Diffuse expression of MUC6 defines a distinct clinicopathological subset of pulmonary invasive mucinous adenocarcinoma.

Invasive mucinous adenocarcinoma (IMA) of the lung is a unique variant of lung adenocarcinoma. Aberrant mucin expression is associated with cancer development and metastasis. However, the clinicopathological significance of mucin expression in IMA is not fully understood. Herein, we evaluated the clinicopathological, immunohistochemical, and molecular characteristics of 70 IMA tumors. EGFR, KRAS, GNAS, and TP53 mutations were assessed by PCR-based sequencing. Next-generation sequencing was used to assess cases without EGFR/KRAS mutations. A NanoString-based screening for fusions was performed in all IMAs without mitogenic driver mutations. Expression of mucins (MUC1, MUC2, MUC4, MUC5AC, and MUC6) was evaluated by immunohistochemistry and categorized as follows: negative (<10% of tumor cells), patchy expression (<90% of tumor cells), or diffuse expression (≥90% of tumor cells). Immunohistochemical testing for transcription factors (TTF-1, CDX2, HNF1ß, HNF3α, HNF3ß, and HNF4α) was also performed. As expected, KRAS mutations were the most common (in 67% of cases), followed by small numbers of other alterations. Patchy or diffuse expression of MUC1, MUC2, MUC4, MUC5AC, and MUC6 was observed in 52% or 6%, 3% or 0%, 30% or 3%, 26% or 73%, and 59% or 27% of cases, respectively. Furthermore, all IMAs were generally positive for HNF1ß (100%), HNF3α (100%), HNF3ß (100%), and HNF4α (99%) but were positive less often for TTF-1 (6%) and CDX2 (9%). Overall, there was no significant correlation between mucin expression and transcription factor expression. Unexpectedly, diffuse expression of MUC6 was significantly associated with KRAS-wild-type tumors (p = 0.0008), smaller tumor size (p = 0.0073), and tumors in female patients (p = 0.0359) in multivariate analyses. Furthermore, patients with tumors exhibiting diffuse MUC6 expression had significantly favorable outcomes. Notably, none of these patients died of the disease. Our data suggested that diffuse expression of MUC6 defines a distinct clinicopathological subset of IMA characterized by wild-type KRAS and possibly less aggressive clinical course.

High expression of glutamate-ammonia ligase is associated with unfavorable prognosis in patients with ovarian cancer.

Glutamate-ammonia ligase (GLUL), which is also called GS (glutamine synthetase), is the enzyme that catalyzes the synthesis of glutamine from glutamate and ammonia in an ATP-dependent reaction. Here, we found higher expression of GLUL in the ovarian cancer patients was associated with worse disease-free survival (DFS) and overall survival (OS). In addition, GLUL was heterogeneously expressed in various ovarian cancer cells. The mRNA and protein expression levels of GLUL in NIH:OVCAR-3 and ES-2 cells were obviously higher than that in the other types of ovarian cancer cells. Knockdown of GLUL in NIH:OVCAR-3 or ES-2 cells could significantly decrease the proliferation ability. Furthermore, GLUL knockdown markedly inhibited the p38 MAPK signaling pathway in NIH:OVCAR-3 or ES-2 cells. Our findings suggest that decreasing expression of GLUL may be a new approach that can be used for ovarian cancer treatment.

[Expression of ALK protein in 7 371 pulmonary adenocarcinoma samples, with analysis of clinicopathologic features].

