Heng Hong

Claudin-7 inhibits human lung cancer cell migration and invasion through ERK/MAPK signaling pathway

Tight junctions are the most apical component of the junctional complex critical for epithelial cell barrier and polarity functions. Although its disruption is well documented during cancer progression such as epithelial-mesenchymal transition, molecular mechanisms by which tight junction integral membrane protein claudins affect this process remain largely unknown. In this report, we found that claudin-7 was normally expressed in bronchial epithelial cells of human lungs but was either downregulated or disrupted in its distribution pattern in lung cancer. To investigate the function of claudin-7 in lung cancer cells, we transfected claudin-7 cDNA into NCI-H1299, a human lung carcinoma cell line that has no detectable claudin-7 expression. We found that claudin-7 expressing cells showed a reduced response to hepatocyte growth factor (HGF) treatment, were less motile, and formed fewer foot processes than the control cells did. In addition, cells transfected with claudin-7 dramatically decreased their invasive ability after HGF treatment. These effects were mediated through the MAPK signaling pathway since the phosphorylation level of ERK1/2 was significantly lower in claudin-7 transfected cells than in control cells. PD98059, a selective inhibitor of ERK/MAPK pathway, was able to block the motile effect. Claudin-7 formed stable complexes with claudin-1 and -3 and was able to recruit them to the cell-cell junction area in claudin-7 transfected cells. When control and claudin-7 transfected cells were inoculated into nude mice, claudin-7 expressing cells produced smaller tumors than the control cells. Taken together, our study demonstrates that claudin-7 inhibits cell migration and invasion through ERK/MAPK signaling pathway in response to growth factor stimulation in human lung cancer cells.

Increased nucleotide polymorphic changes in the 5′-untranslated region of δ-catenin ( CTNND2 ) gene in prostate cancer

Cancer pathogenesis involves multiple genetic and epigenetic alterations, which result in oncogenic changes in gene expression. δ-Catenin (CTNND2) is overexpressed in cancer, although the mechanisms of its upregulation are highly variable. Here we report that in prostate cancer, the methylation of CpG islands in the δ-catenin promoter was not a primary regulatory event. There was also no δ-catenin gene amplification. However, using the single-strand conformation polymorphism analysis, we observed the increased nucleotide changes in the 5′-untranslated region of δ-catenin gene in human prostate cancer. At least one such change (−9 G>A) is a true somatic point mutation associated with a high Gleasons score, poorly differentiated prostatic adenocarcinoma. Laser capture microdissection coupled with PCR analyses detected the mutation only in cancerous but not in the adjacent benign prostatic tissues. Using chimeric genes encoding the luciferase reporter, we found that this mutation, but not a random mutation or a mutation that disrupts an upstream open reading frame, resulted in a remarkably higher expression and enzyme activity. This mutation did not affect transcriptional efficiency, suggesting that it promotes δ-catenin translation. This is the first report of δ-catenin gene mutation in cancer and supports the notion that multiple mechanisms contribute to its increased expression in carcinogenesis.

Unusual reticulin staining pattern in well-differentiated hepatocellular carcinoma

BackgroundSpecial stains, such as reticulin stain and CD34 immunostain, are very helpful in the diagnosis of well differentiated hepatocellular carcinoma (HCC). Most studies have shown that absent or decreased reticulin stain or an abnormal reticulin pattern with widened trabeculae is reliable for the diagnosis of well-differentiated HCC.Case reportWe report here two cases of well differentiated HCC with an unusual reticulin staining pattern. A strongly positive reticulin network was preserved within the tumor, which surrounded individual tumor cells in a monolayered trabecular pattern. At the same time, an increased CD34 stain was present in the tumor.ConclusionsThis unusual reticulin pattern represents part of the diverse reticulin staining patterns seen in HCC. Although this staining pattern is rare, it should be recognized when diagnosing well-differentiated HCC in small samples such as cellblock of fine needle aspiration or small core biopsies.

δ-Catenin, a Wnt/β-catenin modulator, reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming.

