Ribonucleotide reductase M2 is a promising molecular target for the treatment of oral squamous cell carcinoma

Iwamoto, Kazuki; Nakashiro, Koh‐ichi; Tanaka, Hiroshi; Tokuzen, Norihiko; Hamakawa, Hiroyuki

doi:10.3892/ijo.2015.2912

Cited by 20 publications

(15 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ribonucleotide reductase M2 ( RRM2 ) is the catalytic subunit of ribonucleotide reductase which is an essential enzyme involved in DNA synthesis, and can regulate its enzymatic activity . Several publications have reported that RRM2 was overexpressed in diverse cancer cells .…”

Section: Introductionmentioning

confidence: 99%

DSCAM‐AS1 promotes tumor growth of breast cancer by reducing miR‐204‐5p and up‐regulating RRM2

Liang

Yuan

et al. 2018

Molecular Carcinogenesis

View full text Add to dashboard Cite

Breast cancer (BC) is a common malignancy worldwide. More than 3 700 000 women die of BC every year. DSCAM-AS1 was overexpressed several kinds of cancer and miR-204-5p was lowly expressed, which indicated that miR-204-5p had anti-tumor activity and DSCAM-AS1 had pro-tumor activity. We intended to analyze DSCAM-AS1, miR-204-5p, and ribonucleotide reductase M2 (RRM2). Microarray analysis and quantitative Real Time fluorescence Polymerase Chain Reaction (qRT-PCR) were employed to determine DSCAM-AS1 and miR-204-5p expression. Luciferase reporter assay was applied to examine the target relationship between DSCAM-AS1, miR-204-5p, and RRM2. Cell Counting Kit-8 (CCK-8 assay), transwell assay, and flow cytometry were used to detect cell proliferation, invasion, and apoptosis. The expression of DSCAM-AS1, miR-204-5p, and RRM2 were confirmed by Western blot. We also conducted in vivo assay to verify the effect of DSCAM-AS1. DSCAM-AS1 was up-regulated, while miR-204-5p was down-regulated in BC tissues and cells. DSCAM-AS1 directly targeted miR-204-5p. DSCAM-AS1 promoted the proliferation and invasion of BC cells by reducing miR-204-5p and inhibiting miR-204-5p expression. DSCAM-AS1 expression was related to the expression of RRM2, and miR-204-5p could reverse the function of DSCAM-AS1. RRM2 was up-regulated in BC cells, and miR-204-5p inhibited RRM2 expression by targeting RRM2. Overexpression of RRM2 stimulated proliferation and cell invasion and impeded apoptosis. In vivo experiments showed that knockdown of DSCAM-AS1 decreased the tumorigenesis of BC cells, increased the expression of miR-204-5p. DSCAM-AS1 promoted proliferation and impaired apoptosis of BC cells by reducing miR-204-5p and enhancing RRM2 expression. DSCAM-AS1/miR-204-5p/RRM2 may serve as novel therapeutic targets for BC. K E Y W O R D S Breast cancer, DSCAM-AS1, miR-204-5p, RRM2

show abstract

Section: Introductionmentioning

confidence: 99%

DSCAM‐AS1 promotes tumor growth of breast cancer by reducing miR‐204‐5p and up‐regulating RRM2

Liang

Yuan

et al. 2018

Molecular Carcinogenesis

View full text Add to dashboard Cite

show abstract

“…Moreover, it was reported that CALAA-01, a tumor-targeted nanodrug containing anti-RRM2 siRNA, mediated effective gene silencing in human beings and alleviated the symptom of melanoma 28 . It was also observed that siRNA targeting RRM2 could be used for treating head and neck cancer 29 (including oral squamous cell carcinoma 30 ), ovarian cancer, 31 gastric adenocarcinoma, 32 hepatocellular carcinoma, 33 colorectal cancers, 34 etc. Hence, siRNA against RRM2 displayed versatile anti-tumor activity in various solid tumors.…”

