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1.  Decreased Expression of PTPN12 Correlates with Tumor Recurrence and Poor Survival of Patients with Hepatocellular Carcinoma 
PLoS ONE  2014;9(1):e85592.
Background
Protein tyrosine phosphatase non-receptor type 12 (PTPN12), has been identified as a potent tumor suppressor in human cancers and a critical regulator of cell adhesion and migration. However, the PTPN12 expression and its prognostic significance in HCC have not been well elucidated.
Methodology/Principal Findings
In this study, tissue microarray-based immunohistochemistry (IHC) was investigated in an HCC cohort with adjacent liver tissues as controls. The resulting data were analyzed using receiver operating characteristic curves, Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression modeling. Our results showed that decreased expression of PTPN12 was more frequently observed in HCC tissues compared to the adjacent non-tumorous liver tissues. Further correlation analyses indicated that the decreased PTPN12 expression was closely correlated with tumor recurrence (P = 0.015). Univariate analysis showed a significant association between decreased expression of PTPN12 and adverse cancer-specific survival and recurrence-free survival (P<0.001). In different subsets of overall patients, PTPN12 expression was also a prognostic indicator in patients with stage I/II or stage III/IV (P<0.05). Importantly, multivariate analysis (P<0.05) identified PTPN12 expression in HCC as an independent prognostic factor.
Conclusions/Significance
Our findings provide a basis for the concept that PTPN12 protein expression is frequently decreased or lost in human HCC tissues and that decreased PTPN12 expression may represent an acquired recurrence phenotype of HCC and that PTPN12 expression may act as a biomarker of prognosis for patients with HCC.
doi:10.1371/journal.pone.0085592
PMCID: PMC3901655  PMID: 24475046
2.  Clinicopathological investigation of four cases of desmoplastic small round cell tumor 
Oncology Letters  2012;4(3):423-428.
The purpose of this study was to perform clinicopathological and immunohistochemical analysis and to investigate the Ewing sarcoma gene (EWS)-Wilms' tumor suppressor gene (WT1) fusion within desmoplastic small round cell tumors (DSRCTs). Histology slides and clinical data were reviewed for four patients with DSRCT. A variety of immunohistochemical staining was performed. Fluorescence in situ hybridization (FISH) was performed to detect the EWS-WT1 fusion transcripts resulting from the chromosomal translocation t(11;22)(p13;q12). The patients consisted of four males aged from 26 to 52 years old (mean, 33.5). In three of these patients, the tumors were situated in the abdominal cavity and the tumor from the other patient was located in the pelvic cavity. The tumors were 8–15 cm in diameter (mean tumor diameter, 13), solid and gray-white, with an appearance of nodosity or sublobes, and hemorrhage or necrosis was observed. Microscopically, the tumors consisted of small round cell nests of unequal size. Hyperplastic and thick fibrous connective tissue surrounding the neoplastic cell nests was present in all cases. The tumor nuclei were hyperchromatic and contained inconspicuous nucleoli with a high level of karyokinesis. Immunohistochemical staining revealed diffuse and strong staining for CK, vimentin, desmin and CAM5.2 in all cases. Certain cases also expressed WT-1, EMA, NSE, CD56, CD99 and CK5/6. Staining was negative for myogenin, MyoD1, calretinin, CD117, CD34, HMB45 and CEA. EWS-WT1 fusion transcripts were detected in 3 out of 4 cases, but not in any other tumor types studied as controls using paraffin-embedded tissue by FISH. DSRCT is a highly maligant tumor occuring predominantly in the abdominal or pelvic cavity of young males with multiphenotypic differentiation. Basic morphological features, clinical manifestations and the detection of the EWS-WT1 fusion transcript within the tumor aid the recognition and diagnosis of the tumor.
doi:10.3892/ol.2012.750
PMCID: PMC3673645  PMID: 23741244
desmoplastic small round cell tumor; clinicopathological features; immunophenotype; gene fusion
3.  Accumulation of p62 is associated with poor prognosis in patients with triple-negative breast cancer 
OncoTargets and therapy  2013;6:883-888.
