Promising therapeutic efficacy of a novel reduced expression in immortalized cells/dickkopf‐3 expressing adenoviral vector for hepatocellular carcinoma

Sawahara, Hiroaki; Shiraha, Hidenori; Uchida, Daisuke; Kato, Hironari; Kato, Ryo; Oyama, Atsushi; Nagahara, Teruya; Iwamuro, Masaya; Horiguchi, Shigeru; Tsutsumi, Keisuke; Mandai, Mari; Mimura, Tetsushige; Wada, Nozomu; Takeuchi, Yasuto; Kuwaki, Kenji; Onishi, Hideki; Nakamura, Shinichiro; Watanabe, Masami; Sakaguchi, Masakiyo; Takaki, Akinobu; Nouso, Kazuhiro; Yagi, T.; Nasu, Yasutomo; Kumon, Hiromi

doi:10.1111/jgh.13757

Cited by 12 publications

(9 citation statements)

References 42 publications

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“…As the 3D spheroid structure mimics the physical and biochemical features of a natural solid tumor mass, it may be similar to cells growing in vivo. Thus, our result suggested that secreted DKK3 may effectively penetrate the tumor mass, resulting in fractional killing, which is consistent with the results of previous reports showing that an adenovirus carrying DKK3 induced apoptosis in bladder, prostate, biliary, and liver cancers [ 34 , 35 , 40 , 41 , 42 ]. Taken together, we believe that DKK3 may be a promising cancer therapeutic for overcoming drug resistance, which may be utilized in various types of biopharmaceutics.…”

Section: Discussionsupporting

confidence: 92%

DKK3, Downregulated in Invasive Epithelial Ovarian Cancer, Is Associated with Chemoresistance and Enhanced Paclitaxel Susceptibility via Inhibition of the β-Catenin-P-Glycoprotein Signaling Pathway

Nguyen

Park

Lee

et al. 2022

Cancers

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Dickkopf-3 (DKK3), a tumor suppressor, is frequently downregulated in various cancers. However, the role of DKK3 in ovarian cancer has not been evaluated. This study aimed to assess aberrant DKK3 expression and its role in epithelial ovarian carcinoma. DKK3 expression was assessed using immunohistochemistry with tissue blocks from 82 patients with invasive carcinoma, and 15 normal, 19 benign, and 10 borderline tumors as controls. Survival data were analyzed using Kaplan–Meier and Cox regression analysis. Paclitaxel-resistant cells were established using TOV-21G and OV-90 cell lines. Protein expression was assessed using Western blotting and immunofluorescence analysis. Cell viability was assessed using the MT assay and 3D-spheroid assay. Cell migration was determined using a migration assay. DKK3 was significantly downregulated in invasive carcinoma compared to that in normal, benign, and borderline tumors. DKK3 loss occurred in 56.1% invasive carcinomas and was significantly associated with disease-free survival and chemoresistance in serous adenocarcinoma. DKK3 was lost in paclitaxel-resistant cells, while β-catenin and P-glycoprotein were upregulated. Exogenous secreted DKK3, incorporated by cells, enhanced anti-tumoral effect and paclitaxel susceptibility in paclitaxel-resistant cells, and reduced the levels of active β-catenin and its downstream P-glycoprotein, suggesting that DKK3 can be used as a therapeutic for targeting paclitaxel-resistant cancer.

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Section: Discussionsupporting

confidence: 92%

DKK3, Downregulated in Invasive Epithelial Ovarian Cancer, Is Associated with Chemoresistance and Enhanced Paclitaxel Susceptibility via Inhibition of the β-Catenin-P-Glycoprotein Signaling Pathway

Nguyen

Park

Lee

et al. 2022

Cancers

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“…DKK3 could induce cellular quiescence in prostate cancer cells through activating the p38MAPK signaling pathway [ 9 ]. Further, it was noted that DKK3 mediated Wnt/β-catenin pathway and thereby suppressed in cellular processes in prostate cancer and hepatocellular carcinoma, incorporating with miRNA [ 10 , 11 ]. However, the role of DKK3 that regulating by LINC00261 in the development of prostate cancer was unknown.…”

Section: Introductionmentioning

confidence: 99%

Long noncoding RNA LINC00261 suppresses prostate cancer tumorigenesis through upregulation of GATA6-mediated DKK3

