AMACR expression in colorectal cancer is associated with left-sided tumor localization

Alpha-methylacyl-CoA racemase (AMACR) is an enzyme playing an important role in the beta-oxidation of branched-chain fatty acids and fatty acid derivatives. Altered expression levels of AMACR have been described in various cancers including colorectal cancer (CRC). To determine the potential prognostic impact of AMACR expression, we analyzed 1,315 CRC on a tissue microarray (TMA) by immunohistochemistry (IHC). Clinical follow-up data were available from all cancer patients. Positive AMACR staining was observed in 1,074 (81.7%) of the 1,315 cases including 276 cancers with weak (21.0%) and 798 cancers with strong staining (60.7%). AMACR IHC was significantly associated with tumor grade, stage, non-mucinous phenotype, and left-sided tumor localization (p < 0.0001 each). AMACR positivity was observed in 65.8% of cancers from the right-sided colon, in 73.2% of cancers from the colon transversum, in 81.1% of cancers from the colon descendens, and in 88.9% of the distal left-sided cancers (sigma and rectum; p < 0.0001). However, AMACR staining results were unrelated to clinical outcome. It is concluded that AMACR cannot serve as a prognostic marker in CRC. We hypothesize that the association of AMACR expression with tumor localization may be related to differences in the metabolism/exposure to fatty acids occurring along the colon.     

Wnt5A expression is associated with the tumor metastasis and clinical survival in cervical cancer

Aims: To identify the clinical significance of Wnt5A expression in the development and progression of cervical cancer. Methods: Real-time PCR was performed in 8 pairs of surgically resected cervical cancer and adjacent normal cervical tissues. Immunohistochemistry was performed to examine Wnt5A expression in 94 paraffin-embedded cervical cancer samples. Associatio ns of Wnt5A expression with clinicopathological factors and clinical survival were analyzed. Results: Wnt5A expression was overexpressed in cervical cancer tissues compared with adjacent normal cervix. Wnt5A expression tended to be positively correlated with lymph nodes metastasis (P = 0.028) and recurrence (P = 0.009). Moreover, patients with higher Wnt5A expression in cancer tissues had better overall (P = 0.004) and recurrent-free survival (P = 0.012) than those with lower Wnt5A expression. Multivariate analysis revealed that Wnt5A was an independent prognostic factor (P = 0.026) for predicting overall survival of cervical cancer patients. Conclusion: Upregulation of Wnt5A was associated with metastasis and progression of cervical cancer. The results of our study unravel the significance of Wnt/Ca2+ signaling in cervical cancer.     

Loss of ARID1A expression is associated with poor prognosis in non-small cell lung cancer

Adenine-thymine-rich inactive domain-containing protein 1A (ARID1A) is a large subunit of the switch-sucrose nonfermenting (SWI-SNF) complex. ARID1A is considered to be a tumor suppressor in various cancers. We investigated the clinicopathological significance including prognosis of ARID1A expression in non-small cell lung cancer (NSCLC). ARID1A expression was studied by tissue microarray immunohistochemical analysis of 171 surgically resected NSCLC specimens including adenocarcinoma (ADC) and squamous cell carcinoma (SCC) on tissue microarray. Semiquantitative immunohistochemical score was obtained by multiplying the intensity and percentage scores. The overall score was further simplified by dichotomizing into either negative (score < 4) or positive (score ≥ 4) for each patient. The ARID1A-negative group revealed significantly higher correlations with male sex (p = 0.020), larger tumor size (p = 0.007), SCC than with ADC (p = 0.023) and smoking (p = 0.001). Univariate survival analysis showed that the ARID1A-negative group had a significantly shorter cancer specific survival than the ARID1A-positive group (p = 0.018). Multivariate survival analysis showed that ARID1A negativity (p = 0.022) were independent prognostic factors related with shorter cancer specific survival for NSCLC. In conclusion, Loss of ARID1A expression is a potential molecular marker to predictive of poor prognosis of NSCLC.     