Background
Triple-negative breast cancer (TNBC) is associated with poor prognosis. There is an urgent need for elucidation of novel targets for TNBC therapy and to improve the prognosis of patients. The aim of this study was to evaluate the prognostic value of p62 expression in TNBC.
Methods and results
Expression of p62 in tissue microarray was evaluated by immunohistochemistry in 163 patients with TNBC. The prognostic value of p62 expression was assessed by a Cox regression model adjusted for clinical characteristics. Overexpression of p62 was observed in 51 (31.3%) of 163 TNBC, and significantly correlated with advanced stage and a higher proportion of positive lymph nodes and lymphovascular invasion. A significant correlation was found between p62 expression and disease-free survival and overall survival. Accordingly, the 10-year distant metastasis-free survival for p62-overexpression and p62-underexpression patients were 58.9% and 92.5%, respectively (P<0.0001). Multivariate analysis indicated that p62-negative was a significant independent prognostic factor of disease-free survival (P=0.017), but not for overall survival (P=0.845) in all patients.
Conclusion
Our results suggest that overexpression of p62 in TNBC is associated with a higher risk of distant metastases. This finding could open new avenues for the development of novel therapy strategies for TNBC.
doi:10.2147/OTT.S46222
PMCID: PMC3722135  PMID: 23888115
triple-negative breast cancer; p62; prognosis; tissue microarrays
4.  Overexpression of Cystatin SN positively affects survival of patients with surgically resected esophageal squamous cell carcinoma 
BMC Surgery  2013;13:15.
Background
Cystatin SN is a secreted protein and a cysteine proteinase inhibitor. It has been considered to be a tumor marker for gastrointestinal tract cancer in several functional researches. However, the clinicopathological and prognostic significance of Cystatin SN expression in esophageal squamous cell carcinoma (ESCC) has not been elucidated.
Methods
In our study, the expression of Cystatin SN was detected in 209 surgically resected ESCC tissues and 170 peritumoral normal esophageal mucosae by immunohistochemistry. The prognostic significance of Cystatin SN expression was analysed with Kaplan-Meier plots and the Cox proportional hazards regression models.
Results
The results showed that the immunostaining of Cystatin SN in ESCC tissues was less intense than that in the normal control tissue (P < 0.001). Compared with patients with low tumoral Cystatin SN expression, ESCC patients with tumors high-expression Cystatin SN exhibited increased disease-free survival (DFS) and overall survival (OS) (P < 0.001 and P < 0.001, respectively). Furthermore, the expression level of Cystatin SN could further stratify the ESCC patients by survival (DFS and OS) in the stage II subgroup (P < 0.001 and P < 0.001, respectively). Multivariate analyses showed that Cystatin SN expression, N status and differentiation were independent and significant predictors of survival.
Conclusions
We concluded that ESCC patients whose tumors express high levels of Cystatin SN have favourable survival compared with those patients with low Cystatin SN expression. Tumoral Cystatin SN expression may be an independent predictor of survival for patients with resectable ESCCs.
doi:10.1186/1471-2482-13-15
PMCID: PMC3699386  PMID: 23711283
Esophageal squamous cell carcinoma; Cystatin SN; Immunohistochemistry; Prognosis
5.  VEGF-c expression in an in vivo model of orthotopic endometrial cancer and retroperitoneal lymph node metastasis 
Background
Retroperitoneal lymph node (RLN) metastasis is an important indicator of endometrial cancer (EC) prognosis. Because vascular endothelial growth factor c (VEGF-c) is known to influence lymphangiogenesis and thereby lymph node metastasis, this study assessed the relationship of VEGF-c mRNA expression with RLN metastasis in EC.
Methods
The uterine muscularis mucosae of New Zealand white rabbits were inoculated with a VX2 tumor cell suspension after which they were sacrificed at 15, 18, 21, 24, 27 and 30 days. Control groups consisted of those receiving no treatment or an injection of saline. EC and metastatic RLN tissues along with peripheral blood samples were collected, and VEGF-c mRNA expression was evaluated using fluorescence real-time quantitative PCR.
