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Background Human papillomavirus (HPV) E6/E7 mRNA in situ hybridization (HPV E6/E7 RNAscope) appears to be a sensitive and specific technique in detecting transcriptionally active HPV. We aimed to examine the diagnostic utility of this technique in endocervical adenocarcinoma (ECA), to explore the prognostic factors for ECA patients and develop a clinically useful nomogram based on clinicopathological parameters to predict it. Methods We retrospectively analyzed 200 patients with ECA who had undergone surgery at Sun Yat-sen University Cancer Center from 2010 and 2014. The diagnostic performance of HPV E6/E7 RNAscope were evaluated by receiver operating characteristic (ROC) curve. A prognostic nomogram model including HPV E6/E7 RNAscope was generated based on multivariate Cox regression analysis, then we compared the predictive accuracy of the prognostic model with FIGO staging and treatment using concordance index (C-index), time-dependent ROC (tdROC), and decision curve analysis (DCA). Results The sensitivity and specificity of HPV E6/E7 RNAscope for distinguishing HPV-associated adenocarcinoma (HPVA) from non-HPV-associated adenocarcinoma (NHPVA) in the whole cohort were 75.8% and 80%, respectively. According the univariate analysis and multivariate logistic regression analysis, age, lymphovascular invasion (LVI), lymph node involvement (LNI), and HPV E6/E7 RNAscope were valuable predictive factors for OS. These parameters were incorporated into the nomogram model (nomogram A) compared with FIGO stage and treatment. The C-index of nomogram A for predicting OS was 0.825, which was significantly higher than FIGO stage (C-index = 0.653, p = 0.002) and treatment (C-index = 0.578, p Conclusions HPV E6/E7 RNAscope is highly specific for ECA, and the 4-variable nomogram showed more accurate prognostic outcomes in patients with ECA.

RNA-binding proteins (RBPs) play crucial roles in the post-transcriptional regulation of mRNA during numerous physiological and pathological processes, including tumor genesis and development. However, the role of RNA-binding motif protein 43 (RBM43) in esophageal squamous cell carcinoma (ESCC) has not been reported so far. The current study was the first to evaluate RBM43 protein expression by immunohistochemistry (IHC) in an independent cohort of 207 patients with ESCC, to explore its potential prognostic value and clinical relevance in ESCC. The results indicated that RBM43 protein levels were significantly elevated in ESCC tissues and increased RBM43 expression was associated with age and N categories. In addition, ESCC patients with high expression of RBM43 had shorter overall survival (OS) and disease‐free survival (DFS) than those with low RBM43 expression. Furthermore, when survival analyses were conducted at different clinical stages, overexpression of RBM43 was significantly correlated with shortened survival in patients with ESCC at early stages (TNM stage I–II and N0 stage). Cox regression analysis further proved that high RBM43 expression was an independent predictor of poor prognosis in ESCC patients. In conclusion, increased expression of RBM43 is correlated with malignant attributes to ESCC and predicts unfavorable prognosis, suggesting an effective prognostic biomarker and potential therapeutic target for ESCC.

The “macrotrabecular-massive” (MTM) pattern of hepatocellular carcinoma (HCC) has been suggested to represent a distinct HCC subtype and is associated with specific molecular features. Since the immune microenvironment is heterogenous in HCC, it is important to evaluate the immune microenvironment of this novel variant. CMTM6, a key regulator of PD-L1, is an important immunocheckpoint inhibitor. This study aimed to evaluate the prognostic effect of CMTM6/PD-L1 coexpression and its relationship with inflammatory cells in HCC. We analyzed 619 HCC patients and tumors were classified into MTM and non-MTM HCC subtypes. The expression levels of CMTM6 and PD-L1 in tumor and inflammatory cells were evaluated by immunohistochemistry. The density of inflammatory cells in the cancer cell nest was calculated. Tumoral PD-L1 expression and inflammatory cell density were higher in the MTM type than in the non-MTM type. CMTM6-high expression was significantly associated with shorter OS and DFS than CMTM6-low expression in the whole HCC patient population and the MTM HCC patient population. Moreover, MTM HCC patients with CMTM6/PD-L1 coexpression experienced a higher risk of HCC progression and death. In addition, CMTM6/PD-L1 coexpression was shown to be related to a high density of inflammatory cells. Notably, a new immune classification, based on CMTM6/PD-L1 coexpression and inflammatory cells, successfully stratified OS and DFS in MTM HCC. CMTM6/PD-L1 coexpression has an adverse effect on the prognosis of HCC patients, especially MTM HCC patients. Our study provides evidence for the combination of immune status assessment with anti-CMTM6 and anti-PD-L1 therapy in MTM HCC patients. Electronic supplementary material The online version of this article (10.1007/s00262-020-02691-9) contains supplementary material, which is available to authorized users.

