Ribonucleotide Reductase Large Subunit M1 Predicts Poor Survival Due to Modulation of Proliferative and Invasive Ability of Gastric Cancer

Abstract

ObjectivesWe aimed to investigate the prognostic value of RRM1 in GC patients.MethodsA total of assessable 389 GC patients with clinicopathological and survival information were enrolled from City of Hope (COH, n = 67) and Zhejiang University (ZJU, n = 322). RRM1 protein expression was determined by immunohistochemistry on FFPE tissue samples. Kaplan-Meier and Cox analyses were used to measure survival. Ras/Raf activity and invasion assays were used to evaluate the role of RRM1 in GC cell lines.Results In vitro experiments demonstrated RRM1 activated Ras/Raf/MAPK signal transduction and promoted GC cell proliferation. Meanwhile, RRM1 expression was significantly associated with lymph node involvement, tumor size, Ki67 expression, histological subtype and histological grade in the GC tissue samples (p<0.05). Kaplan-Meier analysis illustrated that high RRM1 expression predicted poor survival in GC patients in the COH and ZJU cohorts (log-rank p<0.01). In multivariate Cox analysis, the hazard ratios of RRM1 for overall survival were 2.55 (95% CI 1.27–5.15) and 1.51 (95% CI 1.07–2.13) in the COH and ZJU sets, respectively. In particular, RRM1 specifically predicted the outcome of advanced GCs with poor differentiation and high proliferative ability. Furthermore, inhibition of RRM1 by siRNA significantly reduced the dNTP pool, Ras/Raf and MMP-9 activities and the levels of p-MEK, p-ERK and NF-κB, resulting in growth retardation and reduced invasion in AGS and NCI-N87 cells.ConclusionsRRM1 overexpression predicts poor survival in GC patients with advanced TNM stage. RRM1 could potentially serve as prognostic biomarker and therapeutic target for GCs.

Tumor and serum gamma-glutamyl transpeptidase, new prognostic and molecular interpretation of an old biomarker in gastric cancer

“…To normalize the reaction conditions, all FFPE tissue samples were reassembled into multiple tissue arrays as we previous reported [38]. …”

Nucleotide metabolism, oncogene-induced senescence and cancer

“…Studies have indicated that RRM1 is a tumor suppressor (Figure 2) [65]; therefore, high RRM1 expression is a predictor of better survival [76–78]. In contrast, other studies have found that high RRM1 expression leads to poor survival [78, 79]. In fact, one study found that depending on what treatment patients received, high RRM1 expression was inconclusive for patient prognosis [80].…”

RRM1 *151A>T, RRM1 ‐756T>C, and RRM1 ‐585T>Gis associated with increased susceptibility of lung cancer in Chinese patients

“…Patients with low tumor RRM1 expression assessed using either qRT‐PCR or IHC survived 3.94 months longer (95% CI, 2.15–5.73; P  =   0.001) than those patients with high RRM1 expression. Meanwhile, RRM1 expression has been shown to be a powerful predictor of survival or chemotherapy susceptibility in patients with carcinomas, such as pancreatic cancer 23, advanced nasopharyngeal carcinoma 24, and gastric cancer 25, treated with adjuvant gemcitabine‐based chemotherapy. Since the specimen of core needle biopsies derived from patient tumors are always inconvenient to obtain, and the technologies of immunohistochemical methods, mRNA expression and quantitative in situ protein analyses, are complicated, it is necessary to identify a more generally applicable methodology.…”