Expression of ribonucleotide reductase M2 subunit in gastric cancer and effects of RRM2 inhibition in vitro

Morikawa, Teppei; Hino, Rumi; Uozaki, Hiroshi; Maeda, Daichi; Ushiku, Tetsuo; Shinozaki, Aya; Sakatani, Takashi; Fukayama, Masashi

doi:10.1016/j.humpath.2010.06.001

Cited by 68 publications

(57 citation statements)

References 30 publications

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“…RRM2 is known to function as a tumor driver during carcinogenesis and high expressed in esophageal cancer, gastric cancer, colon cancer, and hepatocellular cancer [21][22][23][24][25]. This study also showed that RRM2 was higher expressed in most PTC samples and seemed to be more intensively stained in UTC tissues.…”

Section: Discussionsupporting

confidence: 60%

“…Although RRM2 and RRM2B are 80 % similar in amino acid sequence, they have been found to function differently in human tumors. RRM2 overexpression promotes tumor cell proliferation, and silencing RRM2 expression inhibits cell growth and enhances tumor chemosensitivity to gemcitabine in human tumor cell lines [24,27]. The role of RRM2B in cancers is still controversial.…”

Section: Discussionmentioning

confidence: 99%

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Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma

et al. 2015

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Ribonucleotide reductase (RR) has been reported to be associated with several types of cancer while the expression and role of RR in thyroid carcinoma (TC) has not been investigated. Here, we first examined the expression level of three RR subunit proteins (RRM1, RRM2, and RRM2B) in papillary thyroid carcinoma (PTC) and undifferentiated thyroid carcinoma (UTC) patient samples by immunohistochemistry. The results showed that RRM1 was higher expressed in 95.2 % cancer tissues compared with their adjacent normal tissues in 146 PTC samples. The expression level of RRM1 was positively correlated with T stage, lymph node metastasis (LNM), extrathyroidal invasion (ETI), and TNM stage in PTC patients. However, in 12 UTC samples, RRM1 expression was negatively expressed in six cases. To further determine the biological role of RRM1 in TC, ectopic expression or siRNA-mediated knockdown of RRM1 were carried out in the high-differentiated thyroid carcinoma cell line TPC-1 and the poor-differentiated thyroid carcinoma cell line SW579, respectively. In TPC-1 and SW579 cells, overexpression and siRNA knockdown of RRM1 demonstrated that RRM1 promoted DNA synthesis and proliferation in both cell lines as shown by EdU incorporation and cell viability assays. However, RRM1 enhanced cell migration and invasion in TPC-1 cells but inhibited that in SW579 cells as shown by wound healing and transwell assays. Moreover, we also found that RRM1 promoted PTEN expression and reduced Akt phosphorylation in a RR-activity-independent manner in the low-differentiated TC cells but not in the high-differentiated TC cells. In contrast, RRM2 expression was higher expressed in both PTC and UTC patient samples, consisting with its oncogenic role in other cancers. Therefore, we suggest that RRM1 promotes thyroid carcinoma proliferation as a component of RR but may play a different role in the invasion and metastasis of differently differentiated thyroid carcinomas through a non-RR pathway, which could be meaningful to precision treatment of thyroid carcinoma with RR inhibitors.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma

et al. 2015

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“…In keeping with this finding, a previous analysis of RRM2 genomic sequence and promoter region, including consensus TATA box, three CCAAT boxes, and several GC rich sites, provided the hypothesis of its upregulation in favor of cancer transformation and drug resistance (18). According to a previous study (19), RRM2 overexpression that was significantly associated with Epstein-Barr virus, expression of survivin and DNA methyltransferase 1, predicted poor prognosis in patients with gastric cancer. Collectively, these results provided evidence that RRM2 served as a potential biomarker and therapeutic target for gastric cancer.…”

Section: Discussionmentioning

confidence: 67%

Targeting ribonucleotide reductase M2 subunit by small interfering RNA exerts anti-oncogenic effects in gastric adenocarcinoma

et al. 2014

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Abstract. Ribonucleotide reductase M2 subunit (RRM2) is one of the two subunits of human ribonucleotide reductase which plays a critical role in tumor progression. The aim of the present study was to analyze its expression, clinical significance and biological functions in gastric adenocarcinoma. We observed the upregulation of RRM2 mRNA and protein in all nine gastric cancer cell lines examined. In paired primary gastric cancers, both mRNA and protein levels of RRM2 were significantly upregulated in tumors compared with the corresponding non-tumorous gastric tissues. RRM2 protein expression correlated with higher tumor grade, advanced T stage and poor disease-specific survival. RRM2 knockdown in gastric cancer cell lines AGS, MKN1 and MKN28 significantly suppressed cell proliferation, inhibited monolayer colony formation, reduced cell invasion and induced apoptosis. Downregulation of RRM2 suppressed xenograft formation in vivo. Collectively, these findings suggest that RRM2 plays a crucial role in gastric tumorigenesis and may serve as a potential prognostic marker and therapeutic target in gastric cancer.

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“…Note Morikawa et al, in 2010, explored the prognostic value of RRM2 in 112 gastric cancer samples using immunohistochemistry (Morikawa et al, 2010). They found that RRM2 expression was limited to the neck regions of gastric pits, in normal gastric mucosa.…”

Section: Gastric Cancermentioning

confidence: 99%

“…In vitro analysis and inhibition of RRM2 systhesis by small interfering RNA, inhibited the growth of three gastric cancer cell lines, MKN-1, MKN-7, and SNU-719. Furthermore, they demonstarted that overexpression of RRM2 was associated with the gastric cancer progression and suppression of its function could be considered as a potential therapeutic strategy in gastric cancer (Morikawa et al, 2010).…”

Section: Gastric Cancermentioning

confidence: 99%

RRM2 (ribonucleotide reductase M2)

Afrasiabi¹,

Fiuji²,

Mirhafez³

et al. 2014

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Ribonucleotide reductase subunit M2 (RRM2) is located in chromosome-2 p25-p24, converts ribonucleotides to deoxynucleotides which is required for DNA polymerization and repair. It has been shown that RMM2 plays a key role in DNA synthesis, cell growth, and drug resistance of cancer cells. There is accumulating evidence that alteration in the expression level of RRM2 can have a substantial impact on the biological characteristics of cancer cells, including tumor initiation and progression, suggesting its role as a prognostic factor and a possible therapeutic target for cancer therapy. Therefore, this review highlights several recent and clinically relevant aspects of the expression and function of RRM2 in human cancer.

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Expression of ribonucleotide reductase M2 subunit in gastric cancer and effects of RRM2 inhibition in vitro

Cited by 68 publications

References 30 publications

Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma

Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma

Targeting ribonucleotide reductase M2 subunit by small interfering RNA exerts anti-oncogenic effects in gastric adenocarcinoma

RRM2 (ribonucleotide reductase M2)

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