Results
The establishment of an in vivo model of EC with complete RLN metastasis was pathologically confirmed at day 21 post-injection with VX2 cells. As compared to the control groups, VEGF-c mRNA expression increased significantly over time in the tumor site, RLN, and peripheral white blood cells of EC rabbits. Significantly higher VEGF-c mRNA expression was observed in metastatic RLNs as compared to those without metastasis (P < 0.001). In addition, increased VEGF-c mRNA expression was observed in peripheral white blood cells of rabbits with RLN metastasis (P < 0.002).
Conclusion
Injection of a VX2 cell suspension is a simple method of establishing an in vivo EC model. VEGF-c may play an important role in the development of EC and its metastasis to RLN and may be useful marker to predict RLN metastasis.
doi:10.1186/1477-7827-11-49
PMCID: PMC3672014  PMID: 23693075
Vascular endothelial growth factor c; Endometrial cancer; Fluorescence real-time quantitative PCR; Disease animal model; Animal; Rabbit
6.  Prognostic analysis of early-stage squamous cell carcinoma of the vulva 
Aim
The aim of this study was to analyze prognostic factors of early-stage squamous cell carcinoma of the vulva.
Methods
A retrospective analysis was conducted on 35 patients who were treated for early-stage squamous cell carcinoma of the vulva at Sun Yat-sen University Cancer Center from January 1980 to December 2005. The Statistical Package for Social Science (SPSS) was used to compare the different strategies of operation and to analyze the prognostic factors.
Results
Thirty-five patients had early-stage squamous cell carcinoma of the vulva. Of these cases, 26 were well differentiated, seven were moderately differentiated, and two were poorly differentiated. The five-year survival rate was 77.1%. Five cases were in FIGO stage 1a and 30 cases were in stage 1b; median survival times were 182.3 months and 152.5 months, and the five-year survival rates were 100% and 81.5% (P >0.05), respectively. The five-year survival of the patients who underwent local excision; radical vulvectomy and en bloc resection of inguinofemoral lymphadenectomy; orradical vulvectomyen bloc resection of inguinofemoral lymphadenectomy, and pelvic lymph nodes was 50%, 81.8%, and 83.9%, respectively. For these cases, 74.3% of the tumors were medial while 25.7% were lateral, and the five-year survival rates of patients according to tumor location were 87.0% and 64.8% (P <0.05), respectively. The inguinal lymph node not increased and active were 16 cases (45.7%), and increased, active and hard were 17 cases (48.6%), and syncretic were two cases (5.7%), five-year survival rates were 73.3%, 92.9% and 50% (P <0.05), respectively. Of these cases, 74.3% of the tumors were cauliflower-like and 25.7% were nodular; five-year survival rates by tumor type were 91.3% and 66.7% (P <0.05), respectively.
Conclusions
For patients with early-stage squamous cell carcinoma of the vulva, surgical operation is the primary, yet the best, treatment. The related prognostic factors were tumor location (lateral/medial), stage, gross morphology, and clinical state of the inguinal lymph node.
doi:10.1186/1477-7819-11-20
PMCID: PMC3579684  PMID: 23351240
Vulvar squamous cell carcinoma; Surgical; Prognosis
7.  Comparison of Clinical Features and Treatment Outcome of Breast Cancers in Young and Elderly Chinese Patients 
Breast Care  2011;6(6):435-440.
Background
This study aimed to investigate the clinicopathological features and prognosis of operable breast cancers in young and elderly Chinese women.
Patients and Methods
This study included 209 patients aged ≤35 years and 213 patients aged ≥60 but <70 years, who received treatment between January 2000 and December 2004. The clinicopathological features, molecular subtypes, therapeutic strategies, and prognosis were evaluated.
Results
Tumor size was of significant difference between the 2 groups (p = 0.018), with more T2 and T3 tumors in the young group and more lymph node involvement in young patients with stage T1 tumors (p = 0.033). There were more triple-negative and less luminal A tumors in the young group (p = 0.018). 47.1% of tumors were not detected by mammography in the young group as compared to 5.5% in the elderly group (p < 0.001). More patients received chemotherapy in the young group (p < 0.001) and preferred breast-conserving surgery (p = 0.031). The 6-year disease-free survival (DFS) was 80 and 66% in the elderly and the young group, respectively (p = 0.001), but no difference was seen in overall survival.
