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1.  Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes 
Nature genetics  2015;47(8):933-938.
Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia1-3. We report that Autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and required for a timely onset of Gli2-induced skin tumorigenesis in mice. Induction of Aire mRNA in keratinocytes depends upon a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K4. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each are bound to a specific promoter region featuring a NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent pro-inflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia.
doi:10.1038/ng.3355
PMCID: PMC4520766  PMID: 26168014
Keratin 17 (Krt17); Autoimmune regulator (Aire); hnRNP K; Skin; Inflammation; Cancer
2.  Fallopian tube secretory cell expansion: a sensitive biomarker for ovarian serous carcinogenesis 
Recent advances suggest that precancerous lesions of pelvic serous carcinoma originate from tubal secretory cells. The purpose of our study was to determine if an increased number of secretory cells varies with age or location in the fallopian tube and to examine its association with serous neoplasia. Three groups (benign control, high-risk, and pelvic serous carcinoma) of age-matched patients were studied. The age data were stratified into 10-year intervals ranging from 20-29 to older than 80. The number of secretory and ciliated cells from both tubal fimbria and ampulla segments was counted by microscopy and immunohistochemical staining methods. The data were analyzed by standard contingency table and Poisson distribution methods after age justification. We found that the absolute number of tubal secretory cells increased significantly with age in all three groups. But a more dramatic increase of secretory cells was observed in high-risk and pelvic serous carcinoma patients. Secretory cell expansion is more prevalent than secretory cell outgrowth in both fimbria and ampulla tubal segments and is significantly associated with serous neoplasia (P < 0.001). Furthermore, age remained a significant risk factor for serous neoplasia after age adjustment. These findings suggest that secretory cell expansion could serve as a potential sensitive biomarker for early serous carcinogenesis within the fallopian tube. The study also supports a relationship between serous neoplasia and increased secretory to ciliated cell ratios, and the relationship between frequency of secretory cell expansion within the fallopian tube and increasing age and-more significantly-presence of high-risk factors or co-existing serous cancers.
PMCID: PMC4656785  PMID: 26692952
Fallopian tube; tubal secretory cells; pelvic serous carcinoma; ovarian cancer; pathogenesis; carcinogenesis
3.  Flutamide and biomarkers in women at high risk for ovarian cancer: preclinical and clinical evidence 
We hypothesized (1) preclinical biologic evidence exists for the role of androgens in ovarian cancer development and (2) flutamide treatment of women at high risk (HR) for ovarian cancer may identify meaningful tissue biomarkers of androgen action and of ovarian cancer initiation. We showed that androgen ablation of male mice led to a 24-fold decrease in tumor burden from serous ovarian cells. In a phase 2 study, we studied the effect of pre-operative flutamide treatment (125 mg/day × 6 weeks) in 12 women vs. 47 controls, 47% with BRCA mutation. We analyzed immunohistochemical scores of candidate proteins CSF-1, CSF-1R, and ErbB4in the epithelium and stroma of fallopian tube, ovary, and ovarian endosalpingiosis (ES). Flutamide decreased the levels, notably, of CSF-1 and ErbB4 in ovarian stroma (P≤ 0.0006) and ES (P≤ 0.01); ErbB4 in ovarian epithelium (P=0.006) and CSF-1R in ES (P=0.009). Our logistic regression model clearly distinguished the flutamide patients from controls (P ≤ 0.0001). Our analysis of the precision of this model of CSF-1 and ErbB4 expression in ovarian stroma achieved 100% sensitivity and 97% specificity (AUC=0.99). Thus, our data suggest that a short 6-week exposure of flutamide reversed elevated levels of CSF-1 and ErbB4 (both of which we had previously found correlated with HR status). CSF-1 and ErbB4 in ovarian stroma led to a model with high predictive value for flutamide sensitivity. The effect of flutamide on marker expression in ES, previously associated with BRCA carrier status, suggests that ES may be a latent precursor to pelvic serous cancers.
doi:10.1158/1940-6207.CAPR-13-0408
PMCID: PMC4154987  PMID: 24950779
Androgen; high risk; biomarkers; ovary; flutamide
4.  Variants of human papillomavirus type 16 predispose toward persistent infection 
A cohort study of 292 Chinese women was conducted to determine the relationship between human papillomavirus (HPV) type 16 variants and persistent viral infection. Enrolled patients were HPV16 positive and had both normal cytology and histology. Flow-through hybridization and gene chip technology was used to identify the HPV type. A PCR sequencing assay was performed to find HPV16 E2, E6 and E7 gene variants. The associations between these variants and HPV16 persistent infection was analyzed by Fisher’s exact test. It was found that the variants T178G, T350G and A442C in the E6 gene, as well as C3158A and G3248A variants in the E2 gene were associated with persistent HPV16 infection. No link was observed between E7 variants and persistent viral infection. Our findings suggest that detection of specific HPV variants would help identify patients who are at high risk for viral persistence and development of cervical neoplasia.