Background Endocervical adenocarcinoma (ECA) is further classified as human papillomavirus (HPV)-associated (HPVA) or non-HPVA (NHPVA), per the International Endocervical Adenocarcinoma Criteria and Classification (IECC). HPVA is a glandular tumor with stromal invasion and/or exophytic expansile-type invasion, associated with the typical molecular characteristics of high-risk HPV (HR-HPV) infection. Transforming acidic coiled-coil protein-3 (TACC3),an oncogene that is frequently abnormally expressed,represents a vital biomarker for multiple human malignancies. This study aimed to examine the role of TACC3 in the diagnosis and prognosis of ECA. Methods We analyzed 264 patients with ECA who underwent surgical resection, classifying their tumors into HPVA and NHPVA subtypes. The expression levels of TACC3, P16, MLH1, PMS2, MSH2, MSH6 and Ki-67 in tumors were evaluated by tissue microarray using immunohistochemistry (IHC). HPV subtypes were identified in formalin-fixed paraffin-embedded (FFPE) ECA tissues by the polymerase chain reaction (PCR). Results ECA samples showed increased TACC3 expression relative to adjacent non-carcinoma samples. TACC3 expression was higher in HPVA than in NHPA. In the HPVA subtype, high TACC3 expression was significantly correlated with P16-positive, Ki-67-high expression. Furthermore, TACC3 levels were significantly related to tumor histological type (P = 0.006), nerve invasion (P = 0.003), differentiation (P = 0.004), surgical margin (P = 0.012), parametrium invasion (P = 0.040), P16 expression (P P = 0.004). Additionally, Kaplan–Meier analysis showed that TACC3 upregulation was associated with poor overall survival (OS, P = 0.001), disease-free survival (DFS, P P Conclusions Taken together, our findings identify that TACC3 is a promising complementary biomarker for diagnosis and prognosis for patients with ECA.

Small cell neuroendocrine carcinoma of the uterine cervix (SCNEC) is a rare cancer involving the human papilloma virus (HPV), and has few available treatments. The present work aimed to assess the feasibility of SOX2 and HPV statuses as predictive indicators of SCNEC prognosis.The associations of SOX2 and/or high-risk (HR)-HPV RNA in situ hybridization (RISH) levels with clinicopathological characteristics and prognostic outcomes for 88 neuroendocrine carcinoma (NEC) cases were analyzed.Among these patients with SCNEC, SOX2, P16Overall, the results of the present study suggest that the co-expression of SOX2 with HR-HPV RISH in SCNEC may represent a specific subgroup exhibiting remarkably poorer prognostic outcomes compared with the expression of any one marker alone.