Conclusions
Compared with elderly women, young breast cancer patients have different clinicopathological features and molecular subtypes, and poorer DFS. Furthermore, the insidious onset of breast cancer in young women suggests that clinicians should pay more attention to young women with breast abnormalities.
doi:10.1159/000332593
PMCID: PMC3290008  PMID: 22419896
Breast; cancer; Molecular subtypes; Prognostic features; Very young women; Elderly women
8.  High expression levels of COX-2 and P300 are associated with unfavorable survival in laryngeal squamous cell carcinoma 
In order to provide a basis for clinical treatment decisions, we explored whether there was a correlation between the expression of COX-2 and P300 and clinical factors in a group of patients with laryngeal squamous cell carcinoma (LSCC). A retrospective analysis of clinicopathological data was conducted in 80 patients with LSCC who presented between January 1997 and December 1998. An immunohistochemistry tissue microarray was conducted of 80 surgically resected LSCC and 20 adjacent normal tissue specimens. Survival analysis and Kaplan–Meier curves were used to compare the effects of clinicopathological factors on survival. The Cox model was applied for multivariate analysis. The expression level of COX-2/P300 in LSCC tissues and adjacent normal tissues were 47.5/50.0 versus 0.0/15.0 %. The expression of COX-2 and P300 was correlated with higher T category, N category, clinical staging, histological grade and recurrence (P < 0.05). P300 expression was correlated with COX-2 expression (P < 0.05). Univariate survival analysis showed that P300, COX-2, N category, clinical staging and recurrence factors were closely correlated with unfavorable survival (P < 0.05). Multivariate analysis showed that COX-2 expression, histological grade and recurrence were independent prognostic factors for LSCC. High expression levels of COX-2 and P300 indicated poor survival outcomes for patients with LSCC.
doi:10.1007/s00405-012-2275-1
PMCID: PMC3580132  PMID: 23179937
Laryngeal squamous cell carcinoma (LSCC); Prognosis; Survival; P300; COX-2
9.  Skp2 expression unfavorably impacts survival in resectable esophageal squamous cell carcinoma 
Background
The correlation of S-phase kinase–associated protein 2 (Skp2) with metastasis and prognosis in esophageal squamous cell carcinoma (ESCC) is controversial. The purpose of this study was to explore whether there was a correlation between the expression of Skp2 evaluated by immunohistochemistry and the clinical outcome of patients with operable ESCC, and to further determine the possible mechanism of the impact of Skp2 on survival.
Methods
Tissue microarrays that included 157 surgically resected ESCC specimens was successfully generated for immunohistochemical evaluation. The clinical/prognostic significance of Skp2 expression was analyzed. Kaplan-Meier analysis was used to compare the postoperative survival between groups. The prognostic impact of clinicopathologic variables and Skp2 expression was evaluated using a Cox proportional hazards model. A cell proliferation assay and a colony formation assay were performed in ESCC cell lines to determine the function of Skp2 on the progression of ESCC in vitro.
Results
Skp2 expression correlated closely with the T category (p = 0.035) and the pathological tumor-node-metastasis (TNM) stage (p = 0.027). High expression of Skp2 was associated with poor overall survival in resectable ESCC (p = 0.01). The multivariate Cox regression analysis demonstrated that pathological T category, pathological N category, cell differentiation, and negative Skp2 expression were independent factors for better overall survival. In vitro assays of ESCC cell lines demonstrated that Skp2 promoted the proliferative and colony-forming capacity of ESCCs.
Conclusions
Negative Skp2 expression in primary resected ESCC is an independent factor for better survival. Skp2 may play a pro-proliferative role in ESCC cells.
doi:10.1186/1479-5876-10-73
PMCID: PMC3356230  PMID: 22533738
Esophageal surgery; Skp2; Statistics; Survival analysis
10.  Overexpression of ZEB2 in Peritumoral Liver Tissue Correlates with Favorable Survival after Curative Resection of Hepatocellular Carcinoma 
PLoS ONE  2012;7(2):e32838.
Background
ZEB2 has been suggested to mediate EMT and disease aggressiveness in several types of human cancers. However, the expression patterns of ZEB2 in hepatocellular carcinoma (HCC) and its effect on prognosis of HCC patients treated with hepatectomy are unclear.