PMCID: PMC4555745  PMID: 26339417
Human papillomavirus; persistent infection; variants
5.  Metalloprotease NleC Suppresses Host NF-κB/Inflammatory Responses by Cleaving p65 and Interfering with the p65/RPS3 Interaction 
PLoS Pathogens  2015;11(3):e1004705.
Attaching/Effacing (A/E) pathogens including enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC) and the rodent equivalent Citrobacter rodentium are important causative agents of foodborne diseases. Upon infection, a myriad of virulence proteins (effectors) encoded by A/E pathogens are injected through their conserved type III secretion systems (T3SS) into host cells where they interfere with cell signaling cascades, in particular the nuclear factor kappaB (NF-κB) signaling pathway that orchestrates both innate and adaptive immune responses for host defense. Among the T3SS-secreted non-LEE-encoded (Nle) effectors, NleC, a metalloprotease, has been recently elucidated to modulate host NF-κB signaling by cleaving NF-κB Rel subunits. However, it remains elusive how NleC recognizes NF-κB Rel subunits and how the NleC-mediated cleavage impacts on host immune responses in infected cells and animals. In this study, we show that NleC specifically targets p65/RelA through an interaction with a unique N-terminal sequence in p65. NleC cleaves p65 in intestinal epithelial cells, albeit a small percentage of the molecule, to generate the p651–38 fragment during C. rodentium infection in cultured cells. Moreover, the NleC-mediated p65 cleavage substantially affects the expression of a subset of NF-κB target genes encoding proinflammatory cytokines/chemokines, immune cell infiltration in the colon, and tissue injury in C. rodentium-infected mice. Mechanistically, the NleC cleavage-generated p651–38 fragment interferes with the interaction between p65 and ribosomal protein S3 (RPS3), a ‘specifier’ subunit of NF-κB that confers a subset of proinflammatory gene transcription, which amplifies the effect of cleaving only a small percentage of p65 to modulate NF-κB-mediated gene expression. Thus, our results reveal a novel mechanism for A/E pathogens to specifically block NF-κB signaling and inflammatory responses by cleaving a small percentage of p65 and targeting the p65/RPS3 interaction in host cells, thus providing novel insights into the pathogenic mechanisms of foodborne diseases.
Author Summary
The nuclear factor kappaB (NF-κB) signaling pathway is crucial for host defense, as it orchestrates both innate and adaptive immune responses. Beyond the best-studied Rel proteins (p65, RelB, c-Rel, p50 and p52), RPS3 has been recently identified as a “specifier” component of NF-κB, modulating the promoter selectivity and transcriptional specificity of NF-κB. In particular, the RPS3/p65-conferred signaling pathway was recently shown to play a critical role in host proinflammatory transcription and immune responses. Attaching and effacing (A/E) pathogens and others have acquired sophisticated mechanisms to modulate host NF-κB signaling pathways. We have found that NleC, a metalloprotease effector secreted by A/E pathogens, modulates host NF-κB signaling and inflammatory responses through a novel mechanism. NleC specifically recognizes and cleaves a small percentage of p65 and the generated N-terminal fragment of p65 interferes with the p65/RPS3 interaction, thereby amplifying the effect of cleaving only a small percentage of p65 molecules to selectively inhibit NF-κB gene expression. Our findings highlight a previously unappreciated mechanism through which pathogen-encoded proteases interfere with signaling cascades and inflammatory responses in host cells.
doi:10.1371/journal.ppat.1004705
PMCID: PMC4355070  PMID: 25756944
6.  Tubal origin of ovarian endometriosis and clear cell and endometrioid carcinoma 
Current research has strongly proposed that contrary to prior beliefs, many ovarian epithelial cancers (OECs) do not, as their name suggests, originate in the ovaries. Recent findings regarding both high-grade and low-grade serous carcinomas has implicated the fallopian tube as a cell source for these OECs, but until now, there has been little insight into the cellular source for clear cell and endometrioid carcinomas. In this commentary review article, we aimed to discuss the new findings that support the possible contribution from the fallopian tube in clear cell and endometrioid carcinomas. Specifically, we have provided results that showcased ovarian surface epithelia (OSE) and ovarian epithelial inclusions (OEIs) as having mesothelial and tubal origins and have strongly recognized the secondary müllerian system and the ability for tubal epithelia to implant upon the ovarian surface as contributing to fallopian tube-derived OEIs (F-OEIs). We have provided initial indications of these F-OEIs and their relationship to endometriosis and then clear cell and endometrioid carcinomas and subsequently offer our new proposal of a probable tubal origin. This new proposal is a paradigm that drastically changes the understanding behind the origin of these OECs and has significant clinical implications in the near future.
