[show abstract][hide abstract] ABSTRACT: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive pediatric malignancies characterized by biallelic inactivation of the SMARCB1 tumor suppressor gene. We searched for novel genomic aberrations by investigating the copy number and expression alterations of let-7a3/let-7b microRNA (miRNA) and correlated these with expression of high-mobility group AT-hook 2 (HMGA2) oncoprotein, a target of let-7 miRNA family, in 18 AT/RT samples to elucidate potential roles of HMGA2 in the pathogenesis of AT/RT.
Genomic aberrations, let-7a3/let-7b miRNA and HMGA2 expression in AT/RT tissues were identified using quantitative PCR, RT-PCR, and immunohistochemistry. The impact of let-7b miRNA on HMGA2 expression and the malignant potential of human rhabdoid tumor cell G401 (SMARCB1-/-) were investigated by antisense inhibition and ectopic overexpression studies.
The copy number of let-7a3/let-7b miRNA was substantially decreased in 4 of 11 AT/RT samples. A significantly inverse correlation between let-7a3/let-7b miRNA expression and HMGA2 mRNA expression was observed in AT/RT tissues (R = -0.34, P < 0.05). Immunohistochemistry analysis demonstrated that HMGA2 was highly overexpressed in 83.3% (15/18) of AT/RT tissues. Restoration of let-7 miRNA or knockdown of HMGA2 expression significantly suppressed proliferation and colony formation, and almost abolished the invasive potential of G401 cells.
Reduction of let-7a3/let-7b miRNA may be one of mechanisms leading to overexpression of HMGA2 in AT/RT tissues. HMGA2 oncoprotein plays critical roles in the pathogenesis of AT/RT development; and reconstitution of let-7 miRNA or knockdown of HMGA2 oncoprotein may provide a novel therapeutic strategy for the treatment of AT/RT patients.
Clinical Cancer Research 01/2014; · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Rare cases of Merkel cell carcinoma have been encountered in lymph nodes with unknown extranodal primary, which exhibit similar morphologic and immunophenotypic features to those in primary cutaneous Merkel cell carcinomas. However, it is uncertain whether the nodal Merkel cell carcinoma is a primary tumor of the lymph node or represents a metastasis from an occult or regressed extranodal lesion. To establish an accurate diagnosis of the nodal Merkel cell carcinoma can be challenging because of significant morphologic mimics, including lymphoblastic lymphoma and metastatic small cell carcinoma. Moreover, there is no consensus for a diagnostic term, and many different terms have been used, which can be confusing and may not fully reflect the nature of nodal Merkel cell carcinoma. In this study, we investigated the detailed clinicopathologic features of 22 nodal Merkel cell carcinomas, with comparison to 763 primary cutaneous cases retrieved from the literature. Overall, the nodal and cutaneous Merkel cell carcinomas shared similar clinical presentations, morphologic spectrum, and immunophenotype; both were mostly seen in elderly male with a typical neuroendocrine morphology. Most of cases expressed CK20, synaptophysin, and chromogranin A; and PAX5 and TdT were also positive in majority of cases. However, nodal Merkel cell carcinomas had a significantly lower association with Merkel cell polyomavirus than cutaneous cases (31% vs 76%, P=0.001). Therefore, these two entities may arise from overlapping but not identical biological pathways. We also recommend the use of the diagnostic term 'Merkel cell carcinoma of lymph node' to replace many other names used.Modern Pathology advance online publication, 10 January 2014; doi:10.1038/modpathol.2013.250.
[show abstract][hide abstract] ABSTRACT: To investigate the prognostic significance of ribonucleotide reductase small subunit M2 (RRM2) in low- and intermediate-risk prostate cancer (PCa).
A retrospective outcome study was conducted on 164 eligible PCa samples from the City of Hope (n = 90) and the Taipei Medical University (n = 74). The RRM2 protein levels were detected by immunohistochemistry. Biochemical recurrence was assessed using Kaplan-Meier and Cox proportional hazard analyses. Cell invasion assays, Ras/Raf, and matrix metallopeptidase 9 activities were determined to evaluate the role of RRM2 on invasiveness of PCa.