Mutations of Wnt/β-catenin signaling pathway has essential roles in development and cancer. Although β-catenin and adenomatous polyposis coli (APC) gene mutations are well established and are known to drive tumorigenesis, discoveries of mutations in other components of the pathway lagged, which hinders the understanding of cancer mechanisms. Here we report that δ-catenin (gene designation: CTNND2), a primarily neural member of the β-catenin superfamily that promotes canonical Wnt/β-catenin/LEF-1-mediated transcription, displays exonic mutations in human prostate cancer and promotes cancer cell survival adaptation and metabolic reprogramming. When overexpressed in cells derived from prostate tumor xenografts, δ-catenin gene invariably gives rise to mutations, leading to sequence disruptions predicting functional alterations. Ectopic δ-catenin gene integrating into host chromosomes is locus nonselective. δ-Catenin mutations promote tumor development in mouse prostate with probasin promoter (ARR2PB)-driven, prostate-specific expression of Myc oncogene, whereas mutant cells empower survival advantage upon overgrowth and glucose deprivation. Reprogramming energy utilization accompanies the downregulation of glucose transporter-1 and poly (ADP-ribose) polymerase cleavage while preserving tumor type 2 pyruvate kinase expression. δ-Catenin mutations increase β-catenin translocation to the nucleus and hypoxia-inducible factor 1α (HIF-1α) expression. Therefore, introducing δ-catenin mutations is an important milestone in prostate cancer metabolic adaptation by modulating β-catenin and HIF-1α signaling under glucose shortage to amplify its tumor-promoting potential.

Florid cystic endosalpingiosis with extensive peritoneal involvement and concurrent bilateral ovarian serous cystadenoma

Case report A 44-year-old woman presented with a chief complaint of abdominal pain. A CT scan confi rmed bilateral ovarian cystic masses measuring 6.5 cm and 11 cm in size, respectively. At exploratory laparotomy, there were bilateral ovaries masses, as well as extensive involvement of the pelvic cavity by small clear vesicles which covered the uterus, the urinary bladder and the pelvic side walls. Aft er intraoperative frozen section had confi rmed benign histological features of the vesicular lesions, hysterectomy and bilateral salpingo-oophorectomy were done. In gross examination of the hysterectomy specimen, vesicles on the uterine surface measured from 1 to 8 mm in size and were fi lled with clear serous fl uid (Figure 1A). Microscopically, the vesicles were present in subserosal parts of the uterus and showed no signs of deep invasion (Figure 1B). Th e vesicles were lined with a single layer of ciliated epithelium without atypia. No associated endometrial type stroma, haemosiderin deposits or desmoplastic changes of the stroma were present (Figure 1C). Th e fi ndings were consistent with fl orid cystic endosalpingiosis with extensive peritoneal involvement. At the same time, the patient ’ s bilateral ovarian masses were diagnosed as serous cystadenomas. No borderline change or malignancy was identifi ed in the ovarian lesion (Figure 1D). Th e patient remains well 1 year post-operation.

GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis

GPR4 is a proton-sensing G protein-coupled receptor that can be activated by extracellular acidosis. It has recently been demonstrated that activation of GPR4 by acidosis increases the expression of numerous inflammatory and stress response genes in vascular endothelial cells (ECs) and also augments EC-leukocyte adhesion. Inhibition of GPR4 by siRNA or small molecule inhibitors reduces endothelial cell inflammation. As acidotic tissue microenvironments exist in many types of inflammatory disorders, including inflammatory bowel disease (IBD), we examined the role of GPR4 in intestinal inflammation using a dextran sulfate sodium (DSS)-induced acute colitis mouse model. We observed that GPR4 mRNA expression was increased in mouse and human IBD tissues when compared to control intestinal tissues. To determine the function of GPR4 in intestinal inflammation, wild-type and GPR4-deficient mice were treated with 3% DSS for 7days to induce acute colitis. Our results showed that the severity of colitis was decreased in GPR4-deficient DSS-treated mice in comparison to wild-type DSS-treated mice. Clinical parameters, macroscopic disease indicators, and histopathological features were less severe in the DSS-treated GPR4-deficient mice than the DSS-treated wild-type mice. Endothelial adhesion molecule expression, leukocyte infiltration, and isolated lymphoid follicle (ILF) formation were reduced in intestinal tissues of DSS-treated GPR4-null mice. Collectively, our results suggest GPR4 provides a pro-inflammatory role in the inflamed gut as the absence of GPR4 ameliorates intestinal inflammation in the acute experimental colitis mouse model.