OBJECTIVE: To study the expression of ALK protein in pulmonary adenocarcinoma as detected by Ventana immunohistochemistry, with correlation of clinicopathologic features. METHODS: Immunohistochemical study for ALK protein using Ventana ALK (D5F3) kit was carried in 7 371 pulmonary adenocarcinoma samples. The clinicopathologic features were subsequently analyzed. RESULTS: ALK fusion protein was detected in 446 of the 7 371 lung adenocarcinoma samples studied (6.05%). The ALK positivity rate in small biopsy samples was higher than that in surgical specimens [9.02% (153/1 696) versus 5.16% (293/5 675); P<0.01]. ALK fusion protein expression correlated with patient age, sample type and smoking history. ALK positivity rate in each age group increased with younger patient age. ALK positivity rate was 45.45% (10/22) in patients younger than 30 years old. The positivity rate of ALK fusion protein in adenocarcinoma in-situ, minimally invasive adenocarcinoma and invasive adenocarcinoma was 0, 0.48% (2/418) and 5.63% (291/5 165), respectively. The differences of ALK positivity rate amongst different subtypes had statistical significance (P<0.01). Invasive mucinous adenocarcinoma had highest ALK positivity rate, followed by invasive adenocarcinoma with predominantly solid pattern. CONCLUSIONS: ALK fusion protein is more often found in young patients with pulmonary adenocarcinoma, especially in those younger than 30 years old. ALK fusion protein is rarely expressed in early-stage pulmonary adenocarcinoma. Invasive mucinous adenocarcinoma and invasive adenocarcinoma with solid pattern have higher ALK positivity rate than other adenocarcinoma subtypes.

Aberrant Expression of Anaplastic Lymphoma Kinase in Ovarian Carcinoma Independent of Gene Rearrangement.

Ovarian carcinoma is the leading cause of death from gynecologic malignancies. The oncogenic role of anaplastic lymphoma kinase (ALK) is well characterized in many hematopoietic and solid tumors. ALK expression in ovarian carcinoma has been reported but the exact status of ALK protein and its association with clinicopathologic features requires further investigation. ALK expression was determined by immunohistochemistry in 110 primary ovarian carcinomas, including 85 cases of serous carcinoma and 25 cases of mucinous carcinoma. Fluorescence in situ hybridization (FISH) and real-time reverse transcription polymerase chain reaction (RT-PCR) were used for evaluating ALK translocation in ALK-positive ovarian carcinomas. Among 110 ovarian carcinomas, 23 (20.9%) cases were ALK positive by immunohistochemistry. All ALK-positive cases were ovarian high-grade serous carcinoma. ALK expression was detected in 23/85 (27.1%) ovarian serous carcinoma and 0/25 (0%) in ovarian mucinous carcinoma. None of the 23 ALK IHC-positive cases harbored ALK gene translocations by FISH or RT-PCR. ALK protein expression was associated with patient age, tumor stage, and histologic type. Specifically, the probability of ALK protein expression was significantly higher in high-grade serous carcinomas in older patients (above 50 y) with advanced disease (FIGO stage III and IV) compared with the low-grade serous and mucinous carcinomas in younger patients with relatively early disease. In conclusion, aberrant ALK expression is observed in ovarian serous carcinoma but not in mucinous carcinoma, is independent of gene translocation, and might be associated with progression and prognosis.

Expression of phospho-mTOR kinase is abundant in colorectal cancer and associated with left-sided tumor localization.

PURPOSE: To investigate the significance of mammalian target of rapamycin (mTOR) in colorectal cancers. mTOR has recently been suggested as a prognostic biomarker and therapeutic target in an array of human cancers. FINDINGS: phospho-mTOR (p-mTOR) expression was analyzed by immunohistochemistry (IHC) on a tissue microarray containing 1800 colorectal cancers (CRC). Clinical follow-up data were available from all cancer patients. Positive p-mTOR immunostaining was seen in 83.5% of 1640 interpretable CRC and was considered weak in 862 (52.5%) and strong in 508 cases (31.0%). Matching clinico-pathological parameters were available in 1580 cases. p-mTOR staining was more frequent in tubular adenocarcinomas than in the less common histological subtypes (mucinous, medullary, signet cell; P=0.0163) and significantly linked to carcinomas of the left-sided colon and rectum as compared to right-sided CRC (P=0.0066). There was no significant association between p-mTOR expression and patients' gender, tumor stage, tumor grade or nodal status. In a survival analysis, p-mTOR IHC status of all CRC was unrelated to patient survival (P=0.702). In a multivariate analysis including pT, pN, tumor grade, tumor localization and p-mTOR expression, only pT, pN (both P<0.0001) and grade (P=0.0001) showed prognostic impact, but not tumor localization (P=0.9472) or p-mTOR expression (P=0.8879). CONCLUSION: Our observations indicate that p-mTOR overexpression is abundant in CRC and linked to left-sided tumor localization. The high frequency and overexpression of p-mTOR is providing further rationale for targeting this pathway therapeutically in CRC patients. However, a prognostic role of p-mTOR overexpression in CRC could not be confirmed.