Methodology/Principal Findings
In this study, the methods of tissue microarray and immunohistochemistry (IHC) were utilized to investigate ZEB2 expression in HCC and peritumoral liver tissue (PLT). Receiver operating characteristic (ROC), spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. Up-regulated expression of cytoplasmic/nuclear ZEB2 protein was observed in the majority of PLTs, when compared to HCCs. Further analysis showed that overexpression of cytoplasmic ZEB2 in HCCs was inversely correlated with AFP level, tumor size and differentiation (P<0.05). Also, overexpression of cytoplasmic ZEB2 in PLTs correlated with lower AFP level (P<0.05). In univariate survival analysis, a significant association between overexpression of cytoplasmic ZEB2 by HCCs/PLTs and longer patients' survival was found (P<0.05). Importantly, cytoplasmic ZEB2 expression in PLTs was evaluated as an independent prognostic factor in multivariate analysis (P<0.05). Consequently, a new clinicopathologic prognostic model with cytoplasmic ZEB2 expression (including HCCs and PLTs) was constructed. The model could significantly stratify risk (low, intermediate and high) for overall survival (P = 0.002).
Conclusions/Significance
Our findings provide a basis for the concept that cytoplasmic ZEB2 expressed by PLTs can predict the postoperative survival of patients with HCC. The combined cytoplasmic ZEB2 prognostic model may become a useful tool for identifying patients with different clinical outcomes.
doi:10.1371/journal.pone.0032838
PMCID: PMC3290607  PMID: 22393452
11.  Intraparenchymal papillary meningioma of brainstem: case report and literature review 
Both intraparenchymal papillary meningioma and papillary meningioma with cyst formation of brainstem have never been reported. The authors present an extremely rare case of patient with intraparenchymal papillary meningioma of brainstem. A 23-year-old Chinese male presented with a 4-month history of progressive left upper limb and facial nerve palsy. Magnetic resonance imaging revealed a cystic-solid, heterogeneously enhancing mass in pons and right cerebral peduncle with no dural attachment. The tumor was totally removed via subtemporal approach. During surgery, the lesion was found to be completely intraparenchymal. Histological and immunohistochemical examinations were compatible with the diagnosis of papillary meningioma. The lesion recurred nine months after primary surgery, a second surgery followed by radiotherapy was performed. Till to now (nearly 2 years after the treatment), the patient is tumor free survival. Intraparenchymal meningioma of brainstem with cystic formation is very rare, however, it should be considered as a differential diagnosis of a brainstem neoplasm. The present case strongly recommended that postoperative radiotherapy was essential for the patients with papillary meningiomas.
doi:10.1186/1477-7819-10-10
PMCID: PMC3268097  PMID: 22236763
Meningioma; Papillary; Brain stem; Intraparenchymal; Cyst
12.  Prognosticators and Risk Grouping in Patients with Lung Metastasis from Nasopharyngeal Carcinoma: A more accurate and appropriate assessment of prognosis 
Background
Lung metastases arising from nasopharyngeal carcinomas (NPC) have a relatively favourable prognosis. The purpose of this study was to identify the prognostic factors and to establish a risk grouping in patients with lung metastases from NPC.
Methods
A total of 198 patients who developed lung metastases from NPC after primary therapy were retrospectively recruited from January 1982 to December 2000. Univariate and multivariate analyses of clinical variables were performed using Cox proportional hazards regression models. Actuarial survival rates were plotted against time using the Kaplan-Meier method, and log-rank testing was used to compare the differences between the curves.
Results
The median overall survival (OS) period and the lung metastasis survival (LMS) period were 51.5 and 20.9 months, respectively. After univariate and multivariate analyses of the clinical variables, age, T classification, N classification, site of metastases, secondary metastases and disease-free interval (DFI) correlated with OS, whereas age, VCA-IgA titre, number of metastases and secondary metastases were related to LMS. The prognoses of the low- (score 0-1), intermediate- (score 2-3) and high-risk (score 4-8) subsets based on these factors were significantly different. The 3-, 5- and 10-year survival rates of the low-, intermediate- and high-risk subsets, respectively (P < 0.001) were as follows: 77.3%, 60% and 59%; 52.3%, 30% and 27.8%; and 20.5%, 7% and 0%.