Background Small cell neuroendocrine carcinoma of the uterine cervix (SCNEC) is a rare cancer involving the human papilloma virus (HPV), and has few available treatments. The present work aimed to assess the feasibility of SOX2 and HPV statuses as predictive indicators of SCNEC prognosis. Methods The associations of SOX2 and/or high-risk (HR)-HPV RNA in situ hybridization (RISH) levels with clinicopathological characteristics and prognostic outcomes for 88 neuroendocrine carcinoma (NEC) cases were analyzed. Results Among these patients with SCNEC, SOX2, P16INK4A and HR-HPV RISH expression and SOX2/HR-HPV RISH co-expression were detected in 68(77.3%), 76(86.4%), 73(83.0%), and 48(54.5%), respectively. SOX2-positive and HR-HPV RISH-positive SCNEC cases were associated with poorer overall survival (OS, P = 0.0170, P = 0.0451) and disease-free survival (DFS, P = 0.0334, P = 0.0309) compared with those expressing low SOX2 and negative HR-HPV RISH. Alternatively, univariate analysis revealed that SOX2 and HR-HPV RISH expression, either separately or in combination, predicted the poor prognosis of SCNEC patients. Multivariate analysis revealed that the co-expression of SOX2 with HR-HPV RISH may be an independent factor of OS [hazard ratio = 3.597; 95% confidence interval (CI): 1.085–11.928; P = 0.036] and DFS [hazard ratio = 2.880; 95% CI: 1.199–6.919; P = 0.018] prediction in SCNEC. Conclusions Overall, the results of the present study suggest that the co-expression of SOX2 with HR-HPV RISH in SCNEC may represent a specific subgroup exhibiting remarkably poorer prognostic outcomes compared with the expression of any one marker alone.

Jin-Ling Duan,1,* Run-Cong Nie,1,2,* Zhi-Cheng Xiang,1,3,* Jie-Wei Chen,3 Min-Hua Deng,1,2 Hu Liang,1,4 Feng-Wei Wang,1 Rong-Zhen Luo,3 Dan Xie,1,3 Mu-Yan Cai1,3 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2Department of Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 3Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 4Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mu-Yan Cai; Dan XieState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of ChinaTel +86-20-87343193Fax +86-20-87343170Email caimy@sysucc.org.cn; xiedan@sysucc.org.cnBackground and Aim: To assess the profile of global histone modifications in small hepatocellular carcinoma (small HCC) and identify its prognostic value in predicting recurrence.Methods: The expression profiles of global histone modifications, including H2AK5AC, H2BK20AC, H3K4me2, H3K9AC, H3K18AC, H4K12AC, and H4R3me2, were evaluated with immunohistochemistry in 335 HBV related small HCC patients. Two histone signature classifiers were then developed using least absolute shrinkage and selection operator Cox regression. A nomogram was built using the classifier and independent risk factors. The performances of the classifier and nomogram were assessed by receiver operating characteristic curves.Results: Histone modifications were more pronounced in tumor tissues than in adjacent liver tissues. In tumor tissues, the risk score built based on the seven-histone signature exhibited satisfactory prediction efficiency, with an AUC = 0.71 (0.63– 0.79) for 2-year survival in the training cohort. Patients with a high risk score had shorter recurrence-free survival than those with a low risk score (HR: 1.96, 95% CI: 1.24– 3.08, p = 0.004; HR: 1.95, 95% CI: 1.12– 3.42, p = 0.019; and HR: 1.97, 95% CI: 1.39– 2.80, p < 0.001 for the training, validation and total cohorts, respectively). Furthermore, the statistical nomogram built using the histone classifier for early recurrence had a C-index = 0.68. In non-neoplastic liver tissues, the hepatic signature based on H3K4me2 and H4R3me2 was related to late recurrence (HR: 2.00, 95% CI: 1.15– 3.48, p = 0.01).Conclusion: Global histone modifications in tumor and adjacent liver tissues are novel predictors of early and late recurrence, respectively, in HBV-related small HCC patients.Keywords: small hepatocellular carcinoma, histone modifications, recurrence, LASSO, prognosis