PMCID: PMC4449423  PMID: 26045974
Fallopian tube; secondary müllerian system; endometriosis; clear cell carcinoma; endometrioid carcinoma
7.  Effect of luteinizing hormone-induced prohibitin and matrix metalloproteinases on ovarian epithelial tumor cell proliferation 
Recent studies have suggested that elevated gonadotropins contribute to ovarian epithelial tumor (OET) cell proliferation. However, the cellular effects of luteinizing hormone, a member of gonadotropins, on OET proliferation are controversial. Our previous work showed that luteinizing hormone has no effect on cell proliferation, but the molecular mechanism of such finding remains to be clarified. Considering that the cell growth in various types of tumors has been associated with regulations of prohibitin and matrix metalloproteinases, we aim to investigate a possible regulatory role of luteinizing hormone on prohibitin and matrix metalloproteinases to determine the roles of these molecules in OET proliferation. We found that LH stimulation resulted in a dose-dependent expression of prohibitin and MMPs and time-dependent phosphorylations of ERK and AKT. Blocking MAPK or PI3K/AKT signaling could attenuate LH-induced prohibitin and MMPs expression. Additionally, the depletion of prohibitin reduced the level of MMPs expression, and increased prohibitin expression abolished the positive effect of LH-induced MMP-9 on cellular growth. Therefore, we conclude that LH is able to up-regulate both prohibitin and MMP-9 in OET cells without the cellular growth effect due to opposing biologic functions for cell proliferation between these two molecules. The opposing cellular growth function between prohibitin and MMP-9 is a novel finding. Regulation of either molecule may be useful for future targeted therapy for ovarian epithelial cancers.
PMCID: PMC4300715  PMID: 25628924
Prohibitin; MMP-2; MMP-9; LH; proliferation
8.  Utility of Alpha-methylacyl-CoA racemase (p504s) Immunohistochemistry In Distinguishing Endometrial Clear Cell Carcinomas from Serous and Endometrioid Carcinomas 
Human pathology  2013;44(12):10.1016/j.humpath.2013.07.033.
The expression of alpha-methylacyl-coenzyme-A-racemase (AMACR) has previously been reported in 75 to 100% of urethral/bladder clear cell carcinomas, tumors that are known to display broad phenotypic overlap with their identically-named müllerian counterparts. Herein, we assess the utility of AMACR in distinguishing endometrial clear cell carcinomas (CCC) from endometrial serous carcinomas (ESC) and endometrial endometrioid carcinomas (EEC). 111 endometrial carcinomas in a tissue microarray, including 49 CCC, 13 ESC and 49 EEC, were assessed for AMACR immunoreactivity, with results scored semi-quantitatively (scores 0, 1+, 2+, 3+ for 0%, 1-5%, 6-50%, >50% immunoreactive cells respectively). 50 (45%) of the 111 carcinomas were AMACR-positive, with the following score distribution: CCC: 0 (n=12), 1+ (n=12), 2+ (n=3), 3+ (n=22); EEC: 0 (n=38), 1+ (n=4), 2+ (n=4), 3+ (n=3); ESC: 0 (n=11), 1+ (n=1), 2+ (n=0), 3+ (n=1). AMACR expression was significantly more frequent in CCC (75%) than in ESC (15%) or EEC (22%), p<0.0001. The sensitivity and specificity of AMACR expression in classifying a carcinoma as CCC were 0.75 (95% CI: 0.61-0.86) and 0.79 (95% CI: 0.66-0.88) respectively, with an odds ratio of 11.62 (95% CI: 5-28, p < 0.001), and an area under the curve of 0.79 (95% CI: 0.68 to 0.88). These findings indicate that AMACR expression is strongly associated with CCC and displays a relatively robust diagnostic test performance. However, its practical utility may be limited by the focal nature of its expression in 32% of the AMACR-positive CCC cases, as well as its expression in 15-22% of the non-CCC histotypes.
doi:10.1016/j.humpath.2013.07.033
PMCID: PMC3865867  PMID: 24119561
Alpha-methylacyl-CoA-racemase; p504s; AMACR; immunohistochemistry; endometrial clear cell carcinoma
10.  The Clinicopathologic Significance of p53 and BAF-250a (ARID1A) Expression in Clear Cell Carcinoma of the Endometrium 
TP53 mutation (and associated p53 protein overexpression) is probably a negative prognostic marker in endometrial cancers, but its relevance in the rarer histologic subtypes, including clear cell carcinomas, has not been delineated. Preclinical studies suggest functional interactions between p53 and the BAF250a protein, the product of a tumor suppressor gene ARID1A that is frequently mutated in ovarian clear cell carcinoma. In this study, we evaluated the significance of p53 and BAF250a expression, as assessed by immunohistochemistry, in a group of 50 endometrial clear cell carcinomas. Seventeen of 50 cases (34%) were p53 positive; the remaining 33 cases had a p53 wild-type (p53-wt) immunophenotype. Of the 11 relapses/recurrences in the entire dataset, 73% were in the p53[+] group (p=0.008). On univariate analyses, the median overall survival for the p53-wt patients (83 mo) was longer than the p53[+] patients (63 mo) (p=0.07), and the median progression-free survival for the p53-wt group (88 mo) was significantly longer than the p53[+] group (56 mo) (p=0.01). On multivariate analyses, p53 expression was not associated with reduced overall or progression-free survival. Additionally, p53 status was not significantly associated with pathologic stage or morphologic patterns. Ten of the 50 cases (20%) showed a complete loss of BAF250a expression. There was no significant correlation between p53 and BAF250a expression. The p53+/BAF250a−, p53+/BAF250a+, p53-wt/BAF250a+, and p53-wt/BAF250a− composite immunophenotypes were identified in 8%, 26%, 54% and 12% of cases respectively, and neither loss of BAF250a expression nor composite p53/BAF250a expression patterns were associated with reduced overall or progression-free survival. In conclusion, a significant subset of CCC express p53, and these cases are apparently not definable by their morphologic features. p53 expression may be a negative prognostic factor in this histotype, and warrants additional studies. Loss of BAF250a expression has no prognostic significance in endometrial clear cell carcinomas.
