2p25.1

C2orf48,R2,RR2,RR2M

Pancreatic cancer

Youns and colleagues recently showed that RRM2 is overexpressed in the pancreatic cancer cell lines. They performed a gene expression profiling to identify novel molecular targets modulating the growth inhibitory effects of COX-2 inhibitor NS-398 in pancreatic cancer. They found that RRM2 was down-regulated in BxPC-3, MiaPaCa-2 and ASPC-1 cell lines after treatment with NS-398. Moreover, they identified RRM2 as a biomarker for the chemo-preventive effect of NS-398 in pancreatic cancer cells (Youns et al., 2011). Previous study illustrated that over-expression of RRM2 was associated with resistance to gemcitabine in pancreatic cancer (Nakano et al., 2007). In this study the expression level of RRM2 was analysed by q-PCR in different subclones during the development of acquired resistance to gemcitabine. This analysis showed that the expression level of RRM2 enhanced during the development of gemcitabine resistance. Moreover, they also evaluated the expression levels of other genes, RRM1, dCK, hENT1. This results illustrated that expression ratio significantly correlated with gemcitabine sensitivity in eight pancreatic cancer cell lines, whereas no single gene expression level correlated with the sensitivity, indicating that the sensitivity of pancreatic cancer cells to gemcitabine is dependent on the ratio of four factors involved in gemcitabine transport and metabolism. On the one hand, the ratio of the four gene expression associated with acquired gemcitabine-resistance in pancreatic cancer cells (Nakano et al., 2007). Moreover, Duxbury et al., showed that small interfering RNA targeting RRM2 enhanced chemosensitivity to gemcitabine in pancreatic adenocarcinoma (Duxbury et al., 2004), suggesting its role as an attractive target for pancreatic cancer.

Lung cancer

Several studies have been shown that RRM2 is overexpressed in lung cancer. In particular, Souglakos and colleagues showed that patients with low level of RRM2 had a significantly higher response rate (60% vs 14.2%), time to progression (9.9 vs 2.3 months), and overall survival (15.4 vs 3.6 months) in metastatic lung adenocarcinoma patients treated with gemcitabine plus docetaxel with respect to the patients with high level of RRM2 (Souglakos et al., 2008). Furthermore, Boukovinas et al., evaluated the effect of RRM2 expression on outcome to gemcitabine plus docetaxel in advanced non-small-cell lung cancer (NSCLC) patients. RRM1, RRM2 and BRCA1 mRNA levels were determined by quantitative PCR and correlated with response, time to progression and survival. This study showed that the probability of response decreased (RRM2: Odds Ratio, 0.94; p

Breast cancer

It has been shown that RRM2 is overexpressed in human breast carcinoma tissue (DCIS, Jensen et al., 1994). Recently Kretschmer and colleagues identified molecular markers for the ductal carcinoma in situ using WAP-TNP8 mouse model. In particular, they identified seven marker genes (RRM2, MUC1, SPP1, FOXM1, EXO1, NUSAP1 and DEPDC1), which were overexpressed at a very early stage of premalignancy and preneoplasia of breast carcinomas (Kretschmer et al., 2011).

Ovarian cancer

Ferrandina and colleagues found a association between RRM2 expression level and relative risk of death in ovarian cancer. In this study they evaluated the mRNA expression levels of several genes involved in transportation and metabolism of gemcitabine, including RRM2, in 25 primary ovarian carcinomas using q-PCR. They showed that samples with high RRM2 expression had a less overall survival, OS, (median OS=19 months) with respect to the samples with low RRM2 level (median OS=36 months; Ferrandina et al., 2010).

Fellenberg et al., in 2007 investigated the prognostic value of eight genes including RRM2 in 35 formalin-fixed osteosarcoma biopsies. They observed a significant relation between RRM2 expression with overall survival of the patients. However, the prognostic value of this gene did not confirm by multivariate analysis and further studies are needed to evaluate the prognostic role of RRM2 in osteosarcoma (Fellenberg et al., 2007).

Bladder cancer

Lu and colleagues investigated whether global gene expression profiling can help in predecting the suitability of rodent models of bladder cancer for the detection of cancer-related genes and prediction of cancer prevention in human bladder cancer and carcinogen-induced rodent models. They found that 13~34% of whole genome were differentially expressed between tumor and normal tissues in humans, Fischer-344 rats, and B6D2F1 mice. Approximately 20% of these differentially expressed genes overlapped among species, corresponding to 2.6 to 4.8% of whole genes in the genome. A number of genes were consistently dysregulated in bladder tumors in both humans and rodents. Among these genes, RRM2 was up-regulated in tumor tissue across three species, suggesting its role as a potential factor in contributing to bladder carcinogenesis (Lu et al., 2010).

Hepatocellular carcinoma

Patients with hepatocellular carcinoma (HCC) suffer from chronic hepatitis or liver cirrhosis. Satow and colleagues performed whole-genome RNA interference-based functional screening in order to identify genes that sensitize lung cancer cells to drug and genes required for proliferation and survival of HCC cells. In this study four genes (AKR1B10, HCAP-G, RRM2, and TPX2) were found to be expressed strongly in HCC, suggeting their role as potential therapeutic targets in hepatocellular carcinoma (Satow et al., 2010).

Gastric cancer

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. Moreover, they observed RRM2 overexpression in 72 cases (64.3%), among 112 gastric cancer tissues. 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).

Parkinson disease

The inhibitory effect of dopamine on RRM1/2 has been reported in Parkinson disease. Dopamine inhibits RNR through two pathways: (I) dopamine acts as an effective radical scavenger and scavenge the tyrosyl radical of RRM2, which is important for initiating of catalytic process in RRM1 active site and (II) chelates the iron center of RRM2 which acts as a chelator for iron and other metals. In addition nitric oxide induces dopaminergic neuronal cells through inhibiting RNR (Woldman et al,. 2005; Ebadi and Sharma, 2003).