Thymidylate synthase, topoisomerase-1 and microsatellite instability: relationship with outcome in mucinous colorectal cancer treated with fluorouracil.

BACKGROUND: Mucinous colorectal cancer (CRC) exhibits distinct clinical and pathological features, including poorer response to fluorouracil (FU) compared with non-mucinous tumours. PATIENTS AND METHODS: We compared the expression of thymidylate synthase (TYMS) and topoisomerase-1 (TOPO1) and DNA microsatellite instability (MSI) in 87 patients (35 mucinous and 52 non-mucinous CRCs) enrolled in three randomized trials, evaluating infused FU as first-line treatment. RESULTS: Mucinous CRCs more frequently had high TOPO1 expression than did non-mucinous tumors (41% vs. 15%, p=0.028). The median overall survival was 14.2 months for patients with mucinous CRC with low TOPO1 expression compared with 9.7 months for high TOPO1-expressing cases (p=0.016). After adjusting for confounding variables, low TOPO1 expression was statistically favourably associated with overall survival (hazard ratio=0.55; p=0.041). CONCLUSION: Our data suggest the TOPO1 expression levels to be a prognostic marker in patients with mucinous CRC treated with FU. If further verified, these data might redefine therapeutic strategies by identifying categories of patients with a worse prognosis.

RECQL1 DNA repair helicase: a potential therapeutic target and a proliferative marker against ovarian cancer.

OBJECTIVE: This study analyzed the clinicopathological correlation between ovarian cancer (OC) and RECQL1 DNA helicase to assess its therapeutic potential. METHODS: Surgically resected OC from 118 retrospective cases, for which paraffin blocks and all clinical data were complete, were used in this study. RECQL1 and Ki-67 immunostaining were performed on sections to correlate RECQL1 staining with subtype and patient survival. Ten OC and two normal cell lines were then examined for RECQL1 expression and were treated with siRNA against RECQL1 to assess its effect on cell proliferation. RESULTS: Of the 118 cases of adenocarcinoma (50, serous; 26, endometrioid; 21, clear cell; 15, mucinous; 6, other histology), 104 (90%) showed varying levels of RECQL1 expression in the nuclei of OC cells. The Cox hazards model confirmed that diffuse and strong staining of RECQL1 was correlated with histological type. However, RECQL1 expression did not correlate with overall patient survival or FIGO stage. In vitro, RECQL1 expression was exceptionally high in rapidly growing OC cell lines, as compared with normal cells. Using a time-course analysis of RECQL1-siRNA transfection, we observed a significant inhibition in cell proliferation. CONCLUSIONS: RECQL1 DNA helicase is a marker of highly proliferative cells. RECQL1-siRNA may offer a new therapeutic strategy against various subtypes of OC, including platinum-resistant cancers, or in recurrent cancers that gain platinum resistance.

The role of K-RAS and B-RAF mutations as biomarkers in metastatic colorectal cancer.

PURPOSE: Unlike cetuximab, there is a paucity of biomarkers for bevacizumab as predictors of outcome in metastatic colorectal cancer (mCRC) patients. Obviously exploring the worth of some potential markers in this setting is warranted. The purpose of this study was to investigate the predictive value of the presence of K-RAS and B-RAF mutations on the outcome of patients with mCRC treated with FOLFIRI and bevacizumab combination therapy. METHODS: A total of 172 patients with mCRC were evaluated. K-RAS and B-RAF mutations were analyzed by quantitative PCR. Median progression-free survival (PFS) and overall survival (OS) were compared utilizing chi-square and Mann-Whitney U tests, respectively. RESULTS: Forty-four percent (N=77) of the patients were found to harbor K-RAS mutations and 6 (7.5%) were positive for B-RAF mutations. In baseline no difference in PFS and OS was observed between the groups with or without K-RAS mutation. No relationship was established between K-RAS and B-RAF mutation status and baseline CEA and CA19-9 tumor markers levels. CONCLUSION: K-RAS and B-RAF mutations do not seem to be predictive of treatment outcome as potential biomarkers for bevacizumab therapy in mCRC. However, not only the presence of K-RAS and B-RAF mutations but also the different biological behavior of the various subtypes of mutations should be considered as potential determinants in the final outcome of this disease.

