Yansu Chen

Prognostic and Predictive Role of JWA and XRCC1 Expressions in Gastric Cancer

Purpose: To investigate the expression pattern and significance of DNA repair genes JWA and X-ray repair cross complement group 1 (XRCC1) in gastric cancer. Experimental Design: Expressions of JWA and XRCC1 were assessed by immunohistochemistry in a training cohort and they went into a second testing cohort and finally to a validating cohort. Prognostic and predictive role of JWA and XRCC1 expression status in cases treated with surgery alone or combined with adjuvant chemotherapy was evaluated, respectively. Results: JWA and XRCC1 protein levels were significantly downregulated in gastric cancer lesions compared with adjacent noncancerous tissues. Low tumoral JWA or XRCC1 expression significantly correlated with shorter overall survival (OS), as well as with clinicopathologic characteristics in patients without adjuvant treatment. Multivariate regression analysis showed that low JWA and XRCC1 expressions, separately and together, were independent negative markers of OS. Adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) significantly improved OS compared with surgery alone (log-rank test, P = 0.01). However, this effect was evident only in the JWA or XRCC1 low expression group (HR = 0.44; 95% CI: 0.26–0.73; P = 0.002, and HR = 0.44, 95% CI: 0.26–0.75; P = 0.002, respectively); Adjuvant fluorouracil-leucovorin-platinol (FLP) did not improve OS, except in the patients with low JWA and XRCC1 expressions (P = 0.010 for JWA and 0.024 for XRCC1, respectively). Conclusions: JWA and XRCC1 protein expressions in tumor are novel candidate prognostic markers and predictive factors for benefit from adjuvant platinum-based chemotherapy (FLO or FLP) in resectable human gastric carcinoma. Clin Cancer Res; 18(10); 2987–96. ©2012 AACR.

CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer

Objective CHIP (carboxy terminus of Hsc70 interacting protein) is an E3 ubiquitin ligase that can induce ubiquitination and degradation of several tumour related proteins, and acts as a suppressor of tumour metastasis. This study explored the biological function and clinical significance of CHIP in gastric cancer (GC). Methods The prognostic value of CHIP expression was evaluated using tissue microarray and immunohistochemical staining in two independent human GC cohorts. The role of CHIP on tumorigenicity and angiogenesis was determined in vitro and in vivo. Results CHIP expression was significantly decreased in GC lesions compared with paired non-cancerous tissues. Low tumoral CHIP expression significantly correlated with clinicopathological characteristics in patients, as well as with shorter overall survival in both cohorts. Multivariate Cox regression analysis revealed that CHIP expression was an independent prognostic factor for human GC patients. Moreover, CHIP overexpression impeded the formation of anchorage independent colonies in soft agar, suppressed the growth of xenografts in nude mice and inhibited endothelial cell growth and tube formation by suppressing nuclear factor κB (NF-κB) mediated interleukin 8 (IL-8) expression in vitro. In vivo studies also confirmed that CHIP inhibited blood vessel formation and recruitment of CD31 positive cells in matrigel plugs. Also, CHIP interacted with NF-κB/p65 and promoted its ubiquitination and degradation by proteasome, terminating NF-κB activity and inhibiting IL-8-induced angiogenesis, which correlated with subsequent tumour metastasis. Conclusions Decreased CHIP expression in GC resulted in increased angiogenesis and contributed to GC progression and poor prognosis. CHIP expression is a GC candidate clinical prognostic marker and a putative treatment target.

The Prognostic Value of SOX2 Expression in Non-Small Cell Lung Cancer: A Meta-Analysis

Objective To investigate the association of SOX2 expression in tumor with clinicopathological features and survival of non-small-cell lung carcinoma (NSCLC) patients. Methods Publications assessing the clinicopathological characteristics and prognostic significance of SOX2 in NSCLC were identified up to May 2013. A meta-analysis of eligible studies was performed using standard statistical methods to clarify the association between SOX2 expression and these clinical parameters. Results A total of eight studies met the inclusion criteria. Analysis of these data showed that SOX2 expression was positively associated with squamous histology, (pooled OR = 5.26, 95% CI: 1.08–25.6, P = 0.040). Simultaneously, we also found that SOX2 expression was positively associated with overall survival (pooled HR = 0.65, 95% CI: 0.47–0.89, P = 0.007, random-effect). Conclusions SOX2 expression in tumor is a candidate positive prognostic biomarker for NSCLC patients.