Expression of RRM2 was significantly increased in patients with higher Gleason score, who had advanced T stage, and who were margin/capsule positive (P<0.05). Analysis revealed that the expression of RRM2 positively associated with biochemical recurrence of PCa in the City of Hope set (hazard ratio = 5.26; 95% CI 1.50-24.71) and the Taipei Medical University set (hazard ratio = 2.55; 95% CI 1.30-9.22). In stratification analysis, RRM2 was significantly correlated with poor outcome in patients with lower-risk PCa, including those with Gleason score 4 to 7, margin(-), capsule(-), and stage T1-T2. In patients with Gleason score 4 to 7, the risk of recurrence was proportional to RRM2 protein levels. The prognostic performance of RRM2 was superior to that of pathoclinical factors, including margin/capsule status and T stage. An in vitro study demonstrated that RRM2 could promote tumor invasion activities in PCa cell lines. Suppression of RRM2 reduced the Ras/Raf and matrix metallopeptidase 9 activities.
RRM2 plays a critical role in proliferation and invasion of PCa. Adding RRM2 as a biomarker in clinical assessments may increase model precision in predicting recurrence in patients with low-risk PCa.
[show abstract][hide abstract] ABSTRACT: Background
Preclinical studies have demonstrated that low-dose hydroxyurea (HU) enhances the cytotoxic effects of gemcitabine on human cancer cells; however, the combination has not been well studied on patients with recurrent, locally persistent head and neck squamous cell carcinomas (HNSCC). Additionally, the potential biomarkers to predict the response of HNSCC to the regimen remain largely unknown.
Twenty-two HNSCC patients underwent two-day HU (500 mg/m2, day 1 and 8) and gemcitabine (500 mg/m2, day 2 and 9) infusions every 21 days for a median of two (1–12) cycles until disease progression or adverse effects prohibited further therapy. RNA from pre-therapy tissues was subjected to cDNA microarray analysis to identify differentially expressed genes between stable and progressive disease. Validation of selected genes was performed by quantitative RT-PCR and immunohistochemistry.To further investigate the impact of growth arrest and DNA-damage-inducible protein alpha (GADD45α)on cellular sensitivity to the combination of HU and gemcitabine, GADD45α was over expressed in human oropharyngeal carcinoma KB cells.
Ten patients displayed partial remission and/or stable disease, while nine patients displayed progressive disease. The progression free survival for stable disease was 5.88 months and the median overall survival was 12.4 months, while the progression free survival and the median overall survival for all patients were 1.71 and 7.23 months, respectively. A set of 112 genes was differentially expressed between stable and progressive disease. mRNA expression of c-Fos, BCL2/adenovirus E1B 19 kDa-interacting protein 3, paired-like homeodomain 1 and phosphoglycerate kinase 1 was more highly expressed in progressive disease, while mRNA and protein expressin of GADD45α and GADD45γ were significantly decreased in progressive disease in stable disease. Moreover, over expression of GADD45α sensitized KB cells to the combination of HU and gemcitabine.
The combination of HU and gemcitabine may be useful in HNSCC control with reasonable tolerance and toxicity. Based on gene expression profiles, a subset of patients may be potentially identified to gain increased treatment benefits.
Head & Neck Oncology 02/2013; 5(3):25. · 3.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: Immunohistochemical expression of napsin A in primary pulmonary mucinous tumors is not well established. Napsin A immunoreactivity was evaluated in 43 mucin-producing adenocarcinomas of the lung consisting of 18 tumors formerly classified as mucinous bronchioloalveolar carcinoma, 15 colloid adenocarcinomas, 5 solid predominant adenocarcinomas with mucin production, and 5 adenocarcinomas with signet ring cell features, as well as in 25 extrapulmonary mucinous adenocarcinomas of different anatomic sites. Immunohistochemical expression of thyroid transcription factor 1 (TTF-1) was also compared. Thirty-three percent of mucinous lung tumors exhibited positive immunoreactivity for napsin A, whereas 42% expressed TTF-1. All 25 extrapulmonary mucinous adenocarcinomas lacked expression of napsin A and TTF-1. Mucin-producing neoplasms of the lung infrequently express napsin A, suggesting that immunohistochemical assessment of napsin A may have limited diagnostic usefulness for distinguishing primary and metastatic mucinous adenocarcinomas involving the lung.