MDM2 expression is associated with progress of disease and WAF1 expression in resected lung cancer

Although MDM2, p21/WAF1, and p53 are considered as regulating each other based on in vitro studies, the relation in human lung cancer is not fully understood. The expressions of these proteins were examined immunohistochemically in 112 resected non-small cell lung cancer specimens and the correlation between them were analyzed. MDM2 was expressed in 45% of all lung cancers. In advanced stage, MDM2-positive cases were observed more frequently than in early stage, showing significant difference. No significant difference was observed in the prognosis of the patients regardless of the expression of any protein. Although no correlation was observed between MDM2 expression and p53 expression, or between p21/WAF1 expression and p53 expression, MDM2 expression was strongly related with p21/WAF1 expression. Therefore, MDM2 expression may relate to the progress of the stage of lung cancer, and MDM2 expression and p21/WAF1 expression may be associated not through the p53-related pathway.     

PTEN and Ki67 expression is associated with clinicopathologic features of non-small cell lung cancer

Phosphatase and tensin homolog deleted on chromosome 10（PTEN） and the proliferating antigen Ki67 have been widely studied in several tumors.However,their role as indicator in non-small cell lung cancer（NSCLC）remains unknown.Here,we investigated the expression of PTEN and Ki67 in NSCLC tissues and paired normal lung tissues to identify whether these proteins are associated with lung cancer development and survival.Immunohistochemistry for PTEN and Ki67 was performed on 67 lung cancer tissues and 41 paired adjacent normal lung tissues to detect the expression of these two proteins.The expression of PTEN in NSCLC tissues（32.8%） was significantly lower than that in normal tissues（82.9%,P 〈 0.05）.In contrast,the expression of Ki67 in NSCLC tissues（76.1%） was significantly higher than that in normal tissues（27.3%,P 〈 0.05）.Expression of both PTEN and Ki67 were strongly associated with tumor histology,clinical stage,lymph node metastasis,differentiation and4-year postoperative survival rate（P 〈 0.05）.However,PTEN expression was negatively correlated with Ki67 expression（r =-0.279,P 〈 0.05）.In conclusion,low PTEN expression and Ki67 overexpression are associated with malignant invasion and lymph node metastasis of NSCLC.These proteins may serve as diagnostic and prognostic biomarkers of NSCLC.     

Elevated thymosin beta15 expression is associated with progression and metastasis of non-small cell lung cancer

Thymosin beta15 (Tbeta15) is a small protein that comprises 44 amino acid residues. Tbeta15 is upregulated in malignant human prostate and breast tumors. The expression of Tbeta15 correlates with the metastatic potential of mouse lung cancer and human breast carcinoma cells. However, the correlation of Tbeta15 expression with human lung cancer remains unclear. Using immunohistochemistry and in situ hybridization, we analyzed the expression of Tbeta15 in tumors and tumor-adjacent tissues obtained from 76 patients with non-small cell lung cancer (NSCLC). The relationship between Tbeta15 expression and clinicopathological factors was investigated. Our findings showed that in NSCLC, Tbeta15 protein and mRNA were mainly expressed in the cytoplasm, and their expression correlated with stage (p=0.018 for both), differentiation (p=0.013 and 0.006, respectively), and lymph node metastasis (p=0.001 and 0.009, respectively). Tbeta15 expression was examined in PG-BE1 and PG-LH7 lung cancer cells. We found that both Tbeta15 protein and mRNA were highly expressed in BE1 cells as compared to LH7 cells. After transfecting the PG-LH7 cells with the pEGFP-Tbeta15 plasmid in order to increase Tbeta15 expression, the migration ability of the cells was enhanced. These findings suggest that increased Tbeta15 expression correlates with the progression and metastasis of NSCLC.     

