Insulin-like Growth factor-II mRNA-binding Protein Research Articles

Immunohistochemical Expression of IMP3 in Cutaneous Basal Cell Carcinoma

Background. Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) is an oncofetal protein upregulated in tumor cells during carcinogenesis. It has been linked to adverse clinical outcome in many malignancies.
 This study was aimed to evaluate an immunohistochemical expression status of IMP3 in cutaneous basal cell carcinoma (BCC) and to correlate it with the Ki-67 index values.
 Methods. Biopsy specimens from 32 cases of BCC were enrolled into this analysis. All samples were immunohistochemically stained for IMP3 (Clone 69.1) and Ki-67 antigen (Clone MIB-1).
 Results. IMP3 showed a weak expression in 11 (34.4%) cases, a moderate expression in 11 (34.4%) cases, a strong expression in 5 (15.6%) cases, and negative staining in 5 (15.6%) cases. Among seven BCCs exhibiting aggressive-growth features, all but one showed weak reactivity. In contrast, all five BCCs manifesting strong IMP3 positivity consisted of the indolent-growth histologic subtypes. BCCs with infiltrative histomorphology did not appear to have a tendency towards more striking production of IMP3. There was no significant relationship between the IMP3 expression status and the proliferation status (Ki-67 ≤ 50% vs. Ki-67 > 50%) of the tumor tissue (p > 0.05).
 Conclusions. The vast majority of cutaneous BCCs express IMP3, suggesting this oncoprotein is implicated in BCC carcinogenesis. However, more pronounced expression does not seem to be associated with aggressive-growth phenotype of BCC or higher proliferative activity of neoplastic cells.

Prognostic Value of IGF2 mRNA-Binding Protein 3 (IGF2BP3) Intratumoral Expression in Melanoma Patients at the Time of Diagnosis: Comparative Analysis of RT-qPCR Versus Immunohistochemistry

Simple SummaryAround 80% of skin cancer deaths are due to melanoma. An accurate prognosis of melanoma clinical behavior from primary tumors is important for therapeutic patient management, currently based on histopathological features. The aim of our retrospective study was to investigate the clinical significance of IGF2BP3 mRNA and protein expression in melanoma progression and to evaluate which quantification method, RT-qPCR or immunohistochemistry, provides a more reliable prognostic value of IGF2BP3 expression in primary tumors. We found that IGF2BP3 mRNA expression correlated better with clinicopathologic melanoma features than the corresponding proteins and that patients with higher IGF2BP3 mRNA levels were at more risk for earlier development of metastasis, confirming its impact on melanoma survival. Our findings support the use of IGF2BP3 mRNA levels as an independent prognostic biomarker and the implementation of its RT-qPCR analysis for routine melanoma assessment, even for the earliest stages, to improve melanoma clinical outcomes and individualized treatment.Screening for prognostic biomarkers is crucial for clinical melanoma management. Insulin-like growth factor-II mRNA-binding protein 3 (IGF2BP3) has emerged as a potential melanoma diagnostic and prognostic biomarker. It is commonly tested by immunohistochemistry (IHC). Our study retrospectively examines IGF2BP3 mRNA and protein expression in primary melanomas, their correlation with clinicopathologic factors, clinical outcome, and selected miRNAs expression, and their efficiency in predicting melanoma progression and survival. RT-qPCR and IHC on IGF2BP3 expression were performed in 61 cryopreserved and 63 formalin-fixed paraffin-embedded primary melanomas, respectively, and correlated to clinicopathologic factors, distant metastasis-free survival (DMFS), and melanoma -specific survival (MSS). The correlation between RT-qPCR and IHC was significant but moderate. IGF2BP3 mRNA showed a stronger association with clinicopathologic factors (Breslow thickness, ulceration, mitosis rate, growth phase, development of metastasis, and melanoma-specific survival) than its protein counterpart. Interestingly, higher IGF2BP3 mRNA expression was detected in primary melanomas that further metastasized to distant sites and was an independent prognostic factor for the risk of unfavorable DMFS and MSS. RT-qPCR outperformed IHC in sensitivity and in predicting worse clinical outcomes. Therefore, RT-qPCR may successfully be implemented for routine IGF2BP3 assessing for the selection of melanoma patients with a higher risk of developing distant metastasis and dying of melanoma.

Knockdown of m6A Reader IGF2BP3 Inhibited Hypoxia-Induced Cell Migration and Angiogenesis by Regulating Hypoxia Inducible Factor-1α in Stomach Cancer.

Hypoxia is a common feature of solid tumors including stomach cancer (SC) and is closely associated with cancer malignant progression. N6-methyladenosine (m6A), a common modification on RNA, is involved in the regulation of RNA fate and hypoxic responses in cancers. However, the interaction between m6A reader insulin-like growth factor-II mRNA-binding protein 3 (IGF2BP3) and SC hypoxic microenvironment is poorly defined. In the present study, expression levels of IGF2BP3 and hypoxia inducible factor-1α (HIF1A) were examined by bioinformatics analysis and RT-qPCR and western blot assays. Cell migratory ability was assessed through Transwell and wound healing assays. The angiogenic potential was evaluated by VEGF secretion, tube formation, and chick embryo chorioallantoic membrane (CAM) assays. The interaction between IGF2BP3 and HIF1A was explored using bioinformatics analysis and RIP and luciferase reporter assays. The results showed that IGF2BP3 and HIF1A were highly expressed in SC tissues and hypoxia-treated SC cells. IGF2BP3 knockdown inhibited hypoxia-induced cell migration and angiogenesis in SC. IGF2BP3 positively regulated HIF1A expression by directly binding to a specific m6A site in the coding region of HIF1A mRNA in SC cells. HIF1A overexpression abrogated the effects of IGF2BP3 knockdown on hypoxia-induced cell migration and angiogenesis in SC. In conclusion, IGF2BP3 knockdown inhibited hypoxia-induced cell migration and angiogenesis by down-regulating HIF1A in SC.