JWA suppresses tumor angiogenesis via Sp1-activated matrix metalloproteinase-2 and its prognostic significance in human gastric cancer

JWA, a multifunctional microtubule-binding protein, plays an important role in regulating tumor metastasis via inhibition of matrix metalloproteinase-2 (MMP-2). Recent investigations suggest that MMP-2 is an angiogenesis-associated molecule. In this study, we provide novel evidence that JWA inhibits tumor angiogenesis in gastric cancer (GC). In two independent retrospective GC cohorts, we found that the expression of JWA was downregulated and that of MMP-2 was upregulated in GC tissues compared with the same in normal gastric mucosa. For patients treated with surgery alone, a strong and independent negative prognostic value was shown for low JWA and high MMP-2 expressions separately, which was even stronger when combined (hazard ratio = 7.75, P < 0.001, in the training cohort; hazard ratio = 2.31, P < 0.001, in the validation cohort). Moreover, we found that loss of JWA expression was strongly correlated with increased GC angiogenesis. In vitro, JWA inhibited MMP-2 at both messenger RNA and protein levels by modulating Sp1 activity. Knockdown of endogenous JWA resulted in enhanced human umbilical vein endothelial cell tube formation and MMP-2 expression. Furthermore, JWA was found to inhibit Sp1 activity via an ubiquitin-proteasome-dependent mechanism and to downregulate the expression of the proangiogenic MMP-2. Our findings imply that JWA and MMP-2 may serve as promising prognostic markers in resectable GC, with JWA as a useful biomarker of angiogenesis in GC and a potential therapeutic target by MMP-2 modulation.

Synergistic Role between p53 and JWA: Prognostic and Predictive Biomarkers in Gastric Cancer

Expression of p53 appears to be correlated to prognosis in patients with malignancy, but its role in gastric carcinoma has remained controversial. Recently we reported that JWA, an ADP-ribosylation-like factor 6 interacting protein 5 (ARL6ip5), was both prognostic for overall survival and predictive for platinum-based treatment of gastric cancer. In this study, we aimed to investigate p53 expression as a prognostic and predictive marker in resectable gastric cancer, alone and in combination with JWA. Expression of p53 was examined in three large patient cohorts (total n = 1155) of gastric cancer. High expression of p53 was significantly correlated with unfavorable clinicopathologic parameters and decreased overall patient survival. Furthermore, patients with high p53 expression in tumors acquired remarkable survival benefit from adjuvant first-line platinum-based-chemotherapy. The synergy between p53 and JWA in predicting patient outcome was demonstrated, while no significantly elevated predictive value concerning chemotherapy was observed. Thus, p53 expression is a potent prognostic and predictive factor for resectable gastric cancer with adjuvant platinum-based chemotherapy. A combined effect of p53 with JWA as efficient prognostic indicators was found for the first time.

MDM2 is a useful prognostic biomarker for resectable gastric cancer

Expression of MDM2 protein appears to be increased in malignancy and correlated to prognosis of tumors, but its role in gastric cancer remains controversial. Our recent investigations indicated that JWA was a novel candidate biomarker for gastric cancer. To evaluate the impact of MDM2 protein expression alone, and in combination with JWA, on the prognostic and predictive of patients with resectable gastric cancer, expression of MDM2 and JWA were examined by immunohistochemistry in three large cohorts (total n = 1131) of patient with gastric cancer. We found that MDM2 protein levels were significantly upregulated in gastric cancer (70.4%, 57 of 81) compared with adjacent non‐cancerous tissues. High tumoral MDM2 expression significantly correlated with clinicopathologic characteristics, as well as with shorter overall survival (OS; P < 0.001 for all cohorts) in patients without adjuvant treatment. The effect of adjuvant fluorouracil–leucovorin–oxaliplatin (FLO) in improving OS compared with surgery alone was evident only in the high MDM2 group (hazard ratio = 0.57; 95% confidence interval, 0.37–0.89; P = 0.013). Furthermore, knockdown of MDM2 and overexpression of JWA had a synergistic effect on suppression of gastric cancer cell proliferation and migration. Patients with low MDM2 and high JWA expression had a better outcome of survival compared with the other groups (P < 0.001 for all cohorts). For the first time, our data suggest that MDM2 is a potent prognostic and predictive factor for benefit from adjuvant fluorouracil–leucovorin–oxaliplatin chemotherapy in resectable gastric cancer. The combination of MDM2 expression and JWA could serve as a more effective candidate prognostic biomarker for gastric cancer.