Conclusions
In this study, clinical variables provided prognostic indicators of survival in NPC patients with lung metastases. Risk subsets would help in a more accurate assessment of a patient's prognosis in the clinical setting and could facilitate the establishment of patient-tailored medical strategies and supports.
doi:10.1186/1748-717X-6-104
PMCID: PMC3179719  PMID: 21871101
lung metastasis; nasopharyngeal carcinoma; prognosis; risk subset
13.  High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma 
Background
It has been suggested that p300 participates in the regulation of a wide range of cell biological processes and mutation of p300 has been identified in certain types of human cancers. However, the expression dynamics of p300 in hepatocellular carcinoma (HCC) and its clinical/prognostic significance are unclear.
Methods
In this study, the methods of reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry (IHC) were utilized to investigate protein/mRNA expression of p300 in HCCs. Receiver operating characteristic (ROC) curve analysis, spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data.
Results
Up-regulated expression of p300 mRNA and protein was observed in the majority of HCCs by RT-PCR and Western blotting, when compared with their adjacent non-malignant liver tissues. According to the ROC curves, the cutoff score for p300 high expression was defined when more than 60% of the tumor cells were positively stained. High expression of p300 was examined in 60/123 (48.8%) of HCCs and in 8/123 (6.5%) of adjacent non-malignant liver tissues. High expression of p300 was correlated with higher AFP level, larger tumor size, multiplicity, poorer differentiation and later stage (P < 0.05). In univariate survival analysis, a significant association between overexpression of p300 and shortened patients' survival was found (P = 0.001). In different subsets of HCC patients, p300 expression was also a prognostic indicator in patients with stage II (P = 0.007) and stage III (P = 0.011). Importantly, p300 expression was evaluated as an independent prognostic factor in multivariate analysis (P = 0.021). Consequently, a new clinicopathologic prognostic model with three poor prognostic factors (p300 expression, AFP level and vascular invasion) was constructed. The model could significantly stratify risk (low, intermediate and high) for overall survival (P < 0.0001).
Conclusions
Our findings provide a basis for the concept that high expression of p300 in HCC may be important in the acquisition of an aggressive phenotype, suggesting that p300 overexpression, as examined by IHC, is an independent biomarker for poor prognosis of patients with HCC. The combined clinicopathologic prognostic model may become a useful tool for identifying HCC patients with different clinical outcomes.
doi:10.1186/1479-5876-9-5
PMCID: PMC3022728  PMID: 21205329
14.  High Expression of H3K27me3 in Human Hepatocellular Carcinomas Correlates Closely with Vascular Invasion and Predicts Worse Prognosis in Patients 
Molecular Medicine  2010;17(1-2):12-20.
It has been suggested that trimethylation of lysine 27 on histone H3 (H3K27me3) is a crucial epigenetic process in tumorigenesis. However, the expression dynamics of H3K27me3 and its clinicopathological/prognostic significance in hepatocellular carcinoma (HCC) are unclear. In this study, immunohistochemical analysis (IHC) was used to examine protein expression of H3K27me3 in HCC tissues from two independent cohorts and corresponding nontumorous hepatocellular tissues by tissue microarray. The optimal cutpoint of H3K27me3 expression was assessed by the X-tile program. Our results showed that the cutpoint for high expression of H3K27me3 in HCCs was determined when more than 70% of the tumor cells showed positive staining. High expression of H3K27me3 was observed in 134 of 212 (63.2%) and 76 of 126 (60.4%) of HCCs in the testing and validation cohorts, respectively. Correlation analysis demonstrated that high expression of H3K27me3 in HCCs was significantly correlated with large tumor size, multiplicity, poor differentiation, advanced clinical stage and vascular invasion (P < 0.05). In addition, high expression of H3K27me3 in HCC patients was associated closely with shortened survival time, independent of serum α-fetoprotein levels, tumor size and multiplicity, clinical stage, vascular invasion and relapse as evidenced by univariate and multivariate analysis in both cohorts (P < 0.05). In different subsets of HCC patients, H3K27me3 expression was also a prognostic indicator in patients with stage II tumors (P < 0.05). Thus, these findings provide evidence that a high expression of H3K27me3, as detected by IHC, correlates closely with vascular invasion of HCCs and is an independent molecular marker for poor prognosis in patients with HCC.
