Eiichi; Fukumoto, Takumi; Obika, Satoshi; Kikuchi, Akira

doi:10.1158/1535-7163.mct-18-0824

Cited by 44 publications

(50 citation statements)

References 32 publications

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“…When the relationship between IHC staining of ARL4C and prognosis in surgically resected lung cancer patients was evaluated, ARL4C expression in lung adenocarcinoma was inversely correlated with relapse‐free survival. These results are consistent with the analyzed data from GSE datasets of lung cancer and our previous reports on liver cancers and liver tumors that metastasize from colon cancer . Furthermore, multivariate analysis using clinical data in this study identified high ARL4C expression as an independent prognostic factor in relapse‐free survival.…”

Section: Discussionsupporting

confidence: 92%

“…ARL4C represents a molecular target for the treatment of lung, colon and liver cancers, and ARL4C ASO‐1316 is effective in primary and metastatic liver tumors expressing ARL4C . Whether ARL4C ASO‐1316 affects proliferation and migration of lung cancer cells harboring KRAS or EGFR mutations was examined.…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with ARL4C functions, ARL4C expression is associated with progression of tumorigenesis, including colorectal, tongue, liver, gastric, renal cell and ovarian cancers as well as glioblastoma . Therefore, ARL4C may represent a molecular target for the treatment of these cancers.…”

Section: Introductionmentioning

confidence: 83%

“…Small airway epithelial cells stably expressing a dominant‐negative p53, CDK4 and hTERT (kindly provided by Dr RA Weinberg; SAEC‐Triple) were generated using retroviral vectors as previously described . SAEC‐Triple stably expressing ARL4C‐WT, ARL4C G2A , KRAS G12V , or ARL4C‐WT and KRAS G12V were generated using a lentivirus as previously described . A549 and H1975 cells stably expressing GFP or ARL4C‐GFP and stably expressing luciferase (Luc) were generated using a lentivirus as previously described .…”

Section: Methodsmentioning

confidence: 99%

“…The direct injection of ARL4C siRNA into xenograft tumors induced by HCT116 colorectal cancer cells inhibited tumor growth in immunodeficient mice . In addition, subcutaneous injection of an anti–sense oligonucleotide (ASO) against ARL4C (ARL4C ASO‐1316) suppressed liver tumor formation induced by HLE hepatocellular carcinoma cells …”

Section: Introductionmentioning

confidence: 99%

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ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target

et al. 2020

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Lung adenocarcinoma is the most common histological type of lung cancer and is classified into adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA). Atypical adenomatous hyperplasia (AAH) lesions are possible precursors to adenocarcinoma. However, the mechanism underlying the stepwise continuum of lung adenocarcinoma is unclear. In this study, the involvement of ADP‐ribosylation factor (ARF)‐like (ARL) 4C (ARL4C), a member of the small GTP‐binding protein family, in the progression of lung adenocarcinoma and the possibility of ARL4C as a molecular target for lung cancer therapy were explored. ARL4C was frequently expressed in AAH and ARL4C expression in immortalized human small airway epithelial cells promoted cell proliferation and suppressed cell death. In addition, ARL4C was expressed with increased frequency in AIS, MIA and IA in a stage‐dependent manner, and the expression was correlated with histologic grade, fluorine‐18 fluorodeoxyglucose uptake and poor prognosis. An anti–sense oligonucleotide (ASO) against ARL4C (ARL4C ASO‐1316) inhibited RAS‐related C3 botulinum toxin substrate activity and nuclear import of Yes‐associated protein and transcriptional coactivator with PDZ‐binding motif, and suppressed in vitro proliferation and migration of lung cancer cells with KRAS or epidermal growth factor receptor (EGFR) mutations. In addition, transbronchial administration of ARL4C ASO‐1316 suppressed orthotopic tumor formation induced by these cancer cells. Thus, ARL4C is involved in the initiation of the premalignant stage and is associated with the stepwise continuum of lung adenocarcinoma. ARL4C ASO‐1316 would be useful for lung adenocarcinoma patients expressing ARL4C regardless of the KRAS or EGFR mutation.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target

et al. 2020

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RAF1–MEK/ERK pathway‐dependent ARL4C expression promotes ameloblastoma cell proliferation and osteoclast formation

Fujii

Ishibashi

Kokura

et al. 2021

The Journal of Pathology

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Ameloblastoma is an odontogenic neoplasm characterized by slow intraosseous growth with progressive jaw resorption. Recent reports have revealed that ameloblastoma harbours an oncogenic BRAFV600E mutation with mitogenactivated protein kinase (MAPK) pathway activation and described cases of ameloblastoma harbouring a BRAFV600E mutation in which patients were successfully treated with a BRAF inhibitor. Therefore, the MAPK pathway may be involved in the development of ameloblastoma; however, the precise mechanism by which it induces ameloblastoma is unclear. The expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C), induced by a combination of the EGF-MAPK pathway and Wnt/β-catenin signalling, has been shown to induce epithelial morphogenesis. It was also reported that the overexpression of ARL4C, due to alterations in the EGF/RAS-MAPK pathway and Wnt/β-catenin signalling, promotes tumourigenesis. However, the roles of ARL4C in ameloblastoma are unknown. We investigated the involvement of ARL4C in the development of ameloblastoma. In immunohistochemical analyses of tissue specimens obtained from 38 ameloblastoma patients, ARL4C was hardly detected in non-tumour regions but tumours frequently showed strong expression of ARL4C, along with the expression of both BRAFV600E and RAF1 (also known as C-RAF). Loss-of-function experiments using inhibitors or siRNAs revealed that ARL4C elevation depended on the RAF1-MEK/ERK pathway in ameloblastoma cells. It was also shown that the RAF1-ARL4C and BRAFV600E-MEK/ ERK pathways promoted cell proliferation independently. ARL4C-depleted tumour cells (generated by knockdown or knockout) exhibited decreased proliferation and migration capabilities. Finally, when ameloblastoma cells were co-cultured with mouse bone marrow cells and primary osteoblasts, ameloblastoma cells induced osteoclast formation. ARL4C elevation in ameloblastoma further promoted its formation capabilities through the increased RANKL expression of mouse bone marrow cells and/or primary osteoblasts. These results suggest that the RAF1-MEK/ ERK-ARL4C axis, which may function in cooperation with the BRAFV600E-MEK/ERK pathway, promotes ameloblastoma development.

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Bridged Nucleic Acids for Therapeutic Oligonucleotides

Islam

Obika

2022

Handbook of Chemical Biology of Nucleic Acids

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Chemically Modified Antisense Oligonucleotide Against ARL4C Inhibits Primary and Metastatic Liver Tumor Growth

Cited by 44 publications

References 32 publications

ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target

ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target

RAF1–MEK/ERK pathway‐dependent ARL4C expression promotes ameloblastoma cell proliferation and osteoclast formation

Bridged Nucleic Acids for Therapeutic Oligonucleotides

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