Wei

2020

Cancer Cell Int

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Background Prostate cancer is one of the leading causes of cancer death in males. Recent studies have reported aberrant expression of lncRNAs in prostate cancer. This study explores the role of LINC00261 in prostate cancer progression. Methods The differentially expressed genes, transcription factors, and lncRNAs related to prostate cancer were predicted by bioinformatics analysis. Prostate cancer tissue samples and cell lines were collected for the determination of the expression of LINC00261 by reverse transcription quantitative polymerase chain reaction. The binding capacity of LINC00261 to the transcription factor GATA6 was detected by RIP, and GATA6 binding to the DKK3 promoter region was assessed by ChIP. In addition, luciferase reporter system was used to verify whether LINC00261 was present at the DKK3 promoter. After gain- and loss-of function approaches, the effect of LINC00261 on prostate cancer in vitro and in vivo was assessed by the determination of cell proliferation, invasion and migration as well as angiogenesis. Results LINC00261, GATA6, and DKK3 were poorly expressed in prostate cancer. LINC00261 could inhibit transcriptional expression of DKK3 by recruiting GATA6. Overexpression of LINC00261 inhibited prostate cancer cells proliferation, migration, and invasion as well as angiogenesis, which could be reversed by silencing DKK3. Furthermore, LINC00261 could also suppress the tumorigenicity of cancer cells in vivo. Conclusions Our study demonstrates the inhibitory role of LINC00261 in prostate cancer progression, providing a novel biomarker for early detection of prostate cancer.

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“…Furthermore, an increasing amount of research has reported that oncolytic adenoviruses are capable of infecting and expressing exogenous functional genes with no target cells. The functional/effector genes can be classified in four categories by their functions: (1) Tumor-suppressor gene (51, 52); (2) Cytotoxic gene; (3) Immune-modulating gene (53); (4) Tumor-antigens (54). The following is the detailed introduction of genes carried by oncolytic adenoviral vectors for HCC treatment.…”

Section: Genetic Modifications Of Oncolytic Adenovirusmentioning

confidence: 99%

Oncolytic Adenovirus—A Nova for Gene-Targeted Oncolytic Viral Therapy in HCC

et al. 2019

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Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide, particularly in China. Despite the development of HCC treatment strategies, the survival rate remains unpleasant. Gene-targeted oncolytic viral therapy (GTOVT) is an emerging treatment modality—a kind of cancer-targeted therapy—which creates viral vectors armed with anti-cancer genes. The adenovirus is a promising agent for GAOVT due to its many advantages. In spite of the oncolytic adenovirus itself, the host immune response is the determining factor for the anti-cancer efficacy. In this review, we have summarized recent developments in oncolytic adenovirus engineering and the development of novel therapeutic genes utilized in HCC treatment. Furthermore, the diversified roles the immune response plays in oncolytic adenovirus therapy and recent attempts to modulate immune responses to enhance the anti-cancer efficacy of oncolytic adenovirus have been discussed.

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Promising therapeutic efficacy of a novel reduced expression in immortalized cells/dickkopf‐3 expressing adenoviral vector for hepatocellular carcinoma

Abstract: Ad-SGE-REIC treatment not only enhanced cell killing effects in vitro but also elicited significant therapeutic effects, with tumor growth suppression, in vivo. REIC/Dkk-3 gene therapy using Ad-SGE-REIC potentially represents an innovative new therapeutic tool for HCC.

Cited by 12 publications

References 42 publications

DKK3, Downregulated in Invasive Epithelial Ovarian Cancer, Is Associated with Chemoresistance and Enhanced Paclitaxel Susceptibility via Inhibition of the β-Catenin-P-Glycoprotein Signaling Pathway

DKK3, Downregulated in Invasive Epithelial Ovarian Cancer, Is Associated with Chemoresistance and Enhanced Paclitaxel Susceptibility via Inhibition of the β-Catenin-P-Glycoprotein Signaling Pathway

Long noncoding RNA LINC00261 suppresses prostate cancer tumorigenesis through upregulation of GATA6-mediated DKK3

Oncolytic Adenovirus—A Nova for Gene-Targeted Oncolytic Viral Therapy in HCC

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