Correlation between chemosensitivity to anticancer drugs and telomerase reverse transcriptase mRNA expression in gastric cancer.

BACKGROUND: The determination of sensitive chemotherapy drugs for gastric cancer (GC) is one of the greatest challenges of adjuvant therapy. Here we evaluated the chemosensitivity of GC to anticancer drugs and the telomerase reverse transcriptase (hTERT) mRNA expression, and investigated the relationship of them. METHODS: The GC cells which were collected from 68 patients with primary GC were primary cultured. The chemosensitivity of GC cells to anticancer drugs was evaluated successfully using the MTT assay for 60 cases of GC cells, and the hTERT mRNA expression was examined in 60 cases of GC tissues and corresponding normal gastric mucosa and 6 cases of chronic superficial gastritis mucosa by in situ hybridization. RESULTS: Taxol, cisplatin and 5-fluorouracil were in general more effective than adriamycin and mitomycin for GC cells, and the chemosensitivity to anticancer drugs was associated with tumor histological types and a worse tumor grade. Compared to normal gastric mucosa tissues, hTERT mRNA expression was significantly increased in GC (P<0.05), which was related with a worse differentiation and drug-resistance to 5-fluorouracil or adriamycin in GC. CONCLUSIONS: These data demonstrate for the first time that examinations of hTERT mRNA expression as an important factor could be used to select the chemotherapeutic drugs for GC patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1793217009875483.

Endocervical glandular neoplasia associated with lobular endocervical glandular hyperplasia is HPV-independent and correlates with carbonic anhydrase-IX expression: a Gynaecological Oncology Group Study.

BACKGROUND: Lobular endocervical glandular hyperplasia (LEGH) is a rare lesion of the uterine cervix. It has been proposed that LEGH may represent a precursor lesion to a group of mucinous adenocarcinoma with gastric phenotype (GA) that is independent of high-risk human papillomavirus (H-HPV) infection. Carbonic anhydrase-IX (CA-IX) is highly expressed in conventional glandular lesions (CGLs). However, expression of CA-IX in LEGH or GA has not been studied. METHODS: In all, 12 CGLs, 7 LEGHs, 6 LEGHs with coexisting adenocarcinoma in situ (AIS, 3) and GA (3) were identified from Japanese women with a cytological diagnosis of atypical glandular cells of undetermined significance. Immunostaining was used to detect CA-IX and p16(INK)4(a) (hereafter termed p16) protein expression in the tissues and CA-IX protein expression in the Papanicolaou smears (PSs). Polymerase chain reaction was used to detect H-HPV DNA in liquid-based cytology. RESULTS: Out of 12 (83%) CGLs, 10 were positive with H-HPV and high levels of CA-IX expression were seen in all (100%) cases. P16 protein expression was observed in 11 out of 12 (92%) cases. None of the LEGHs, LEGHs with AIS or GA were positive for H-HPV and only 8 out of 13 (62%) showed focal weak (1+) p16 expression. In contrast, all cases (100%) exhibited strong CA-IX protein expression. CONCLUSION: Our study suggests that there are different molecular mechanisms of carcinogenesis resulting in CGLs vs LEGHs associated with AIS or GA. There is also a possible link between LEGHs and GAs. Furthermore, CA-IX expression may serve as a useful biomarker for the detection of GAs in the absence of H-HPV infection.

Indoleamine 2,3-dioxygenase affects the aggressiveness of intraductal papillary mucinous neoplasms through Foxp3+CD4+CD25+ T cells in peripheral blood.

OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) have a high malignant potential. We previously reported that peripheral Foxp3(+)CD4(+)CD25(+) T-cell (Foxp3(+) Treg) populations significantly increase with IPMN pathological aggressiveness. Dendritic cell-mediated induction of active Tregs from naive CD4(+) T cells requires indoleamine 2,3-dioxygenase (IDO). Here, we evaluated whether an IDO-Foxp3(+) Treg interaction plays a role in IPMN pathological aggressiveness. METHODS: We evaluated peripheral blood samples and resected specimens from 12 patients with IPMN. We analyzed Foxp3(+)CD4(+)CD25(+) T cells in peripheral blood by fluorescence-activated cell sorting, evaluated the resected specimens by anti-IDO antibody staining, and compared them with the patients' clinicopathological factors. RESULTS: The pathological aggressiveness of IPMN was significantly associated with the number of peripheral Foxp3(+) Tregs (P < 0.05) and IDO-positive cells per high-power field (HPF) (P < 0.01). There was a significant correlation between the numbers of peripheral Foxp3(+) Tregs and IDO-positive cells/HPF (r = 0.625, P < 0.01). Patients with 7 or more IDO-positive cells/HPF had a significantly higher recurrence rate than those with less than 7 IDO-positive cells/HPF (P < 0.01, log-rank test). CONCLUSIONS: Peripheral Foxp3(+) Tregs accurately reflect the aggressiveness of IPMNs. An increase in Foxp3(+) Tregs can be induced by local IDO-positive cells in IPMN.

Expression of pyruvate dehydrogenase kinase-1 in gastric cancer as a potential therapeutic target.

In contrast to mitochondria in healthy cells, which utilize oxidative phosphorylation, malignant cells undergo elevated glycolysis for energy production using glucose. The objectives of this study were to evaluate whether the expression of various molecules, including pyruvate dehydrogenase kinase-1 (PDK-1), is involved in the altered glucose metabolism associated with gastric cancer prognosis and to assess the role of a therapeutic agent in targeting glucose metabolism in gastric cancer. Immunohistochemistry was performed on gastric cancer tissues obtained from 152 patients who underwent curative resection to assess the expression of hypoxia-inducible factor-1α (HIF-1α), glucose transporter-1 (GLUT-1), hexokinase-2 (HK-2) and PDK-1. In an in vitro analysis, the lactate production and glucose uptake levels, cellular viability and 5-fluorouracil (5-FU) responses were evaluated before and after treatment with dichloroacetate (DCA), a PDK-1 inhibitor, in the MKN45 and AGS gastric cancer cell lines and in the non-cancerous HEK293 cell line. GLUT-1 and PDK-1 expression was significantly associated with tumor progression, although only PDK-1 expression was an independent prognostic factor for patients who received 5-FU adjuvant treatment. There was no significant difference in cell viability between the HEK293 and gastric cancer cell lines following DCA treatment. However, DCA treatment reduced lactate production and increased responsiveness to 5-FU in MKN45 cells, which expressed high levels of PDK-1 in comparison to the other cell lines. Thus, PDK-1 may serve as a biomarker of poor prognosis in patients with gastric cancer. In addition, PDK-1 inhibitors such as DCA may be considered an additional treatment option for patients with PDK-1-expressing gastric cancers.

Pyrophosphatase overexpression is associated with cell migration, invasion, and poor prognosis in gastric cancer.

Inorganic pyrophosphatase (PPase) catalyzes the hydrolysis of pyrophosphate to form orthophosphate. Pyrophosphate can substitute for ATP under certain circumstances. We previously conducted a proteomic analysis to investigate tumor-specific protein expression in gastric cancer, and PPase was identified as a potential gastric tumor-specific marker; it was therefore selected for further study. Clinicopathological analysis, using proteomic analysis and immunohistochemistry, was used to validate PPase as a prognostic marker in gastric cancers. Proteomic analysis showed that PPase was overexpressed in patients with lymph node (LN) metastases and high tumor node metastasis (TNM) stages (p < 0.05). Based on immunohistochemistry, patients whose tumors overexpressed PPase had higher T stages, LN metastasis, a higher TNM stage, a higher cancer recurrence rate, and shorter survival times than patients whose tumors exhibited PPase underexpression (p < 0.05). Gain-of-function and loss-of-function approaches were employed to examine the malignant phenotypes of PPase-overexpressing or PPase-depleted cells. A decrease in PPase expression caused a significant decrease in gastric cancer cell migration and invasion in vitro, whereas forced overexpression of PPase enhanced migration but not invasion. Our findings indicate that PPase is involved in gastric tumor progression and that PPase may be a useful marker for poor prognosis of human gastric cancers.