Background The BRCA mutation (BRCAm) in males has been reported to confer a higher risk for the development of various tumors. However, little is known about its clinicopathologic features and prognostic implications. Design We conducted a retrospective pan-tumor survey on 346 cases of BRCA-associated tumors in males. Comparative analyses were conducted among male and female patients with BRCAm (n = 349), as well as in male patients without BRCAm (n = 4577). Results Similar incidences of BRCAm (6.0 vs. 6.6%) and age at diagnosis of tumor (median, 65 vs. 60 years) were observed in male and female patients. Carcinomas of the lung, bladder, stomach, and cutaneous melanoma were the frequent tumors demonstrating BRCAm in males, of which the majority were stage II or III diseases with a higher frequency of BRCA2 mutations. Compared to that in the non-BRCAm group, cutaneous melanoma (16.3 vs. 5.0%), lung cancer (19.4 vs. 11.8%), bladder cancer (15.6 vs. 5.6%), and stomach cancer (11.9 vs. 5.5%) accounted for a higher proportion in the BRCAm group. Advanced disease and more mutation counts (median, 322 vs. 63 mutations) were also found in the BRCAm group. A total of 127 BRCA1 and 311 BRCA2 mutations were identified, of which 21.8 and 28.6% were deleterious, respectively. Frequent deleterious variants were identified in carcinomas of the breast (100.0%), colorectum (62.2%), prostate (43.3%), and stomach (42.9%). BRCA1 fusions with NF1, FAM134C, BECN1, or LSM12 and recurrent BRCA2 mutations at P606L/S, E832K/G, and T3033Lfs*29 were detected. Frameshift mutations in BRCA2 at N1784 (N1784Kfs*3, N1784Tfs*3) were frequently observed in both male and female patients. Compared with those in females, BRCA mutations in males were associated with decreased overall survival (OS) and progression-free survival (PFS). Male patients with deleterious BRCAm displayed increased OS compared with non-BRCAm carriers. The subgroup analysis demonstrated that BRCAm was associated with increased OS in gastric and bladder cancers, decreased PFS in prostate, esophageal, and head and neck cancers, and decreased OS in glioma/glioblastoma in males. Conclusion These findings provide an overview of the distinct characteristics and clinical outcomes of male patients with BRCA-associated tumors, suggesting the importance of further genetic BRCA testing in males.

Breast metastases from solid non-breast tumor types are rare; however, they should be always considered in the differential diagnosis of a breast lesion owing to the associated poor patient prognosis and the requirement of different therapeutic strategies compared with those used to treat primary breast cancer. The aim of the current study was to summarize the characteristics of metastases to the breast in a southern Chinese population. The medical records and pathological sections of 22 patients with pathologically confirmed extra-mammary metastases to the breast that presented to Sun Yat-sen University Cancer Center between January 2000 and December 2015 were retrospectively reviewed. The median age of onset for breast metastasis was 43 years (range, 10-62 years) and 19 (86.4%) patients had a known history of a primary tumor. The mean interval from diagnosis of the primary tumor to breast metastasis was 16.5 months (range, 6-56 months). A unilateral (45.5% left, 36.4% right), upper outer quadrant (15/22, 68.2%) lesion of the breast was most frequently initially detected by self-checking (63.6%). The most common origin of the primary tumor was the lung (22.7%). Nasopharyngeal carcinoma accounted for a high proportion of the metastases (18.2%). The median duration of survival from the time of diagnosis of a breast metastasis was 14 months (range, 2-74 months). A total of 10 patients (45.5%) succumbed to the disease. The results also indicated that overall survival in patients that underwent surgery was improved compared with patients who did not undergo surgery. The results of the present study demonstrated that clinical history, imaging findings, pathology from the primary tumor and immunostaining were required in combination to establish an accurate diagnosis. Further investigation into the improvement of the prognosis of patients with metastases to the breast following surgery is required.

Background We retrospectively compared the prognostic value between the AJCC 8th edition anatomic (AS) and prognostic staging (PS) system for triple negative breast cancer (TNBC) in a cohort from two involved institutions and a large population database. Methods Clinicopathological data of TNBCs were identified in two involved institutions (SYSUCC-PWH cohort). Data from SEER database during 2010–2015 was also accessed. We restaged all cases into AS and PS group according to the AJCC 8th staging system. Results A total of 611 and 31,941 TNBCs were identified in two cohorts, with a median follow-up of 53.5 and 27 months respectively. PS upstaged 46.1% of patients in SYSUCC-PWH cohort, and 62.4% in SEER cohort. No significant difference was observed in C index between AS and PS models for disease-specific survival (DSS), progression-free survival (PFS) or overall survival (OS) in either cohort. χ2 statistic and Hazard Ratio for PFS, DSS and OS showed better discrimination between IA and IB, IIB and IIIA, IIIA and IIIB in AS model than PS model. Besides, patients with IIIC unchanged stage showed worse PFS compared to those with AS IIIA or IIIB upstaged to PS IIIC in both cohorts(p = 0.049, p Conclusions Our findings demonstrated that prognostic staging system did not provide better discriminatory ability in predicting TNBCs prognosis than anatomic staging system.