American Journal of Clinical Pathology 02/2013; 139(2):160-6. · 2.88 Impact Factor
[show abstract][hide abstract] ABSTRACT: The development of resistance against anticancer drugs has been a persistent clinical problem for the treatment of locally advanced malignancies in the head and neck mucosal derived squamous cell carcinoma (HNSCC). Recent evidence indicates that the DNA translesion synthesis (TLS) polymerase η (Pol η; hRad30a gene) reduces the effectiveness of gemcitabine/cisplatin. The goal of this study is to examine the relationship between the expression level of Pol η and the observed resistance against these chemotherapeutic agents in HNSCC, which is currently unknown.
Sixty-four mucosal derived squamous cell carcinomas of head and neck (HNSCC) from 1989 and 2007 at the City of Hope National Medical Center (Duarte, CA) were retrospectively analyzed. Pretreatment samples were immunostained with anti-Pol η antibody and the correlation between the expression level of Pol η and clinical outcomes were evaluated. Forty-nine cases treated with platinum (n=40) or gemcitabine (n=9) based chemotherapy were further examined for Pol η expression level for comparison with patient response to chemotherapy.
The expression of Pol η was elevated in 67% of the head and neck tumor samples. Pol η expression level was significantly higher in grade 1 to grade 2 tumors (well to moderately differentiated). The overall benefit rate (complete response+ partial response) in patients treated with platinum and gemcitabine based chemotherapy was 79.5%, where low Pol η level was significantly associated with high complete response rate (p=0.03), although not associated with overall survival. Furthermore, no significant correlation was observed between Pol η expression level with gender, age, tobacco/alcohol history, tumor stage and metastatic status.
Our data suggest that Pol η expression may be a useful prediction marker for the effectiveness of platinum or gemcitabine based therapy for HNSCC.
PLoS ONE 01/2013; 8(12):e83978. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: We aimed to investigate the prognostic value of RRM1 in GC patients.
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.
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.
RRM1 overexpression predicts poor survival in GC patients with advanced TNM stage. RRM1 could potentially serve as prognostic biomarker and therapeutic target for GCs.
PLoS ONE 01/2013; 8(7):e70191. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Growing evidence indicates that deregulation of microRNAs (miRNAs) contributes to tumorigenesis. Dysregulation of miR-657 has been observed in several types of cancers, but its biological function is still largely unknown. Our results showed that miR-657 expression can be induced by hepatitis viral proteins and is significantly increased in hepatocellular carcinoma (HCC) tissues. Moreover, introduction of miR-657 dramatically increases proliferation and colony formation of HCC cells in vitro and induces tumor development in immunodeficient mice. Further studies showed that miR-657 directly targets the TLE1 3'UTR and activates NF-κB pathways that contribute to hepatocarcinogenesis. This study identified a mechanism whereby of miRNA-657 contributed to HCC through novel cancer pathways, and provides new insights into the potential molecular mechanisms of hepatic carcinogenesis. (HEPATOLOGY 2012.).
[show abstract][hide abstract] ABSTRACT: Aromatase inhibitors (AIs) are important drugs for treating postmenopausal patients with hormone receptor-positive breast cancer. However, acquired resistance to AI therapies is a significant problem. Our study has revealed that the histone deacetylase inhibitor LBH589 treatment abrogated growth of AI-resistant cells in vitro and in vivo, causing cell cycle G2/M arrest and induced apoptosis. LBH589 treatment also reduced the level of NF-κB1 which is overexpressed when AI resistance develops. Analyzing paired tumor specimens from 12 patients, we found that NF-κB1 expression was increased in recurrent AI-resistant tumors as compared to the paired primary tumors before AI treatment. This finding was consistent with up-regulated NF-κB1 expression seen in a collection of well-established AI-resistant cell lines. Furthermore, knockdown of NF-κB1 expression significantly suppressed the proliferation of AI-resistant cells. Treatment of AI-resistant cell lines with LBH589 suppressed NF-κB1 mRNA and protein expression. In addition, LBH589 treatment abrogated growth of AI-resistant tumors in mice, and was associated with significantly decreased levels of NF-κB1 in tumors. In all, our findings strongly support further investigation of LBH589 as a novel therapeutic strategy for patients with AI-resistant breast cancer, in part by suppressing the NF-κB1 pathway.