Subtype specific elevated expression of hyaluronidase-1 (HYAL-1) in epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is morphologically heterogeneous being classified as serous, endometrioid, clear cell, or mucinous. Molecular genetic analysis has suggested a role for tumor suppressor genes located at chromosome 3p in serous EOC pathogenesis. Our objective was to evaluate the expression of HYAL1, located at chromosome 3p21.3, in these EOC subtypes, and to investigate its correlation with the expression of steroid hormone receptors. METHODOLOGY/PRINCIPAL FINDINGS: We determined the mRNA expression of HYAL1, estrogen receptor (ER)-α, ERß and progesterone receptor (PR) in EOC tumor samples and cell lines using quantitative RT-PCR. We also examined the expression of these genes in a publicly available microarray dataset. HYAL-1 enzyme activity was measured in EOC cell lines and in plasma samples from patients. We found that HYAL1 mRNA expression was elevated in clear cell and mucinous EOC tissue samples, but not in serous and endometrioid samples, normal ovaries or benign tumors. Similar results were obtained by two different techniques and with tissue sample cohorts from two independent institutions. Concordantly, HYAL1 mRNA levels and enzymatic activity were elevated only in EOC cell lines derived from clear cell and mucinous subtypes. We also showed that HYAL1 mRNA was inversely correlated to that of ERα specifically in clear cell and mucinous EOCs. Additionally, ectopic expression of ERα in a clear cell EOC cell line (ER- and PR-negative) induced 50% reduction of HYAL1 mRNA expression, supporting a role of ERα in HYAL1 gene regulation. Significantly, HYAL-1 activity was also high in the plasma of patients with these EOC subtypes. CONCLUSIONS/SIGNIFICANCE: This is the first report showing high HYAL-1 levels in EOC and demonstrating HYAL1 gene repression by ERα. Our results identify Hyaluronidase-1 as a potential target/biomarker for clear cell and mucinous EOCs and especially in tumors with low ERα levels.

The utility of pleural amylase measurement in metastatic mucinous adenocarcinoma.

We describe a case of exudative pleural effusion in a patient with mucinous pulmonary adenocarcinoma. Pleural fluid examination showed markedly raised amylase with normal serum amylase concentration. There was no clinical or radiological evidence of oesophageal rupture or pancreatitis. The case illustrates the importance of considering pulmonary malignancy in the context of amylase-rich pleural effusion. Causes of amylase-rich pleural effusion and the significance of isoenzyme analysis are discussed.

N-Acetylgalactosaminyltransferase-14 as a potential biomarker for breast cancer by immunohistochemistry.

BACKGROUND: The post-translational modification of proteins, including glycosylation, differs between normal and tumor cells. The UDP-N-acetyl-D-galactosamine polypeptide N-acetylgalactosaminyltransferases (GalNAc-Tases) family of enzymes regulates the initial steps of mucin O-glycosylation and is responsible for the altered glycosylation state observed in cancer cells. Recently it was found that GalNAc-T14 mRNA is heterogeneously expressed in breast carcinomas compared to normal tissue, however the expression profile of GalNAc-T14 protein in breast carcinomas compared to normal tissue is still unknown. In this study, we assessed the expression profile of GalNAc-T14 protein in malignant and non-malignant breast tissues by immunohistochemistry to evaluate whether GalNAc-T14 might be a potential biomarker for breast cancer. METHODS: In formalin-fixed tissues, the expression level of GalNAc-T14 protein was evaluated by immunohistochemistry assay in breast tissues. Expression profiles were assessed in normal tissues, benign fibroadenomas and several types of carcinomas. RESULTS: Our results showed that GalNAc-T14 was heterogeneously expressed in breast carcinomas compared to non-malignant tissue. GalNAc-T14 expression was observed in 47/56 (83.9%) carcinoma samples, 7/48 (14.6%) non-malignant breast tissue samples. GalNAc-T14 expression level was associated with histological grade. For this enzyme a significant association with invasive ductal type, mucinous adenocarcinoma and ductal carcinoma in situ (DCIS) type was found. CONCLUSION: Our results provide evidence that GalNAc-T14 may be a potential biomarker for breast cancer by immunohistochemistry. GalNAc-T14 expression level was associated with histological grade. GalNAc-T14 expression can provide new insights about breast cancer glycobiology.