Background Topoisomerase II alpha (TOP2A) protein has been shown to be a proliferation marker associated with tumor grade and Ki67 index. The prognostic effect of TOP2A seems different among different subtypes of breast cancer. The current study evaluated the prognostic impact of TOP2A protein on luminal breast cancer. Method Altogether 434 stage I-II luminal breast cancer patients who underwent curative surgery in Sun Yat-Sen University Cancer Center between 2007 and 2009 were enrolled. TOP2A protein expression was assessed by immunohistochemistry. Clinical and pathological data were retrospectively collected. Result With a cut-off value of 30%, 127 (29.3%) patients were classified as TOP2A overexpression. TOP2A overexpression was associated with a higher tumor grade and Ki67 index. Patients with TOP2A high expression showed a significantly higher rate of distant metastasis and shorter distant metastasis free survival (DMFS) compared with patients with low TOP2A expression. The prognostic influence of TOP2A expression was more significant in years 5–8 after diagnosis, and more pronounced in stage II patients, luminal B disease, and patients treated with adjuvant endocrine therapy alone. Multivariate survival analysis revealed TOP2A overexpression was an independent fact for worse DMFS. Conclusion TOP2A protein showed a time dependent influence on prognosis in stage I-II luminal breast cancer, suggesting it might be a potential predictor of late recurrence for this group of patients.

Summary Background It has been suggested that the p300 transcriptional coactivator participates in the regulation of a wide range of cell biological processes, and mutations in p300 have been identified in various cancers. Objectives To investigate p300 expression in cutaneous squamous cell carcinoma (cSCC) tissues and its effect on the outcome of patients with cSCC. Methods Immunohistochemistry (IHC) was performed on a tissue microarray to investigate p300 expression levels in cSCC tissues. Receiver operating characteristic (ROC) curve analysis, Kaplan–Meier plots and a Cox proportional hazards regression model were used to analyse the data. Results Based on the ROC curves, we defined the cut-off score for high p300 expression as > 55% of tumour cells positively stained. High expression of p300 was observed in 86 of 165 (52·1%) of the cSCC samples and six of 30 (20%) of the adjacent normal skin tissue samples (P

// Jianjun Tang 1, * , Gang Wang 1, * , Meifang Zhang 1, * , Feng-yan Li 1 , Yi Sang 1 , Boqing Wang 1, 2 , Kaishun Hu 1 , Yuanzhong Wu 1 , Rongzhen Luo 1 , Dan Liao 1 , Jingying Cao 1 , Xin Wang 1 , Li Wang 1 , Ruhua Zhang 1 , Xiaoshi Zhang 1 , Wu-Guo Deng 1 , Dan Xie 1 , Rui-hua Xu 1 , Tiebang Kang 1 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China 2 Department of Hepatobiliarypancreatic Surgery, Affiliated Tumor Hospital, Xinjiang Medical University, Urumqi 830000, China * These authors contributed equally to this work Correspondence to: Tiebang Kang, e-mail: kangtb@mail.sysu.edu.cn Keywords: CBX8, Polycomb Group protein, colorectal cancer, metastasis, proliferation, p53, integrin Received: July 23, 2014 Accepted: September 13, 2014 Published: October 24, 2014 ABSTRACT The effect of polycomb chromobox (Cbx) proteins in cancer is context-dependent. The Chromobox homolog 8 (CBX8) was originally characterized as a transcriptional repressor, which inhibits cell proliferation in Ink4a-Arf-dependent and -independent manner. However, the role of CBX8 in colorectal cancer remains unknown. Here, we found that high CBX8 expression was associated with a low rate of distant metastasis and good prognosis in CRC patients, even though CBX8 was up-regulated in CRC cell lines and clinical samples. Knockdown of CBX8 inhibited CRC proliferation in vitro and in vivo, mostly by increasing p53 and its downstream effectors. However, knockdown of CBX8 enhanced CRC migration, invasion and metastasis in vitro and in vivo, in part through direct up-regulation of integrin β4 (ITGB4) that in turn decreased RhoA activity. Collectively, the knockdown of CBX8 inhibited CRC proliferation, while promoting its metastasis, thus exerting paradoxical effects in CRC progression.