doi:10.1038/modpathol.2013.35
PMCID: PMC3886836  PMID: 23524907
11.  IMP3 as a cytoplasmic biomarker for early serous tubal carcinogenesis 
Background
Serous tubal intraepithelial carcinoma (STIC) and the p53 signature in tubal mucosa have been supported to be precursor lesions in high-grade serous carcinoma (HGSC) of the fallopian tube, ovary, and peritoneum. It remains critical to find biomarkers for precursor lesions in order to detect HGSCs efficiently. IMP3 is an oncoprotein that has been explored in human malignancies. No studies have specifically addressed the expression of IMP3 in precursor or early lesions of HGSC. The main purposes of this study are to evaluate if IMP3 plays any role in the process of pelvic serous carcinogenesis by examining its expression in HGSC precursor lesions, to examine the relationship between IMP3 and p53 in those precursor lesions, and to check if IMP3 can be used as a biomarker for early diagnosis.
Methods
Immunohistochemistry for IMP3 and p53 was performed and evaluated in 48 HGSCs with STIC, 62 HGSCs without STIC, and 60 benign cases as negative controls. Sections of fallopian tubes with or without STIC , as well as cancers within the ovaries, were studied. IMP3 signature was defined as strong IMP3 cytoplasmic staining in 10 or more consecutive benign-looking tubal epithelial cells. The relationship between IMP3 and p53 overexpression was examined.
Results
In the 48 HGSC patients with STIC, IMP3 was positive in 46% of STIC lesions and had a similar positive rate in the invasive components of HGSC. IMP3 was also expressed in normal appearing tubal epithelia (IMP3 signature) in 15 (31%) of 48 HGSC cases with STIC and 10 (16%) of 62 cases without STIC. In contrast, no single IMP3 signature was found in the benign control group. Concordant expression of IMP3 and p53 signatures in the STIC group was found in up to one-third of the cases. There were also five (10%) STIC cases with positive IMP3 and negative p53.
Conclusions
We conclude that IMP3 may be involved in the process and progression of pelvic HGSC and may serve as a complimentary biomarker in diagnosing STIC.
doi:10.1186/s13046-014-0060-2
PMCID: PMC4223529  PMID: 25038792
IMP3; Serous tubal intraepithelial carcinoma; STIC; p53 signature; High-grade serous carcinoma
12.  Epidemiology of Functional Abdominal Bloating and Its Impact on Health Related Quality of Life: Male-Female Stratified Propensity Score Analysis in a Population Based Survey in Mainland China 
PLoS ONE  2014;9(7):e102320.
Background
The epidemiology of Functional abdominal bloating (FAB) and its impact on health-related quality of life (HRQoL) in Chinese people remains unclear.
Methods
Randomised, stratified, multi-stage sampling methodology was used to select a representative sample of the general population from five cities in China (n = 16,078). All respondents completed the modified Rome II questionnaire; 20% were asked to complete the 36-item Short Form (SF-36). The associated factors of FAB were analyzed. The effects of FAB on HRQoL were estimated with gender stratification using propensity score techniques in 20% subsample.
Results
Overall, 643 individuals (4.00%) had FAB and it was more prevalent in males than in females (4.87% vs. 3.04%, P<0.001). For males, self-reported history of dyspepsia was most strongly associated with FAB (OR = 2.78; 95% CI: 1.59, 4.72). However, the most strongly associated factor was self-reported health status for females (moderate health vs. good health: OR = 2.06, 95% CI: 1.07, 3.96. P = 0.030; poor health vs. good health: OR = 5.71, 95% CI: 2.06, 15.09). Concerning HRQoL, FAB was found to be related to two domains: role limitation due to physical problems (P = 0.030) and bodily pain (P<0.001) in females. While, in males, there were significant differences in multiple domains between those with and without FAB.
Conclusion
The prevalence of FAB in China was lower than previous reports. Males who had ever been diagnosed with dyspepsia and females who were in a poor self-reported health status were correlated with a higher prevalence of FAB. FAB affected only physical health in females, but impaired both physical and mental health in males.
doi:10.1371/journal.pone.0102320
PMCID: PMC4103840  PMID: 25036100
13.  IMP3 signatures of fallopian tube: a risk for pelvic serous cancers 
Background
Recent advances suggest fallopian tube as the main cellular source for women’s pelvic serous carcinoma (PSC). In addition to TP53 mutations, many other genetic changes are involved in pelvic serous carcinogenesis. IMP3 is an oncofetal protein which has recently been observed to be overexpressed in benign-looking tubal epithelia. Such findings prompted us to examine the relationship between IMP3 over-expression, patient age and the likelihood of development of PSC.