Low CA II expression is associated with tumor aggressiveness and poor prognosis in gastric cancer patients

Background: Carbonic anhydrase II is present in normal gastric mucosa; thus, this study aimed to investigate whether its expression persisted in neoplastic gastric tissues, as well as its prognostic value for gastric cancer patients. Methods: The protein CA II expression pattern was retrospectively analyzed by immunohistochemistry in 181 gastric cancer patients who had undergone gastrectomy. The relationship between the CA II expression level and clinicopathological parameters was investigated. Survival analysis according to CA II expression was measured by Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were used to evaluate the prognostic value of CA II expression. Results: CA II expression was significantly decreased in gastric cancer tissues compared with normal stomach mucosa. Low expression was significantly associated with tumor size, depth of invasion, lymph node involvement, distant metastasis and TNM stage, and it predicted poor survival in gastric cancer patients. Moreover, CA II was an independent prognosis indicator for the overall survival of gastric cancer patients. Conclusions: The down-regulation of CA II expression was observed in gastric cancer and may serve as an independent prognostic factor for the overall survival of gastric cancer patients.     

Aurora C is directly associated with Survivin and required for cytokinesis

Much recent attention has been focused on Aurora C, the third member of the mammalian Aurora kinases family that plays significant roles in mitosis. We report here that using sensitive RT-PCR to amplify the C-terminal, we found that Aurora C is not only expressed highly in testis, but also among 16 other human tissues in a broad-spectrum way. Aurora C, as a chromosomal passenger protein, is co-localized with Aurora B and Survivin in mitotic cells. Aurora C can also be associated with Aurora B and Survivin in vivo and directly binds to Survivin but not Aurora B in vitro. Over-expression of a catalytically inactive mutant of Aurora C impaired the localization of Aurora C to the spindle midzone and severely disturbed the cytokinesis, resulting in multinucleation, all of which are consistent with the results induced by the mutant of Aurora B. Furthermore, we provide evidence that Aurora C could rescue the multinucleate phenotype produced by Aurora B mutant, and vice versa. Overall, these findings demonstrate that Aurora C, a member of the chromosomal passenger complex, is required for cytokinesis.     

Increased expression of microRNA-150 is associated with poor prognosis in non-small cell lung cancer

Objectives: The aim was to evaluate the clinical significance and prognostic value of tissue miR-150 expression in non-small cell lung cancer (NSCLC) patients. Materials and methods: Quantitative real-time PCR was used to analyze the expression of miR-150. Overall survival (OS) was estimated using the Kaplan-Meier method, and the differences in survival were compared using the log-rank test. A Cox proportional hazards model was used for multivariate analysis. Results: Mean miR-150 levels were significantly higher in NSCLC tissues compared with matched non-cancerous tissues (4.07 ± 2.33 vs. 1.00 ± 0.46, P < 0.0001). The level of miR-150 in NSCLC was strongly correlated with lymph node metastasis (P = 0.04), distant metastasis (P = 0.01) and clinical TNM stage (P = 0.02). Kaplan-Meier analysis showed that the cumulative 5-year OS rate was 40.8% in the high expression group, and 69.2% in the low expression group. The log-rank test showed that the OS rate of patients with high miR-150 expression was significantly poorer than that of the remaining cases (P = 0.007). Conclusion: Our data indicated that overexpression of miR-150 in NSCLC tissues has prognostic value.     

High expression of QSOX1 is associated with tumor invasiveness and high grades groups in prostate cancer

Prostate cancer is the most common malignancy in men, and biologically shows highly heterogeneous clinical outcomes, despite early detection. Therefore, the identification of novel molecular markers that are associated with biological aggressiveness is very important for prostatic cancer clinical outcome predictions and treatment choices.Here, we investigate quiescin sulfhydryl oxidase 1 (QSOX1) expression and evaluate its clinicopathological significance and prognostic impact in prostate cancers, with immunohistochemistry on tissue microarrays.QSOX1 over-expression was observed in 12 (11.2%) of prostate cancers. High QSOX1 expression significantly associated with prostate cancer with vascular invasion, neural invasion, extra prostatic extension, higher pT stage, higher pathological tumor stage, higher prognostic grouping, and higher grades groups, but did not associated with worse overall survival. High QSOX1 expression correlates with tumor invasiveness and Gleason grade, reflects aggressive tumor features, and could be an important biomarker and therapeutic target.     