Zhong-Yu Yuan,1–3* Rong-Zhen Luo,1,2,4,* Rou-Jun Peng,1–3 Shu-Sen Wang,1–3 Cong Xue1–3 1State Key Laboratory of Oncology in South China, 2Collaborative Innovation Center for Cancer Medicine, 3Departments of Medical Oncology, Sun Yat-Sen University Cancer Center, 4Departments of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China *These authors contributed equally to this work Background: Triple-negative breast cancer (TNBC) is associated with poor prognosis and high probability of distant metastases. Tumor microenvironments play a pivotal role in tumor metastasis. Tumor-associated macrophages (TAMs) are one of the main cell components, and they are correlated with increasing metastatic risk. The aim of this study is to analyze the prognostic significance of the infiltration of TAMs in patients with TNBC. Materials and methods: Immunohistochemical staining for cluster of differentiation (CD)68 (a marker for macrophages) was performed on tissue microarrays of operable breast cancer among 287 patients with TNBC, and the number of infiltrating TAMs was correlated with clinicopathological parameters. Results: We found that TNBC with a large number of infiltrating TAMs had a significantly higher risk of distant metastasis, as well as lower rates of disease-free survival and overall survival than those with a smaller number of infiltrating TAMs. Multivariate analysis indicated that the number of infiltrating TAMs was a significant independent prognostic factor of disease-free survival (P=0.001) in all patients. Conclusion: Our results suggested that high infiltrating TAMs are a significantly unfavorable prognostic factor for patients with TNBC, and they could become a potentially useful prognostic marker for TNBC. Keywords: breast carcinoma, triple-negative, tumor-associated macrophages, prognosis

Purpose To investigate the correlation between p300 (a transcriptional co-activator) expression and clinical/prognostic characteristics in surgically resected NSCLC patients for the purpose of identifying patients with increased risk of cancer recurrence and providing them with tailored therapy. Methods One hundred and sixty-nine completely resected NSCLC patients were included in this study. Paraffin-embedded primary tumour tissues of patients were supplied to produce a tissue microarray, and immunohistochemistry was used for the evaluation of p300 expression. The clinical/prognostic significance of p300 expression was analysed for statistical significance. Survival was calculated by the Kaplan–Meier method, and the log-rank test was used to assess differences in survival between the groups. The prognostic impact of clinicopathologic variables and p300 expression was evaluated using a Cox proportional hazards model. Results High expression of p300 was associated with poor disease-free survival ( p = 0.027) and overall survival ( p = 0.006) in NSCLC patients. Further analysis suggested that this difference in overall survival also existed in patients with T2 ( p = 0.040), positive lymph nodes ( p = 0.023), stage IIIA ( p = 0.003), adenocarcinoma ( p = 0.021), and a well-differentiated histological grade score ( p = 0.011). The multivariate Cox regression analysis showed that low p300 expression is an independent marker of better disease-free survival (relative risk = 0.628, p = 0.047) and overall survival (relative risk = 0.545, p = 0.024) in operable NSCLC patients. Conclusions Low p300 expression is an independent prognostic marker of better survival in operable NSCLC patients. The combination of clinicopathological TNM staging classification with p300 expression may be useful in identifying patients with increased risk of cancer recurrence to provide them with tailored therapy.