Cytological features of diffuse large B-cell lymphoma can mimic metastatic carcinoma on fine needle aspiration cytology

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δ‐Catenin as a potential cancer biomarker

To the Editors: δ-Catenin/NPRAP/Neurojungin (gene designation: CTNND2) is primarily a neuronal postsynaptic protein expressed in the brains of healthy individuals. However, it is increasingly recognized that this initially described neural specific member of the β-catenin/armadillo superfamily is overexpressed in cancers of peripheral tissues, including prostate, breast, lung, and ovarian cancers. Our previous studies demonstrated that δ-catenin mRNA and protein are overexpressed in primary prostatic adenocarcinomas. Since then, a number of excellent studies have provided strong evidence that δ-catenin overexpression is associated with poor prognosis in cancer, including lung cancer. These studies significantly elevated the expectation that δ-catenin overexpression is a potential cancer biomarker. From the studies of δ-catenin expression and distribution in different cancer types, it is clear that δ-catenin could be expressed as different variants with modifications and localized to different subcellular regions. Increased pathology literature on δ-catenin involvement in cancer progression calls for careful interpretation of δ-catenin expression data to avoid potential misunderstanding of its functions in carcinogenesis. When cancer tissues are examined, it is important to determine whether the full-length, modified fragments, or different variants of δ-catenin are expressed in the cancer cells and whether the revealed δ-catenin distribution in cancer is dependent upon the choices of antibody applications. In this letter, we would like to emphasize and raise awareness of epitope dependent δ-catenin expression in different types of cancer cells. When rAb62, a well-characterized antibody against the epitope N-terminal to the armadillo domain,

Effects of robotic-assisted laparoscopic prostatectomy on surgical pathology specimens

BackgroundRobotic-assisted laparoscopic prostatectomy (RALP) has greatly changed clinical management of prostate cancer. It is important for pathologists and urologists to compare RALP with conventional open radical retropubic prostatectomy (RRP), and evaluate their effects on surgical pathology specimens.MethodsWe retrospectively reviewed and statistically analyzed 262 consecutive RALP (n = 182) and RRP (n = 80) procedures performed in our institution from 2007 to 2010. From these, 49 RALP and 33 RRP cases were randomly selected for additional microscopic examination to analyze the degree of capsular incision and the amount of residual prostate surface adipose tissue.ResultsPositive surgical margins were present in 28.6% RALP and 57.5% RRP cases, a statistically significant difference. In patients with stage T2c tumors, which represent 61.2% RALP and 63.8% RRP patients, the positive surgical margin rate was 24.1% in the RALP group and 58.8% in the RRP group (statistically significant difference). For other pathologic stages, the differences in positive margins between RALP and RRP groups were not statistically significant. The incidence of positive surgical margins after RALP was related to higher tumor stage, higher Gleason score, higher tumor volume and lower prostate weight, but was not related to the surgeons performing the procedure. When compared with RRP, RALP also caused less severe prostatic capsular incision and maintained larger amounts of residual surface adipose tissue in prostatectomy specimens.ConclusionsIn this study RALP showed a statistically significant lower positive surgical margin rate than RRP. Analysis of capsular incision and amount of prostatic surface residual adipose tissue suggested that RALP caused less prostatic capsular damage than RRP.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1278078279667611

HIV Screening and Awareness Survey for Pregnant Women in a Remote Area in Xinjiang Uyghur Autonomous Region of China

Objective: The number of people infected with human immunodeficiency virus (HIV) in China has increased in recent years. HIV screening for pregnant women was performed in a remote area in Xinjiang, as an effort to promote universal HIV screening in pregnant women and to help prevention of mother-to-child transmission. Methods: Pregnant women in Burqin and Jeminay Counties in Xinjiang were offered free voluntary HIV screening. Local mid-level medical workers were trained to use Determine® HIV-1/2 kit for HIV screening. All the tested pregnant women signed a consent form, received HIV education material, and participated in an HIV knowledge survey. Results: All the 890 pregnant women receiving HIV test had negative result. Among these women, 67.6% were Kazakh and 40.9% were farmers. Survey of HIV knowledge showed that these womens awareness about mother-to-child transmission was limited. The levels of HIV knowledge were related with ethnic background, age, education and profession of the pregnant women. Conclusion: The results suggested that HIV infection had not become a significant problem among the pregnant women in this remote area of Xinjiang, but continued efforts to improve the awareness of HIV, especially the knowledge about mother-to-child transmission of HIV, in pregnant women were needed.