doi:10.2119/molmed.2010.00103
PMCID: PMC3022987  PMID: 20844838
15.  DNA polymeraseη protein expression predicts treatment response and survival of metastatic gastric adenocarcinoma patients treated with oxaliplatin-based chemotherapy 
Background
DNA polymerase η (pol η) is capable of bypassing DNA adducts produced by cisplatin or oxaliplatin and is associated with cellular tolerance to platinum. Previous studies showed that defective pol η resulted in enhanced cisplatin or oxaliplatin sensitivity in some cell lines. The purpose of the present study was to investigate the role of pol η protein expression in metastatic gastric adenocarcinoma.
Methods
Four gastric adenocarcinoma cell lines were chosen to explore the relationship between pol η protein expression and oxaliplatin sensitivity by western blotting and MTT assay. Eighty metastatic gastric adenocarcinoma patients treated with FOLFOX or XELOX regimen as first-line chemotherapy were analyzed, corresponding pretreatment formalin-fixed paraffin-embedded tumor tissues were used to detect pol η protein expression by immunohistochemistry. Relationship between pol η protein expression and clinical features and outcome of these patients was analyzed.
Results
A positive linear relationship between pol η protein expression and 48 h IC50 values of oxaliplatin in four gastric cancer cell lines was observed. Positivity of pol η protein expression was strongly associated with poor treatment response, as well as shorter survival at both univariate (8 versus 14 months; P < 0.001) and multivariate (hazard ratio, 4.555; 95% confidence interval, 2.461-8.429; P < 0.001) analysis in eighty metastatic gastric adenocarcinoma patients.
Conclusions
Our study indicates that polη is a predictive factor of treatment response and survival of metastatic gastric adenocarcinoma patients treated with FOLFOX or XELOX as first-line chemotherapy. Therefore confirming the value of polη in studies with prospective design is mandatory.
doi:10.1186/1479-5876-8-126
PMCID: PMC3003639  PMID: 21110884
16.  Assessment of Early Tumor Response to Cytotoxic Chemotherapy with Dynamic Contrast-Enhanced Ultrasound in Human Breast Cancer Xenografts 
PLoS ONE  2013;8(3):e58274.
There is a strong need to assess early tumor response to chemotherapy in order to avoid adverse effects from unnecessary chemotherapy and allow early transition to second-line therapy. This study was to quantify tumor perfusion changes with dynamic contrast-enhanced ultrasound (CEUS) in the evaluation of early tumor response to cytotoxic chemotherapy. Sixty nude mice bearing with MCF-7 breast cancer were administrated with either adriamycin or sterile saline. CEUS was performed on days 0, 2, 4 and 6 of the treatment, in which time-signal intensity (SI) curves were obtained from the intratumoral and depth-matched liver parenchyma. Four perfusion parameters including peak enhancement (PE), area under the curve of wash-in (WiAUC), wash-in rate (WiR) and wash-in perfusion index (WiPI) were calculated from perfusion curves and normalized with respect to perfusion of adjacent liver parenchyma. Histopathological analysis was conducted to evaluate tumor perfusion, tumor cell density, microvascular density (MVD) and proliferating cell density. Significant decreases of tumor normalized perfusion parameters (i.e., nPE, nWiAUC, nWiR and nWiPI) were noticed between adriamycin-treated and control groups (P<0.01) 2 days after therapy. There were significant differences of tumor volumes between control and treated groups on day 6 (P<0.001) while there were no significant differences in tumor volume on days 0, 2 and 4 (P>0.05). Significant decreases of tumor perfusion, tumor cell density, MVD and proliferating cell density were seen in adrianycin-treated group 2 days after therapy when compared to control group (P<0.001). Dynamic CEUS for quantification of tumor perfusion could be used for early detection of cancer response to cytotoxic chemotherapy prior to notable tumor shrinkage.
doi:10.1371/journal.pone.0058274
PMCID: PMC3585723  PMID: 23469274
17.  High Expression of GOLPH3 in Esophageal Squamous Cell Carcinoma Correlates with Poor Prognosis 
PLoS ONE  2012;7(10):e45622.