Section: Introductionmentioning

confidence: 99%

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

Zheng

Wang

Weng

et al. 2018

Molecular Therapy - Nucleic Acids

View full text Add to dashboard Cite

Pancreatic cancer is currently one of the deadliest of the solid malignancies, whose incidence and death rates are increasing consistently during the past 30 years. Ribonucleotide reductase (RR) is a rate-limiting enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides, which are essential for DNA synthesis and replication. In this study, 23 small interfering RNAs (siRNAs) against RRM2, the second subunit of RR, were designed and screened, and one of them (termed siRRM2), with high potency and good RNase-resistant capability, was selected. Transfection of siRRM2 into PANC-1, a pancreatic cell line, dramatically repressed the formation of cell colonies by inducing remarkable cell-cycle arrest at S-phase. When combining with doxorubicin (DOX), siRRM2 improved the efficacy 4 times more than applying DOX alone, suggesting a synergistic effect of siRRM2 and DOX. Moreover, the combined application of siRRM2-loaded lipid nanoparticle and DOX significantly suppressed the tumor growth on the PANC-1 xenografted murine model. The inhibition efficiency revealed by tumor weight at the endpoint of the treatment reached more than 40%. Hence, siRRM2 effectively suppressed pancreatic tumor growth alone or synergistically with DOX. This study provides a feasible target gene, a drug-viable siRNA, and a promising therapeutic potential for the treatment of pancreatic cancer.

show abstract

“…We found piR‐39980 regulates expression of RRM2 by binding to its 3′ UTR, which in turn regulates proliferation and metastasis of cancer cells. RRM2 is a prognostic marker and promising molecular target in a list of cancers including colorectal cancer, breast cancer, ovarian cancer, oral squamous cell carcinoma, gastric adenocarcinoma, and Ewing sarcoma, and associated with poor survival of patients. The higher expression of RRM2 induces cancer and contributes to tumor growth, invasion, and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressive activity of PIWI‐interacting RNA in human fibrosarcoma mediated through repression of RRM2

Das

Roy

Jain

et al. 2018

Molecular Carcinogenesis

View full text Add to dashboard Cite

P‐element induced wimpy testis (PIWI)‐interacting RNAs (piRNAs) are a promising class of small regulatory RNAs, earlier believed to control transposable elements (TEs) activity in germlines are now reported in somatic and cancer cells. The aberrant expression of piRNAs has been documented in various cancers wherein they modulate tumorigenesis either as oncogenes or tumor suppressors by curbing target gene expression. However, there is no report yet on the association of piRNAs in fibrosarcoma, an early metastatic lethal tumor. For the first time, we reported a piRNA, piR‐39980 in fibrosarcoma and investigated its potential role in malignancy by employing several methods such as qRT‐PCR, MTT assay, transwell invasion and migration assay, wound healing assay, flow cytometric cell cycle analysis, Annexin V‐PE apoptosis assay, AO/EB dual staining assay, and chromatin condensation assay. We observed that piR‐39980 significantly attenuated proliferation, migration, invasion, and colony forming ability as well as induced apoptotic cell death of HT1080 fibrosarcoma cells when transiently overexpressed with its piRNA mimics. The dual luciferase reporter assay confirmed that piR‐39980 promotes apoptosis and inhibits proliferation in fibrosarcoma by repressing RRM2 through direct targeting at its 3′UTR through extensive sequence complementary binding, unlike microRNA targeting. In summary, this study revealed that piR‐39980 has a strong anti‐tumor effect and hence could be a promising RNA‐based therapeutic agent for the malignancy of fibrosarcoma.

show abstract

Ribonucleotide reductase M2 is a promising molecular target for the treatment of oral squamous cell carcinoma

Cited by 20 publications

References 32 publications

DSCAM‐AS1 promotes tumor growth of breast cancer by reducing miR‐204‐5p and up‐regulating RRM2

DSCAM‐AS1 promotes tumor growth of breast cancer by reducing miR‐204‐5p and up‐regulating RRM2

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

Tumor suppressive activity of PIWI‐interacting RNA in human fibrosarcoma mediated through repression of RRM2

Contact Info

Product

Resources

About