TRIO amplification and abundant mRNA expression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer

Studies by comparative genome hybridization have suggested that 5p amplification is related to tumor progression in urinary bladder cancer. In this study seven genes (TAS2R, ADCY2, DNAH5, CTNND2, TRIO, ANKH, and MYO10) located to 5p15.31-5p15.1 were analyzed by fluorescence in situ hybridization using a tissue microarray containing samples from tumors and cell lines with known 5p amplification by comparative genome hybridization. Amplification frequency was highest for TRIO, which maps to 5p15.2 and encodes a protein with a putative role in cell-cycle regulation. To further investigate the role of TRIO amplification in bladder cancer, a tissue microarray containing samples from 2317 bladder tumors was used for fluorescence in situ hybridization analysis. TRIO amplification was strongly associated with invasive tumor phenotype, high tumor grade, and rapid tumor cell proliferation (Ki67 LI) (P < 0.0001 each). Only 7 of 456 pTaG1/G2 tumors (1.5%) but 62 of 485 pT1-4 carcinomas (12.8%) had TRIO amplification. TRIO amplification was not associated with poor prognosis. Using a frozen bladder tumor tissue microarray RNA in situ hybridization confirmed that TRIO is up-regulated in amplified tumors. It is concluded that TRIO up-regulation through amplification has a potential role in bladder cancer progression.     

Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation and metastasis in gastric cancer

Choi JH, Song YS, Yoon JS, Song KW, Lee YY. Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation and metastasis in gastric cancer. APMIS 2010; 118: 196–202. The enhancer of zeste homolog 2 (EZH2), a member of the polycomb group of proteins, plays an important role in cell proliferation and cell cycle regulation. EZH2 is overexpressed in aggressive forms of prostate, breast, bladder, and endometrial cancers. However, the role of EZH2 expression in gastric cancer has not been fully determined. This study was conducted to investigate the correlation between EZH2 and cell cycle‐related molecules, and the clinical value of EZH2 expression in gastric cancer. We analyzed EZH2 expression using Western blotting in AGS, MKN‐28, SNU‐16, SNU‐484, SNU‐601, and SNU‐638 gastric cancer cell lines. After transfection of EZH2 siRNA into MKN‐28 cells, the change in cell cycle‐related molecules was assessed by Western blot analysis. Expression of EZH2, Ki‐67, and p53 was determined by immunohistochemical staining of tissue microarrays from specimens of 137 cases of resected gastric cancer. We found high expressions of EZH2 in all of the tested gastric cancer cell lines. RNA interference of EZH2 induced upregulation of p53 and HDAC1 and downregulation of cyclin D1 and cyclin E. High EZH2 expression was observed in 60.6% of gastric cancers and in 6.7% of non‐neoplastic gastric tissues (p < 0.01); 40.1% were positive for p53 in gastric cancers. High EZH2 expression was correlated with Ki‐67 and p53 expressions and was significantly associated with distant metastases and non‐signet ring cells. Our results suggest that high EZH2 expression is associated with tumor cell proliferation and metastasis in gastric cancer.     

Loss of raf-1 kinase inhibitor protein expression is associated with tumor progression and metastasis in colorectal cancer

Raf-1 kinase inhibitor protein (RKIP) is known as a critical down-regulator of the mitogen-activated protein kinase signaling pathway and a potential molecular determinant of malignant metastasis. The aim of this study was to determine the prognostic significance of RKIP expression in colorectal cancer (CRC).Immunohistochemical staining for RKIP was performed on a tissue microarray comprising 1,197 mismatch repair (MMR)-proficient and 141 MMRdeficient CRCs. The association of RKIP with clinicopathologic features was analyzed. Loss of cytoplasmic RKIP was associated with distant metastasis (P = .038), higher N stage (P = .032), vascular invasion (P = .01), and worse survival (P = .001) in the MMR-proficient group. In MMR-deficient CRCs, loss of cytoplasmic RKIP was associated with distant metastasis (P = .043) and independently predicted worse survival (P = .004). Methylation analysis of 28 cases showed that loss of RKIP expression is unlikely to be due to promoter methylation.Loss of RKIP expression is a marker of tumor progression and distant metastasis in MMR-proficient and MMR-deficient CRCs.