Breast Cancer Research and Treatment 11/2012; · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: The overexpression of ribonucleotide reductase small subunit M2 (RRM2) dramatically enhances the ability of the cancer cell to proliferate and to invade. To further investigate the relevance of RRM2 and colorectal cancers (CRC), we correlated the expression of RRM2 with the clinical outcome of CRCs. A retrospective outcome study was conducted on CRCs collected from City of Hope National Medical Center (COH, 217 cases) and Zhejiang University (ZJU, 220 cases). The immunohistochemistry (IHC) was employed to determine the protein expression level of RRM2, and the quantitative real-time PCR was employed to validate. Multivariate Logistic analysis indicated that the adjusted odds ratios (ORs) of RRM2-high for distant metastases were 2.06(95% CI 1.01-4.30) and 5.89(95% CI 1.51-39.13) in the COH and ZJU sets respectively. The Kaplan-Meier analysis displayed that highly expression of RRM2 negatively impacted the overall (OS) and progress-free survival (PFS) of CRC in both sets significantly. The multivariate COX analysis further demonstrated that hazard ratios (HRs) of RRM2-high for OS were 1.88(95% CI 1.03-3.36) and 2.06(95% CI 1.10-4.00) in the COH and ZJU set respectively. Stratification analysis demonstrated that the HR of RRM2-high dramatically increased to 12.22(95% CI 1.62-258.31) in MMR-deficient subgroup in COH set. Meanwhile, a real-time study demonstrated that down-regulation of RRM2 by siRNA could significantly and specifically reduce the cell growth and adhesion ability in HT-29 and HCT-8 cells. Therefore, RRM2 is an independent prognostic factor and prognoses poor survival of CRCs. It is also a potential predictor for identifying good responders to chemotherapy for CRCs.
[show abstract][hide abstract] ABSTRACT: Objective
Bronchobiliary fistula (BBF) is abnormal between the bronchial and biliary tree. Misdiagnosis and delayed treatment may have a high mortality rate. Although some characteristics relevant to BBF have been introduced, difficulties and controversies in diagnosis and treatment need further investigation. MethodologyIn this study, we summarize the diagnostic and surgical treatment experience of a 65-year-old male patient who presented with an irritating cough and biliptysis. Since he had the history of aortic valve replacement surgery and schistosomial cirrhosis, the provisional diagnosis was BBF, which might be secondary to a foreign body reaction or liver cirrhosis and chronic cholecystitis and cholelithiasis. ResultsDuring the surgery, it was discovered that the right lobe of liver was significantly atrophied with irregular contours and the gallbladder was adjacent to the diaphragm with a fistula between the fundus of gallbladder and the right semi-diaphragm. These results confirmed that the BBF in this patient resulted from cholelithiasis associated with serious schistosomial cirrhosis. He was successfully treated with a right hepatic lobe resection and Roux-en-Y hepaticojejunostomy. The diaphragm defect was repaired by imbrication of the repaired liver and lower lobe's edges. ConclusionsA high index of clinical suspicion can be generated by patients who present with recurring irritating cough and production of bile-like sputum. The manifestations and responses to conservative treatment are crucial in clinical judgment and surgical intervention is the primary treatment choice when other approaches have failed or there are complications from the underlying disease.
[show abstract][hide abstract] ABSTRACT: Cancer stem cells (CSC) play critical roles in cancer initiation, progression, and therapeutic refractoriness. Although many studies have focused on the genes and pathways involved in stemness, characterization of the factors in the tumor microenvironment that regulate CSCs is lacking. In this study, we investigated the effects of stromal fibroblasts on breast cancer stem cells. We found that compared with normal fibroblasts, primary cancer-associated fibroblasts (CAF) and fibroblasts activated by cocultured breast cancer cells produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem cell-specific, sphere-forming phenotype in breast cancer cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts required STAT3 activation by diverse breast cancer-secreted cytokines, and in turn, induced NOTCH1 expression and the CSC features in breast cancer cells, constituting a cancer-stroma-cancer signaling circuit. In a xenograft model of paired fibroblasts and breast cancer tumor cells, loss of CCL2 significantly inhibited tumorigenesis and NOTCH1 expression. In addition, upregulation of both NOTCH1 and CCL2 was associated with poor differentiation in primary breast cancers, further supporting the observation that NOTCH1 is regulated by CCL2. Our findings therefore suggest that CCL2 represents a potential therapeutic target that can block the cancer-host communication that prompts CSC-mediated disease progression.