Methods
Fallopian tubes from three groups (low-risk, high-risk, and PSC) of patients with matched ages were studied. Age was recorded in 10 years intervals ranging from age 20 to older than 80. The number of IMP3 signatures (defined by 10 or more tubal secretory cells stained positively and continuously in benign appearing tubal mucosa) from both tubal fimbria and ampulla segments was measured. The data was analyzed by standard contingency table and Poisson distribution methods after age adjustment. IMP3 overexpression was also examined in serous tubal intraepithelial carcinoma and PSC.
Results
The positive IMP3-stained cells are mainly tubal secretory cells. The absolute number of tubal IMP3 signatures increased significantly within each age group. Age remained a significant risk factor for serous neoplasia after age adjustment. IMP3 signatures were more frequent in the patients of both high-risk and PSC groups. The presence of IMP3 signatures in tubal mucosa was significantly associated with tubal or pelvic serous carcinogenesis (p < 0.001).
Conclusions
The findings suggest that tubal secretory cells with IMP3 signatures showing growth advantage could potentially serve as a latent precancer biomarker for tubal or pelvic serous carcinomas in women.
doi:10.1186/s13045-014-0049-5
PMCID: PMC4230642  PMID: 25014991
IMP3 signature; Fallopian tube; Tubal secretory cells; Ovarian cancer; Pelvic serous carcinoma
14.  Biomarkers and endosalpingiosis in the ovarian and tubal microenvironment of women at high-risk for pelvic serous carcinoma 
Introduction: BRCA mutations increase the risk for development of high-grade pelvic serous carcinomas. Tissue biomarkers distinguishing women at high-risk (HR) for ovarian cancer from those at low-risk (LR) may provide insights into tumor initiation pathways. Methods: A prospective study of 47 HR women (40% BRCA carriers) undergoing risk-reducing salpingo-oophorectomy and 48 LR controls undergoing salpingo-oophorectomy was performed. Ovarian/tubal tissues were harvested. Immunohistochemical analysis of candidate proteins CSF-1, CSF-1R, ErbB4 is presented, with scores separately analyzed in epithelium and stroma, in ampulla, fimbria, ovary, and ovarian endosalpingiosis (ES). Comparison was performed between HR and LR groups. Results: Elevated levels of CSF-1 (p=0.005) or ErbB4 (p=0.005) in the ovarian epithelium, or ErbB4 (p=0.005) in the ovarian stroma, were significantly associated with both the HR status and carrying a BRCA mutation, as was nuclear ErbB4 staining. Ovarian ES, an entity which likely derives from the tubal mucosal epithelium, was also associated with HR (p=0.038) and BRCA mutation status (p=0.011). Among the BRCA carriers only, markers also found association when present in the tube as well as in ovarian ES (p < 0.05). ROCs were generated including in the regression model both CSF-1 and ErbB4 expression levels. A model including CSF-1 in ovarian epithelium, ErbB4 in ovarian stroma, and younger age achieves AUC=0.87 (73% sensitivity, 93% specificity) of detection of the HR status. In BRCA carriers, CSF-1 in ovarian epithelium alone achieves AUC=0.85. Conclusions: Our data suggest that elevated levels of CSF-1/ErbB4 in the adnexae correlate with HR/BRCA carrier status. CSF-1/CSF-1R signaling is active in ovarian cancer progression; our data suggests a role in its initiation. ErbB4, in particular nuclear ErbB4, may have a role in tumor initiation as well. Ovarian ES, an entity which may represent a latent precursor to low-grade pelvic serous carcinomas, was surprisingly associated with both HR status and the BRCA carrier cohort. In line with these findings, both ErbB4 and CSF-1R expression in ovarian ES correlated with carrying a BRCA mutation. This analysis, which needs to be validated, indirectly suggests a potential link between ovarian ES and the development of pelvic serous carcinoma in women who are BRCA mutation carriers.
PMCID: PMC3902233  PMID: 24482739
CSF-1; ErbB4; endosalpingiosis; high-risk
15.  Expression of the Oncofetal Protein IGF2BP3 (IMP3) in Endometrial Clear Cell Carcinoma: Assessment of Frequency and Significance 
Human pathology  2013;44(8):1508-1515.
Insulin-like growth factor-II mRNA-binding protein 3 (IGF2BP3 or IMP3) is a biomarker whose expression has been found to be a negative prognostic factor in several neoplasms, including ovarian clear cell carcinoma. In this study, we analyzed the frequency and clinicopathologic significance of IMP3 expression, as assessed by immunohistochemistry and as scored using a modified H-score system, in a cohort of 50 endometrial clear cell carcinomas (CCC). Cases with scores of 0-100, 101-200, and 201-300 were classified as negative/mildly positive (n=17), moderately positive (n=20) and strongly positive (n=13), respectively. A distinctive pattern of increased staining at the myoinvasive front (relative to the main tumor) was evident in 46% of the cases with evaluable foci of myometrial invasion. Moderate/strong IMP3 staining was associated with a tumor architectural pattern that has been reported to be of poor prognostic significance: at least 10% of the tumor composed of solid architecture or individual infiltrating tumor cells (p=0.01). Increasing levels of IMP3 expression showed a trend towards decreasing RFS (median survival 75.6, 81.3 and 48.4 months for the negative/mildly, moderately and strongly positive groups respectively (p=0.09). However, IMP3 expression was not significantly associated with reduced overall survival or RFS in a multivariate analytic model. The finding in a subset of our cases of increased IMP3 expression at the tumoral myoinvasive front is consistent with a role for IMP3 in invasiveness, as is the trend towards reduced RFS in cases expressing IMP3 at high levels. These preliminary findings suggests that IMP3 expression may be involved in the pathogenesis of CCC, and is worthy of further exploration.