SOX2 inhibits metastasis in gastric cancer

PurposeTo investigate the potential role of SOX2 in gastric cancer (GC) metastasis.MethodsThe SOX2 expression was detected using immunohistochemistry on a GC tissue microarray. The correlations of SOX2 expression with clinicopathological factors and 5-year survival were evaluated. To test the role of SOX2 in inhibiting GC metastasis, the cell transwell assay was performed. Real-time PCR and Western blot were used to explore the possible mechanism that SOX2 inhibits GC metastasis.ResultsIn the present study, SOX2 expression was downregulated in GC tissues when compared to matching normal tissues. Moreover, patients with high SOX2 expression in cancerous tissues had less lymph node metastasis and better treatment outcome. At the subcellular level, SOX2 inhibited the GC cell migration and invasion by upregulating p21 expression. Moreover, SOX2 was determined to associate with the nuclear p21 expression. GC patients with high SOX2 and nuclear p21 expression had synergistically less lymph node metastasis and the better overall survival.ConclusionOur results suggest that SOX2 is a promising and favorable metastatic biomarker for GC.

The opposite prognostic significance of nuclear and cytoplasmic p21 expression in resectable gastric cancer patients

BackgroundProtein p21Cip1/Waf1 is a cyclin-dependent kinase inhibitor, which plays important roles in cell cycle arrest, senescence, and apoptosis. Interestingly, the nuclear and cytoplasmic p21 executes various functions in the cell. In this study, we investigated the prognostic impact of subcellular p21 expression in gastric cancer (GC).MethodsExpressions of subcellular p21 was assessed by immunohistochemistry using a tissue microarray in a training cohort and it went into a second testing cohort and finally to a validating cohort. Prognostic and predictive role of subcellular p21 expression status was evaluated. We also studied the roles of subcellular p21 in GC cell migration and invasion.ResultsNuclear and cytoplasmic p21 protein levels were significantly reduced and increased in GC lesions compared with adjacent non-cancerous tissues, respectively. Low nuclear p21 or high cytoplasmic p21 expression significantly correlated with shorter overall survival (OS), as well as with clinicopathologic characteristics in patients. Multivariate regression analysis showed that low nuclear and high cytoplasmic p21 expression, separately and together, were independent negative markers of OS. Finally, we found that nuclear p21 inhibits but cytoplasmic p21 promotes cell migration and invasion abilities.ConclusionsThese findings suggest that nuclear and cytoplasmic p21 protein expression in tumor are novel candidate prognostic markers in resectable human gastric carcinoma, and they exert distinct roles in cell migration and invasion.

Allograft inflammatory factor-1 is an independent prognostic indicator that regulates β-catenin in gastric cancer

Previous studies have revealed that expression of allograft inflammatory factor-1 (AIF-1) protein appears to be increased in malignancies and is correlated with a poorer prognosis in cervical cancer, while its role in gastric cancer has not been reported. We analyzed the expression of AIF-1 in 78 cancer lesions and the corresponding non-cancerous tissues by immunohistochemistry. In contrast with other cancers, we found that AIF-1 protein levels were significantly decreased in 53 of the 78 (67.9%) gastric cancer tissues when compared with the matched normal tissues. This was further confirmed using 7 pairs of fresh gastric cancer tissues and matched adjacent normal tissues. Low tumoral AIF-1 expression was significantly correlated with less favorable clinicopathological characteristics, as well as with reduced overall survival (P<0.001) in the gastric cancer patients. Furthermore, knockdown of AIF-1 obviously increased proliferation, migration and β-catenin expression in BGC-823 and SGC-7901 gastric cancer cells. Taken together, for the first time, we provide evidence that the level of AIF-1 expression may serve as a protective prognostic indicator for gastric cancer.