Cancer Research 04/2012; 72(11):2768-79. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: RRM2B is the DNA damage-inducible small subunit of ribonucleotide reductase, the rate-limiting enzyme in de novo deoxyribonucleoside triphosphate synthesis. Although RRM2B is implicated in DNA repair and the maintenance of mitochondrial DNA content, the regulation and function of RRM2B in senescence have not been previously established. Here, we show that RRM2B is highly induced in a p53-dependent manner during senescence in primary human fibroblast IMR90 cells and is expressed at higher levels in senescent precancerous human prostatic intraepithelial neoplasm lesions compared to adjacent normal prostate glands. Paradoxically, silencing RRM2B expression leads to an increase in the level of reactive oxygen species, mitochondrial membrane depolarization, and premature senescence in a p38MAPK- and p53-dependent manner in young fibroblasts. Consistently, induction of senescence is accelerated in Rrm2b deficient mouse embryo fibroblasts. Our data demonstrate that RRM2B is induced by stress signals prior to the onset of senescence and prevents premature oxidative stress-induced senescence.
[show abstract][hide abstract] ABSTRACT: Cancer of the parotid gland is relatively rare, but carries poor prognosis owing to its prevailing distant metastases. In addition to the disease's basic epidemiology and pathology, we review some current discoveries of its tumorigenesis molecular mechanism. Based on published salivary gland cancer clinical trial data, non-surgical antitumor efficacies amongst a range of chemotherapy, radiation, and concurrent therapy regimens are compared. We also present the current development status of novel radiation therapy and targeted therapeutics, focusing on intensity-modulated radiation therapy (IMRT), and epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) blockages, which are showing promise for improving parotid gland cancer management.
Head & Neck Oncology 09/2011; 3:40. · 3.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mucinous adenocarcinomas (MAs) of various origins may have a similar histologic appearance and frequently metastasize to distant sites, which often causes diagnostic problems in surgical pathology practice. The immunohistochemical profiles of MAs of various origins have not been well studied. We investigated the expression of 10 immunohistochemical markers (CK7, CK20, CDX-2, β-catenin, MUC-1, MUC-2, MUC-6, ER, WT-1, and PAX-8) in 175 cases of MA, including 69 cases from the lower gastrointestinal (GI) tract, 41 from the upper GI tract, 27 from gynecologic organs, 4 from the urinary bladder, 18 from the breast, and 16 from the lung. We found that lower GI MAs (colon, rectum, and anus) frequently expressed CDX-2 (42 of 42, 100%; 33 of 42 with homogenous positivity, 79%), MUC-2 (42 of 42; 100%), CK20 (41 of 42; 98%), and β-catenin (nuclear) (27 of 42; 64%) and rarely expressed MUC-6 (2 of 42; 5%) and CK7 (8 of 42; 19%). Most of the CK7-positive cases were from the rectum and anus (7 of 8; 88%). The expression of these markers in appendiceal MAs was similar to that of low GI tract MAs, except for a lower percentage of homogenous CDX-2 (3 of 27; 11%) and nuclear β-catenin (3 of 27; 11%) expression. Unlike their lower GI tract counterparts, the upper GI tract MAs (ampulla, pancreas/biliary tree, and stomach/esophagus) frequently expressed CK7 (38 of 41; 93%) and MUC-6 (31 of 41; 76%) and were rarely homogenously positive for CDX-2 (4 of 41; 10%) and nuclear positive for β-catenin (8 of 41; 19%). Breast MAs were frequently positive for CK7 (18 of 18; 100%), MUC-1 (18 of 18; 100%), MUC-2 (18 of 18; 100%), ER (16 of 18; 89%), MUC-6 (9 of 18; 50%), and WT-1 (9 of 18; 50%). Lung MAs were frequently positive for CK7 (16 of 16; 100%) and MUC-1 (15 of 16; 94%). Gynecologic MAs were positive for CK7 (25 of 27; 93%) and PAX-8 (13 of 27; 48%). We conclude that homogenous CDX-2 and nuclear β-catenin expressions are commonly seen in lower GI tract MAs. In contrast, appendiceal MAs are usually heterogenously positive for CDX-2 and show cytoplasmic positivity for β-catenin. Unlike lower GI tract MAs, upper GI tract MAs are frequently positive for CK7 and MUC-6. As is the case in appendiceal MAs, the upper GI tract MAs may also be heterogenously positive for CDX-2. Breast MAs are positive for ER and WT-1, whereas gynecologic MAs are positive for PAX-8 and negative for WT-1.