doi:10.1016/j.humpath.2012.12.003
PMCID: PMC3888088  PMID: 23465280
16.  Sam68 modulates the promoter specificity of NF-κB and mediates expression of CD25 in activated T cells 
Nature communications  2013;4:1909.
CD25, the alpha chain of the interleukin-2 receptor, is expressed in activated T cells and plays a significant role in autoimmune disease and tumorigenesis; however, the mechanisms regulating transcription of CD25 remain elusive. Here we identify the Src-associated substrate during mitosis of 68kDa (Sam68) as a novel non-Rel component in the nuclear factor-kappaB (NF-κB) complex that confers CD25 transcription. Our results demonstrate that Sam68 plays an essential role in the induction and maintenance of CD25 in T cells. T cell receptor engagement triggers translocation of the inhibitor of NF-κB kinase alpha (IKKα) from the cytoplasm to the nucleus, where it phosphorylates Sam68, causing complex formation with NF-κB in the nucleus. These findings reveal the important roles of KH domain-containing components and their spatial interactions with IKKs in determining the binding targets of NF-κB complexes, thus shedding novel insights into the regulatory specificity of NF-κB.
doi:10.1038/ncomms2916
PMCID: PMC3684077  PMID: 23715268
17.  Cytologic changes of ovarian epithelial cancer induced by neoadjuvant chemotherapy 
Objective: Neoadjuvant chemotherapy (NACT) followed by cytoreduction has now become a part of standard care for patients with advanced ovarian cancer. Cytologic changes of the cancer cells induced by NACT, however, sometimes may cause confusion in terms of pathologic diagnosis and therefore inappropriate management. The objective of this study was to characterize the histologic or cytologic features of the ovarian cancers from those patients who received NACT in order to improve the diagnostic accuracy and reduce unnecessary clinical workup. Methods: Specimens from 120 patients with advanced ovarian cancer who received NACT were studied. All 120 cases had either cytologic samples from ascites (n=108) or fine needle aspiration (n=12) and the diagnosis of consistent with cancers of ovarian origin was made prior to NACT. There were 70 (58.3%) patients received subsequent tumor debulking surgery after NACT. The time frame between NACT and debulking surgery ranged from 28 to 65 with an average of 45 days. Among the 70 cases with cytoreductive surgery, 48 cases containing both pre-NACT cytology/histology and subsequent debulking specimens were suitable for the study. All 48 post-NACT ovarian cancers were reviewed and the characteristic pathologic features in gross were summarized. Microscopic evaluation and immunohistochemical stainings with antibodies against ER, PR, p53, WT1, PAX8, CK7, CK20, and CDX2 were performed to confirm the primary site and histologic type of the cancers. Results: Grossly, tumor size within the ovaries from those debulking specimens ranged from 2.3 to 6.5 cm in greatest dimension. The cancers were mainly solid (average of 65%) and cystic areas had more or less hemorrhagic appearance. Extensive tumor necrosis and some with fibrosis were present. Microscopically, the non-necrotic cancer cells were arranged in cords, islands and sometimes as scattered single large cells with large amount of eosinophilic cytoplasm with vacuoles. The viable cancer cells contained more or less vacuolated cytoplasm in almost all post chemotherapy cases. Multinucleated tumor giant cells were noted in close to half of the cases. The cancer cells commonly had large hyperchromatic bizarre nuclei with coarse chromatin clumping and sometimes prominent nucleoli. Due to the unusual cytologic changes after NACT, there was a concern of non-ovarian origin or the different histologic type of the cancers. Therefore, immunohistochemical (IHC) staining with the antibodies against ER, PR, PAX8, WT1, CK7, CK20, and CDX2 was performed in all 48 pairs of the cases. The 48 paired samples showed identical immunophenotype in pre- and post-NACT cancers, confirming there was no metastatic or new primary cancer involved in the study. Conclusions NACT can apparently induce significant cytologic/histologic changes in ovarian cancer. Aware of such NACT induced changes will be useful to make correct diagnosis for those patients who have received NACT. IHC with appropriate panels of the antibodies will be helpful to aid the diagnosis, particularly when nuclear change is dramatic and the clinical history of ovarian cancer is not available.