BRCA1-associated protein 1 (BAP1) has been reported as a novel tumor suppressor, while in gastric adenocarcinoma, the function of this protein was still await to be uncovered. Based on a large group of patients with gastric adenocarcinoma, our study aimed to have a further understanding about the correlation of BAP1 expression and patients' clinical outcomes. We performed quantitative PCR and Western blot to examine BAP1 expression in 38 cases of gastric adenocarcinoma samples and adjacent non-cancerous tissues. Immunochemistry was used to evaluate BAP1 expression in a large cohort of 474 paraffin-embedded specimens. The clinical and prognostic significance of BAP1 expression was statistically analyzed. Postoperative survival between groups was using Kaplan-Meier analysis. BAP1 was overexpressed in paracancerous normal mucosa compared with gastric cancer. Decreased BAP1 expression was associated with higher histologic grade (P = 0.044), tumor infiltration (P

Dicer is crucial for the maturation of microRNAs (miRNAs) and its dysregulation may contribute to tumor initiation and progression. The study explored the clinical implications of Dicer and its post-transcriptional regulation by microRNAs in cervical cancer. qRT-PCR and immunohistochemistry investigated Dicer mRNA and protein levels in cervical cancer tissues. The relationship between Dicer expression and survival was analyzed. MiRNA target prediction identified miRNAs that might target Dicer. Luciferase reporter and gain- or loss-of-function assays were performed. The results showed that 36.7% of cervical cancer cases showed low expression of Dicer mRNA and 63.3% cases showed high expression. At the protein level, 51% cases showed negative expression and 49% cases showed positive expression. Dicer mRNA and protein expressions were significantly associated with distant metastasis and recurrence in cervical cancer (P=0.002 and P=0.012, respectively). Multivariate Cox analysis indicated that low Dicer expression (P=0.016) and tumor stage (P=0.047) were independent predictors. Among the miRNAs predicted to target Dicer, 10 were detected by RT-PCR; their expressions were significantly higher in cervical cancers with lower Dicer expression than in those with higher Dicer expression and were negatively correlated with Dicer expression level (PIn vitro experiments demonstrated that miR-130a directly targeted Dicer mRNA to enhance migration and invasion in SiHa cells. Finally, survival analysis indicated that higher expression of miR-130a was significantly associated with poor disease-free survival. Taken together, Dicer expression regulated by miR-130a is an important potential prognostic factor in cervical cancer.

Fibulin-3, originally identified in senescent and Werner syndrome fibroblasts, has been implicated in cell morphology, growth, adhesion and motility. Fibulin-3 exhibits both antitumor and oncogenic activities towards human cancers; however, the role of Fibulin-3 in hepatocellular carcinoma (HCC) remains elusive. In this study, we showed that both the mRNA and protein levels of Fibulin-3 were remarkably downregulated in HCC cell lines and fresh tissues. Immunohistochemical data revealed that Fibulin-3 was decreased in tumorous tissues in 67.1% (171/255) of cases compared to the corresponding adjacent nontumorous tissues. The results of statistical analysis indicated that low Fibulin-3 expression, defined by the receiver operating characteristic curve (ROC), was significantly associated with tumor differentiation (P = 0.008), clinical stage (P = 0.014) and serum AFP levels (P

Background Previously, we found an 11-gene signature could predict pelvic lymph node metastasis (PLNM), and WNT2 is one of the key genes in the signature. This study explored the expression and underlying mechanism of WNT2 in PLNM of cervical cancer. Methods WNT2 expression level in cervical cancer was detected using western blotting, quantitative PCR, and immunohistochemistry. Two WNT2-specific small interfering RNAs (siRNAs) were used to explore the effects of WNT2 on invasive and metastatic ability of cancer cells, and to reveal the possible mechanism of WNT2 affecting epithelial-mesenchymal transition (EMT). The correlation between WNT2 expression and PLNM was further investigated in clinical cervical specimens. Results Both WNT2 mRNA and protein expression was upregulated in cervical cancer. High WNT2 expression was significantly associated with tumor size, lymphovascular space involvement, positive parametrium, and most importantly, PLNM. PLNM and WNT2 expression were independent prognostic factors for overall survival and disease-free survival. WNT2 knockdown inhibited SiHa cell motility and invasion and reversed EMT by inhibiting the WNT2/β-catenin pathway. WNT2 overexpression in cervical cancer was associated with β-catenin activation and induction of EMT, which further contributed to metastasis in cervical cancer. Conclusion WNT2 might be a novel predictor of PLNM and a promising prognostic indicator in cervical cancer.

