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Tytuł pozycji:

Knockdown of RRM1 with Adenoviral shRNA Vectors to Inhibit Tumor Cell Viability and Increase Chemotherapeutic Sensitivity to Gemcitabine in Bladder Cancer Cells.

Tytuł:
Knockdown of RRM1 with Adenoviral shRNA Vectors to Inhibit Tumor Cell Viability and Increase Chemotherapeutic Sensitivity to Gemcitabine in Bladder Cancer Cells.
Autorzy:
Zhang X; Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Taoka R; Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Liu D; Department of General Thoracic Surgery, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Matsuoka Y; Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Tohi Y; Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Kakehi Y; Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Sugimoto M; Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Źródło:
International journal of molecular sciences [Int J Mol Sci] 2021 Apr 15; Vol. 22 (8). Date of Electronic Publication: 2021 Apr 15.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Original Publication: Basel, Switzerland : MDPI, [2000-
MeSH Terms:
Gene Knockdown Techniques*
Adenoviridae/*genetics
Deoxycytidine/*analogs & derivatives
Genetic Vectors/*metabolism
RNA, Small Interfering/*metabolism
Ribonucleoside Diphosphate Reductase/*metabolism
Urinary Bladder Neoplasms/*drug therapy
Urinary Bladder Neoplasms/*pathology
Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; Cell Survival/drug effects ; Cell Survival/genetics ; Deoxycytidine/pharmacology ; Deoxycytidine/therapeutic use ; Down-Regulation/drug effects ; Down-Regulation/genetics ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Male ; Mice, Inbred BALB C ; Mice, Nude ; Ribonucleoside Diphosphate Reductase/genetics ; Urinary Bladder Neoplasms/genetics ; Xenograft Model Antitumor Assays ; Gemcitabine ; Mice
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Contributed Indexing:
Keywords: RRM1; adenoviral vector; chemotherapeutic sensitivity; gemcitabine; gene therapy; shRNA
Substance Nomenclature:
0 (RNA, Small Interfering)
0W860991D6 (Deoxycytidine)
EC 1.17.4.1 (RRM1 protein, human)
EC 1.17.4.1 (Ribonucleoside Diphosphate Reductase)
0 (Gemcitabine)
Entry Date(s):
Date Created: 20210430 Date Completed: 20210512 Latest Revision: 20240226
Update Code:
20240226
PubMed Central ID:
PMC8071414
DOI:
10.3390/ijms22084102
PMID:
33921102
Czasopismo naukowe
RRM1-an important DNA replication/repair enzyme-is the primary molecular gemcitabine (GEM) target. High RRM1-expression associates with gemcitabine-resistance in various cancers and RRM1 inhibition may provide novel cancer treatment approaches. Our study elucidates how RRM1 inhibition affects cancer cell proliferation and influences gemcitabine-resistant bladder cancer cells. Of nine bladder cancer cell lines investigated, two RRM1 highly expressed cells, 253J and RT112, were selected for further experimentation. An RRM1-targeting shRNA was cloned into adenoviral vector, Ad-shRRM1. Gene and protein expression were investigated using real-time PCR and western blotting. Cell proliferation rate and chemotherapeutic sensitivity to GEM were assessed by MTT assay. A human tumor xenograft model was prepared by implanting RRM1 highly expressed tumors, derived from RT112 cells, in nude mice. Infection with Ad-shRRM1 effectively downregulated RRM1 expression, significantly inhibiting cell growth in both RRM1 highly expressed tumor cells. In vivo, Ad-shRRM1 treatment had pronounced antitumor effects against RRM1 highly expressed tumor xenografts ( p < 0.05). Moreover, combination of Ad-shRRM1 and GEM inhibited cell proliferation in both cell lines significantly more than either treatment individually. Cancer gene therapy using anti-RRM1 shRNA has pronounced antitumor effects against RRM1 highly expressed tumors, and RRM1 inhibition specifically increases bladder cancer cell GEM-sensitivity. Ad-shRRM1/GEM combination therapy may offer new treatment options for patients with GEM-resistant bladder tumors.
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