PMCID: PMC3796234  PMID: 24133590
Ovarian cancer; cytological changes; chemotherapy; immunohistochemical
18.  PAX8: a sensitive and specific marker to identify cancer cells of ovarian origin for patients prior to neoadjuvant chemotherapy 
Background
Neoadjuvant chemotherapy followed by cytoreduction surgery has been used where an accurate cytologic or pathologic diagnosis is usually required before the initiation of neoadjuvant chemotherapy. However, it is difficult to make definitive diagnosis of presence of cancer cells, particularly gynecologic versus non-gynecologic origin, from those ascites specimens due to the absence of specific biomarkers of gynecologic cancers. In the present study, we evaluated if, in addition to the routine morphologic diagnosis, the biomarker PAX8 could be useful in recognition of ovarian epithelial cancer cells prior to the neoadjuvant chemotherapy.
Methods
Two hundred and two cytology specimens including 120 pretreatment ovarian cancer samples, 60 benign controls, and 22 malignant non-gynecologic cases were studied. All cytology slides were morphologically reviewed in a blinded fashion without knowing corresponding pathology diagnosis, if present. A total of 168 cytology specimens with a cell block were stained with PAX8 and Calretinin. These included patients with potential for ovarian cancer neoadjuvant chemotherapy (n = 96), metastatic cancers (n = 22), and benign controls (n = 50).
Results
Among the 96 ascitic samples prior to neoadjuvant chemotherapy, 76 (79%) showing morphologic features consistent with cancers of ovarian primary were all PAX+/Calretinin-. The remaining 20 (21%) cases were positive for adenocarcinoma, but morphologically unable to be further classified. Among the 22 metastatic cancers into the pelvis, one case with PAX8+/Calretinin- represented a renal cell carcinoma and the remaining 21 PAX8-/Calretinin- metastatic cancers were either breast metastasis (n = 4) and the metastasis from gastrointestinal tract (n = 17). Among the 50 benign control pelvic washing cases, 5 PAX8+/Calretinin-cases represented endosalpingiosis (n = 4) and endometriosis (n = 1), 25 PAX8-/Calretinin + cases showed reactive mesothelial cells, and the remaining 20 specimens with PAX8-/Calretinin- phenotype typically contained inflammatory or blood cells without noticeable diagnostic epithelia.
Conclusions
PAX8 identifies all Müllerian derived benign or malignant epithelia. When combining with Calretinin, PAX8 is a sensitive marker to diagnose the carcinomas of ovarian origin, which will be ideal to be used for those patients with a possible advanced ovarian cancer prior to receiving neoadjuvant chemotherapy.
doi:10.1186/1756-8722-6-60
PMCID: PMC3751714  PMID: 23958394
PAX8; Ascitic fluid; Ovarian cancer; Neoadjuvant chemotherapy; Origin; Marker
19.  Lynch syndrome related endometrial cancer: clinical significance beyond the endometrium 
Lynch syndrome (LS), an autosomal dominant inherited cancer susceptibility syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes. LS is the most common presentation of hereditary colorectal cancer (CRC), accounting for about 2–5% of all CRC cases. More recently, it is found that a similar number of endometrial cancers is also due to one of the MMR gene mutations. There has been significant progress in LS-related CRC in terms of molecular pathogenesis, risks, genetic basis, and cancer prevention. In contrast, the advance about LS-related endometrial cancer (EC) is very much limited. In this commentary, we summarize the main clinicopathologic features of LS-related EC and propose universal screening for LS in individuals with endometrial cancer.
doi:10.1186/1756-8722-6-22
PMCID: PMC3623651  PMID: 23531335
20.  Struma ovarii simulating ovarian sertoli cell tumor: a case report with literature review 
Struma ovarii, as a monodermal variant of ovarian teratoma, constitutes about less than 3% of ovarian teratomas. It is difficult to be macroscopically recognized. Multiple appearances under microscope serve as another reason to mislead the accurate pathologic evaluation. Here, we report an unusual case of struma ovarii occurred in a 77 years old woman, which is currently known as the oldest age for this disease. The frozen section morphologically showed sex cord like elements and was suspicious for a sex-cord stromal tumor, probably a Sertoli cell tumor. Final pathological diagnosis was confirmed as struma ovarii based on the typical morphologic thyroid follicles and immunohistochemical staining results.