Bone is one of the most common sites of metastasis in patients with non-small-cell lung cancer (NSCLC). Over-expression of bone sialoprotein (BSP) and osteopontin (OPN) in tumour samples has shown prognostic significance in bone metastasis (BM) of breast and prostate cancer, respectively. However, their importance in BM of NSCLC has not been verified. Therefore, we planned a large cohort retrospective study to investigate the relationship between the expression of these two biomarkers (BSP and OPN) and BM in surgically resected NSCLC patients.180 completely resected NSCLC patients were included in this study. 40 patients subsequently developed BM. Paraffin-embedded primary tumour tissues of patients were supplied to produce a tissue microarray, and immunohistochemistry method was used for evaluation of the expression of BSP and OPN. Different expressions of these two biomarkers among BM group and non-BM group were estimated by chi(2) test. BM-free survival was analyzed by Kaplan-Meier method. The prognostic impact of clinicopathologic variables and biomarker expression was evaluated by Cox proportional hazards model.BSP expression was associated with BM (p=0.007), whereas OPN expression did not reach statistical significance (p=0.245). Univariate analysis showed that expression of BSP (p=0.010) and N staging (p0.005) was associated with BM-free survival. Multivariate analyses showed BSP expression (HR=3.322, p=0.003), N staging (HR=1.879, p=0.001), and T staging (HR=1.618, p=0.024) were independent prognostic factors for BM.BSP protein expression in the primary resected NSCLC is strongly associated with BM and could be used to identify high-risk patients. Correlation of OPN protein expression and BM needs further investigation.

Karyopherin alpha 2 (KPNA2), a member of the karyopherin family, has a central role in nucleocytoplasmic transport and is overexpressed in many cancers. Our previous study identified KPNA2 as significantly upregulated in epithelial ovarian carcinoma (EOC), correlating with poor survival of patients. However, the precise mechanism of this effect remains unclear. The aim of the present study was to examine the role of KPNA2 in the proliferation and tumorigenicity of EOC cells, and its clinical significance in tumor progression. Real-time quantitative RT-PCR analysis revealed high expression levels of KPNA2 in 162 out of 191 (84.8%) fresh EOC tissues, which was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage, differentiation, histological type, recurrence, and prognosis of EOC patients. Our results showed that upregulation of KPNA2 expression significantly increased the proliferation and tumorigenicity of EOC cells (EFO-21 and SK-OV3) in vitro and in vivo, by promoting cell growth rate, foci formation, soft agar colony formation, and tumor formation in nude mice. By contrast, knockdown of KPNA2 effectively suppressed the proliferation and tumorigenicity of these EOC cells in vitro and in vivo. Our results also indicated that the molecular mechanisms of the effect of KPNA2 in EOC included promotion of G1/S cell cycle transition through upregulation of c-Myc, enhanced transcriptional activity of c-Myc, activation of Akt activity, suppression of FOXO3a activity, downregulation of cyclin-dependent kinase (CDK) inhibitor p21Cip1 and p27Kip1, and upregulation of CDK regulator cyclin D1. Our results show that KPNA2 has an important role in promoting proliferation and tumorigenicity of EOC, and may represent a novel prognostic biomarker and therapeutic target for this disease.

Rong-Zhen Luo,1,2,* Zhong-Yu Yuan,1,3,* Mei Li,1,2 Shao-Yan Xi,1,2 Jia Fu,1,2 Jiehua He1,21State Key Laboratory of Oncology in South China, 2Department of Pathology, 3Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China*These authors contributed equally to this workBackground: 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