Ribonucleotide reductase large subunit M1 predicts poor survival due to modulation of proliferative and invasive ability of gastric cancer.
OBJECTIVE
We aimed to investigate the prognostic value of RRM1 in GC patients.


METHODS
A 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.


CONCLUSIONS
RRM1 overexpression predicts poor survival in GC patients with advanced TNM stage. RRM1 could potentially serve as prognostic biomarker and therapeutic target for GCs.
Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Qinchuan
Q
Wang
Xiyong
X
Liu
Jichun
J
Zhou
Yasheng
Y
Huang
Shengjie
S
Zhang
Jianguo
J
Shen
Sofia
S
Loera
Xiaoming
X
Yuan
Wenjun
W
Chen
Mei
M
Jin
Stephen
S
Shibata
Yingbin
Y
Liu
Peiguo
P
Chu
Linbo
L
Wang
Yun
Y
Yen
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012189:Retrospective Studies; D012262:Ribonucleoside Diphosphate Reductase; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult; D048490:raf Kinases / Q000378:metabolism
D025521:Tumor Suppressor Proteins; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)