PMCID: PMC3563194  PMID: 23412916
Struma ovarii; sertoli cell tumor; ovary
21.  Morphologic and other clinicopathologic features of endometrial clear cell carcinoma: a comprehensive analysis of 50 rigorously classified cases 
Clear cell carcinoma of the endometrium (CCC) is an uncommon histotype whose analyses have generally been hampered by its rarity and issues of interobserver diagnostic variability. In this study, we analyzed the clinicopathologic features of 50 CCCs that were assembled from multiple institutions and which we considered to be morphologically unambiguous after a rigorous review process for diagnostic accuracy. Forty-four (88%) of the 50 CCC cases showed an admixture of the classic architectural patterns (glandular, papillary, solid and cystic in decreasing order of prevalence). Mitotic indices were variable but were generally low: 60% of cases had a mitotic index of 3 or lower. The predominant cell type lining glands and papillae was invariably hobnail and/or cuboidal. Stratification of nuclei (greater than 3 cells) or columnar cells on glands and papillae were uncommon and never diffusely present. 82% of cases showed an admixture of polygonal cells with clear and eosinophilic cytoplasm; only clear cells were present in 4% and only eosinophilic cells were present in 10%. Hobnail cells were common, being identifiable in 86% of cases, and being diffuse in 60%. Only 2 cases had a predominance of nuclear grade 3 cells. Psammoma, hyaline and targetoid bodies were identified in 32%, 52% and 20% of cases respectively. Clear cell endometrial intraepithelial carcinoma was identified in 41.7% of cases with evaluable background endometrium. The 5-year progression free survival (PFS) for the entire cohort was 61%, and was 88%, 75%, 22% and 28.6% for stages I to IV respectively. On univariate analyses, age >65 years, advanced FIGO stage, and the presence of any lymph node metastases were associated with reduced PFS (p=0.02, 0.002, and 0.002 respectively). On multivariate analyses, the only variable associated with reduced PFS was age >65 years. The 5-year overall survival (OS) for the entire cohort was 78%, and was 94%, 87.5%, 66.7%, and 42.8% for stages I to IV respectively. On univariate analyses, the following factors were associated with reduced OS: age >65 years (p=0.04), advanced FIGO stage (p=0.003), distant metastases (p=0.003), myometrial invasion >30% (p=0.01), a mitotic index >4 (p=0.014), and a specific architectural pattern (at least 10% of the tumor composed of solid masses or individual infiltrating tumor cells, p=0.02). On multivariate analyses, only age >65 years and advanced stage were associated with reduced OS (p=0.023 and 0.022 respectively). In summary, endometrial CCC has a wide morphologic spectrum that is detailed and illustrated herein, but also has core cytoarchitectural features that are of high diagnostic utility. Morphologically unambiguous CCC apparently have patient outcomes that are more favorable than has previously been reported, indicating that ambiguous tumors should be classified separately. The existence of morphologically ambiguous clear-cell rich carcinomas that do not fit the conventional histotypic groupings, is a likely reflection of the biologic complexity of endometrial carcinomas in general; these cases should be reported descriptively, and studied separately from conventional CCC.
PMCID: PMC3555196  PMID: 23359866
Clear cell carcinoma; endometrium; morphologic features
24.  Ovarian serous carcinoma: recent concepts on its origin and carcinogenesis 
Recent morphologic and molecular genetic studies have led to a paradigm shift in our conceptualization of the carcinogenesis and histogenesis of pelvic (non-uterine) serous carcinomas. It appears that both low-grade and high-grade pelvic serous carcinomas that have traditionally been classified as ovarian in origin, actually originate, at least in a significant subset, from the distal fallopian tube. Clonal expansions of the tubal secretory cell probably give rise to serous carcinomas, and the degree of ciliated conversion is a function of the degree to which the genetic hits deregulate normal differentiation. In this article, the authors review the evidentiary basis for aforementioned paradigm shift, as well as its potential clinical implications.
doi:10.1186/1756-8722-5-8
PMCID: PMC3328281  PMID: 22405464
Ovarian cancer; Fallopian tube; Carcinogenesis; Serous carcinoma; p53 signatures
25.  High levels of Nrf2 determine chemoresistance in type II endometrial cancer 
Cancer research  2010;70(13):5486-5496.
Type II endometrial cancer, which mainly presents as serous and clear cell types, has proved to be the most malignant and recurrent carcinoma among various female genital malignancies. The transcription factor, Nrf2, was first described as having chemopreventive activity. Activation of the Nrf2-mediated cellular defense response protects cells against the toxic and carcinogenic effects of environmental insults by upregulating an array of genes that detoxify reactive oxygen species (ROS) and restore cellular redox homeostasis. However, the cancer-promoting role of Nrf2 has recently been revealed. Nrf2 is constitutively upregulated in several types of human cancer tissues and cancer cell lines. Furthermore, inhibition of Nrf2 expression sensitizes cancer cells to chemotherapeutic drugs. In this study, the constitutive level of Nrf2 was compared in different types of human endometrial tumors. It was found that Nrf2 was highly expressed in endometrial serous carcinoma (ESC), whereas complex hyperplasia (CH) and endometrial endometrioid carcinoma (EEC) had no or marginal expression of Nrf2. Likewise, the ESC derived SPEC-2 cell line had a higher level of Nrf2 expression and was more resistant to the toxic effects of cisplatin and paclitaxel than that of the Ishikawa cell line, which was generated from EEC. Silencing of Nrf2 rendered SPEC-2 cells more susceptible to chemotherapeutic drugs while it had a limited effect on Ishikawa cells. Inhibition of Nrf2 expression by overexpressing Keap1 sensitized SPEC-2 cells or SPEC-2-derived xenografts to chemotherapeutic treatments using both cell culture and SCID mouse models. Collectively, we provide a molecular basis for the use of Nrf2 inhibitors to increase the efficacy of chemotherapeutic drugs and to combat chemoresistance, the biggest obstacle in chemotherapy.
doi:10.1158/0008-5472.CAN-10-0713
PMCID: PMC2896449  PMID: 20530669
Nrf2; chemoresistance; and endometrial cancer

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