Background
Whether the expression of Golgi phosphoprotein 3 (GOLPH3) correlates with esophageal cancer tumorigenesis is currently unclear. The aim of this study was to examine GOLPH3 expression in patients with esophageal squamous cell cancer (ESCC) and explore its clinical significance.
Methods
Differences in the expression of GOLPH3 at the mRNA and protein level were examined via quantitative reverse transcriptase PCR and western blotting, respectively. GOLPH3 expression levels in ESCC tissue were determined through immunohistochemistry, and were compared in accordance with specific clinicopathological features of the patients and tissue specimens. Factors associated with patient survival were also analyzed.
Results
A notably higher level of GOLPH3 expression was found in ESCC cell lines and tissues at both mRNA and protein levels. High expression of GOLPH3 in ESCC patients was positively associated with clinical stage, TNM classification, histological differentiation and vital status (all P<0.0001). Expression of GOLPH3 was found to be an independent prognostic factor in ESCC patients. ESCC patients expressing high levels of GOLPH3 exhibited a substantially lower 5-year overall survival than GOLPH3-negative patients. Furthermore, a significant correlation between high GOLPH3 expression and shorter overall survival time was found in different subgroups of ESCC patients stratified by the clinical stage, T classification, and lymph node metastasis.
Conclusions
Experiments demonstrated potential involvement of GOLPH3 in the development, differentiation, and tumorigenesis of ESCC, and concludes the possibility of its use as a diagnostic and prognostic marker in patients with ESCC.
doi:10.1371/journal.pone.0045622
PMCID: PMC3462781  PMID: 23056210
18.  Overexpression of Karyopherin 2 in Human Ovarian Malignant Germ Cell Tumor Correlates with Poor Prognosis 
PLoS ONE  2012;7(9):e42992.
Background
The aim of this study was to identify a biomarker useful in the diagnosis and therapy of ovarian malignant germ cell tumor (OMGCT).
Methods
The karyopherin 2 (KPNA2) expression in OMGCT and normal ovarian tissue was determined by standard gene microarray assays, and further validated by a quantitative RT-PCR and immunohistochemistry. The correlation between KPNA2 expression in OMGCT and certain clinicopathological features were analyzed. Expression of SALL4, a stem cell marker, was also examined in comparison with KPNA2.
Results
KPNA2 was found to be over-expressed by approximately eight-fold in yolk sac tumors and immature teratomas compared to normal ovarian tissue by microarray assays. Overexpression was detected in yolk sac tumors, immature teratomas, dysgerminomas, embryonal carcinomas, mature teratomas with malignant transformation and mixed ovarian germ cell tumors at both the transcription and translation levels. A positive correlation between KPNA2 and SALL4 expression at both the transcription level (R = 0.5120, P = 0.0125), and the translation level (R = 0.6636, P<0.0001), was presented. Extensive expression of KPNA2 was positively associated with pathologic type, recurrence and uncontrolled, ascitic fluid presence, suboptimal cytoreductive surgery necessity, resistance/refraction to initial chemotherapy, HCG level and SALL4 level in OMGCT patients. KPNA2 was found to be an independent factor for 5-year disease-free survival (DFS) of OMGCT (P = 0.02). The 5-year overall survival (OS) and DFS rate for KPNA2-low expression patients (88% and 79%, n = 48) were significantly higher than the OS and DFS rate for KPNA2-high expression patients (69% and 57.1%, n = 42)(P = 0.0151, P = 0.0109, respectively). The 5-year OS and DFS rate for SALL4-low expression patients (84% and 74%, n = 62) was marginally significantly higher than the high expression patients (78.6% and 71.4%, n = 28)(P = 0.0519, P = 0.0647, respectively).
Conclusions
KPNA2 is a potential candidate molecular marker and important prognostic marker in OMGCT patients.
doi:10.1371/journal.pone.0042992
PMCID: PMC3433466  PMID: 22962582

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