The American journal of surgical pathology 08/2011; 35(12):1830-6. · 4.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: The distinction of malignant mesothelioma from reactive mesothelial proliferation remains to be a major challenge for surgical pathologists. In this study, we investigated whether insulin-like growth factor II messenger ribonucleic acid-binding protein 3 (IMP3), an oncofetal protein, can be used as a biomarker to distinguish between malignant and reactive mesothelial cells. A total of 109 cases (mesothelioma, n=45; reactive mesothelial proliferation, n=64) were examined by immunohistochemistry for IMP3 expression. IMP3 showed strong cytoplasmic staining in 33 of 45 (73%) mesothelioma cases. In contrast, the expression of IMP3 was undetectable in all (64 cases) benign reactive mesothelial proliferations. Among the IMP3-positive mesotheliomas, 27 (82%) exhibited diffuse IMP3 expression. The vast majority of IMP3-positive subtypes of mesotheliomas showed IMP3 expression in >50% of malignant cells, as this diffuse staining pattern occurred in 17 (81%) cases of epithelial, 4 (100%) cases of sarcomatoid, and 6 (75%) cases of mixed types of mesothelioma. In addition, 2 cases, which were initially diagnosed as atypical mesothelial proliferations and later confirmed to be mesotheliomas, showed diffuse IMP3 expression. Our findings suggest that IMP3 is a new positive biomarker for malignant mesothelioma. IMP3 immunohistochemical staining can be used as an adjunct tool in the distinction of malignant mesothelioma from reactive mesothelial proliferations.
The American journal of surgical pathology 06/2011; 35(6):878-82. · 4.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ribonucleotide reductase subunit RRM2B (p53R2) has been reported to suppress invasion and metastasis in colorectal cancer (CRC). Here, we report that high levels of RRM2B expression are correlated with markedly better survival in CRC patients. In a fluorescence-labeled orthotopic mouse xenograft model, we confirmed that overexpression of RRM2B in nonmetastatic CRC cells prevented lung and/or liver metastasis, relative to control cells that did metastasize. Clinical outcome studies were conducted on a training set with 103 CRCs and a validation set with 220 CRCs. All participants underwent surgery with periodic follow-up to determine survivability. A newly developed specific RRM2B antibody was employed to carry out immunohistochemistry for determining RRM2B expression levels on tissue arrays. In the training set, the Kaplan-Meier and multivariate Cox analysis revealed that RRM2B is associated with better survival of CRCs, especially in stage IV patients (HR = 0.40; 95% CI = 0.18-0.86, P = 0.016). In the validation set, RRM2B was negatively related to tumor invasion (OR = 0.45, 95% CI = 0.19-0.99, P = 0.040) and lymph node involvement (OR = 0.48, 95% CI = 0.25-0.92, P = 0.026). Furthermore, elevated expression of RRM2B was associated with better prognosis in this set as determined by multivariate analyses (HR = 0.48, 95% CI = 0.26-0.91, P = 0.030). Further investigations revealed that RRM2B was correlated with better survival of CRCs with advanced stage III and IV tumors rather than earlier stage I and II tumors. Taken together, our findings establish that RRM2B suppresses invasiveness of cancer cells and that its expression is associated with a better survival prognosis for CRC patients.
Cancer Research 03/2011; 71(9):3202-13. · 8.65 Impact Factor