Oxidative stress-induced antioxidant enzyme expression is an early phenomenon in ovarian carcinogenesis.

Oxidative stress and antioxidant enzymes have been widely investigated in various carcinomas. However, there is only some information about their role in ovarian carcinogenesis or in ovarian carcinomas in vivo. We studied immunohistochemical nuclear and/or cytoplasmic expression of oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine, as well as major antioxidative enzymes peroxiredoxins (PRDX) I-VI and thioredoxin (TXN) in ovarian tumours. The material consisted of 20 benign (10 serous, 10 mucinous) and 51 borderline (33 serous, 18 mucinous) epithelial ovarian tumours. The markers of oxidative stress, 8-OHdG and nitrotyrosine, were seen already in benign tumours (in 20% and 45% of the tumours, respectively) and their expression patterns were similar in benign and borderline tumours. The levels of PRDX II, III, IV, V and VI were significantly higher in borderline than in benign tumours (p<0.02 for all). Specifically for PRDX II (for both nuclear and cytoplasmic expression, p<0.00005) and PRDX VI (for cytoplasmic expression, p=0.0003 and for nuclear expression, p=0.0005) the difference between benign and borderline tumours was remarkable. In general, serous benign and borderline tumours expressed higher antioxidant enzyme levels than mucinous ones. Nuclear TXN was expressed more strongly in benign than in borderline tumours (p=0.003). Oxidative stress occurs already in benign ovarian tumours and the levels are comparable to borderline tumours. However, some of the antioxidant enzymes, especially PRDX II and VI, are more profoundly induced in borderline ovarian tumours, reflecting their possible role as cancer preventers. This difference could also offer a potential tool for differential diagnosis between benign and borderline epithelial ovarian tumours.

TGM2 is a novel marker for prognosis and therapeutic target in colorectal cancer.

BACKGROUND: Transglutaminase 2 (TGM2) plays a role in cell growth and survival through the antiapoptosis signaling pathway. METHODS: We analyzed TGM2 gene expression in 91 paired cases of colorectal cancer (CRC) and noncancerous regions and seven CRC cell lines to demonstrate the importance of TGM2 expression for the prediction of prognosis of CRC. TGM2 expression was higher in CRC tissue than in corresponding normal tissue by real-time reverse transcriptase-polymerase chain reaction (P = .015). RESULTS: Patients in the high TGM2 expression group showed a poorer overall survival rate than those in the low expression group (P = .001), indicating that the increase in TGM2 expression was an independent prognostic factor. TGM2 was also expressed in the seven CRC cell lines. The in vitro proliferation assay showed that TGM2 expression is involved with tumor growth. CONCLUSIONS: The present study suggests that TGM2 is useful as a predictive marker for patient prognosis and may be a novel therapeutic target for CRC.

High expression of N-acetylglucosaminyltransferase V in mucinous tumors of the ovary.

N-acetylglucosaminyltransferase V (GnT-V) is an enzyme that catalyzes beta1-6 branching of N-acetylglucosamine (GlcNAc) on asparagine-linked oligosaccharides of cell proteins. The present study aimed to investigate GnT-V expression and its prognostic significance in epithelial ovarian cancer. GnT-V expression was studied by immunohistochemistry in 83 surgically resected ovarian cancers, and the staining intensity was evaluated. High GnT-V expression in cancer cells was found in 17 (20.5%) of the 83 cases, and was positively correlated with early FIGO staging. In the histological type, mucinous adenocarcinoma showed significantly strong immunostaining compared to the non-mucinous type (P<0.001). In 36 mucinous tumors, the GnT-V immunostaining score was significantly higher in cancer than in benign and borderline tumors (P<0.001). NOM-1, a human ovarian mucinous adenocarcinoma cell line, expressed strong GnT-V protein and swainsonine treatment suppressed beta1-6GlcNAc branching and reduced migration ability significantly (P<0.001). These results suggested that GnT-V might be involved in the malignant potential of mucinous ovarian cancer.