Expression of IMP3 in a retrospective cohort of melanomas with selective lymph node biopsy.

Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3), which is a member of the insulin-like growth factor mRNA-binding protein family, is expressed at high levels in many types of cancer, where it plays an important role in cell proliferation, as well as in the processes of invasion, migration, and metastasis. Its expression has also been demonstrated in malignant melanoma, but not in other benign skin lesions, which has raised the possibility of using it as a predictive and prognosis marker. Its relationship with sentinel lymph node biopsy, however, has not been explored yet. A retrospective study including 120 histological samples of patients diagnosed with malignant cutaneous melanoma in Granada, between 2012 and 2018, was developed. All patients had had a sentinel lymph node biopsy (SLNB) performed at Hospital Universitario San Cecilio. IMP3 immunostaining was simultaneously carried out in the cutaneous lesion. We observed a significant difference regarding the percentage of cells expressing IMP3 (29.73 ± 3.81 for negative SLNB vs 44.86 ± 5.91 for positive SLNB, P = .020). Our endpoint calculated according to the ROC curve of 35% was significant with P = .007. H (P = .013) and AR (P = .016) indexes, created by the percentage of positive tumor cells and the intensity of the IMP3 expression, were also statistically significant. The most optimal cut-off points to predict the positivity of the SLNB were 35 for the percentage of positive tumor cells and 70 for the H score. We found a significant association between the expression of IMP3 and the regional nodal status defined by the SLNB on malignant melanomas in our series.

Histopathology and immunohistochemistry as prognostic factors for poorly differentiated thyroid cancer in a series of Polish patients

Poorly differentiated thyroid cancer (PDTC) is a rare but aggressive type of thyroid cancer (TC) and the main cause of death from non-anaplastic follicular cell-derived TC. Although the Turin criteria are well defined, the pathological features that could serve as diagnostic and prognostic factors remain controversial. Forty-nine consecutive PDTC cases were identified in a single cancer center between 2000 and 2018. We analyzed the impact of routine histopathological and immunohistochemical features and several parameters that are not routinely included in pathology reports such as the presence of atypical mitoses, the amount of necrosis, or insulin-like growth factor-II mRNA-binding protein 3 immunostaining on the survival of patients with PDTC. Overall survival (OS) and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. Of the 49 PDTC 34 (69.4%) showed the insular pattern of growth. The median of poorly differentiated area was 95% (range, 1-100), and 30 (61.2%) patients had a predominant (>50%) insular area. The 5-year OS and DSS rates at a median follow-up of 57 months were 60.6% and 64.3%, respectively. Univariate analysis showed that tumor size >4 cm, presence of atypical mitoses, Ki-67 >5%, and thyroglobulin (Tg)-negative immunostaining were associated with a higher risk of PDTC-related death. Atypical mitoses and Tg negativity were independent factors of worse DSS in multivariate analysis. Patients with insular and predominant insular areas showed a 3- and 6-fold higher risk of PDTC death when they displayed atypical mitoses. In PDTC, the presence of atypical mitoses may be helpful in identifying patients with poorer outcome and worth including in pathology reports, particularly in tumors with a dominant insular pattern of growth. Additionally, the inclusion of Tg immunostaining may be considered in a prognostic context, and not only as a diagnostic feature.

Cancer-testis antigens as biomarkers for Merkel cell carcinoma: Pitfalls and opportunities.

The prognosis and treatment options for metastatic Merkel cell carcinoma (MCC) are poor. The immune-privileged status of cancer-testis (CT) antigens imparts tumor specificity, making them ideal candidates for targeted immunotherapy. We investigate the usefulness of the CT antigens SPA17 (sperm protein-17 [SP-17]), IGF2BP3 (insulin-like growth factor-II mRNA-binding protein 3 [IMP-3]), and transmembrane protein with epidermal growth factor (EGF)-like and two follistatin-like domains 1 (TMEFF1) as potential MCC biomarkers and evaluate their possible utility in immunotherapy and molecularly targeted image-guided treatment. The CT antigens SP-17, IMP-3, and TMEFF1 were selected using transcriptome profiling to identify CT antigens expressed in MCC tumors. Antibodies directed against these CT antigens were stained. Twelve normal skin tissue samples were used as a control. The average percentage of positive cells in each tumor was computed. Twelve of 14 (86%) MCC cases showed crisp nuclear staining for SP-17, with 2.06% of cells staining positive. IMP-3 showed crisp, perinuclear staining in all 14 MCC cases, with 52.93% MCC cells staining positive. TMEFF1 showed perinuclear staining in all 14 MCC cases, with 96.51% of tumor cells staining positive. CT antigens were found to be expressed in both MCC and some control tissues. SP-17 was the most specific yet the least sensitive. IMP-3 and TMEFF1 were both sensitive but not specific. CT antigens may represent valuable treatment targets in MCC.

Addition of IMP3 to L1CAM for discrimination between low- and high-grade endometrial carcinomas: a European Network for Individualised Treatment of Endometrial Cancer collaboration study

Discrimination between low- and high-grade endometrial carcinomas (ECs) is clinically relevant but can be challenging for pathologists, with moderate interobserver agreement. Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) is an oncofoetal protein that is associated with nonendometrioid endometrial carcinomas but has been limited studied in endometrioid carcinomas. The aim of this study is to investigate the diagnostic and prognostic value of IMP3 in the discrimination between low- and high-grade ECs and its added value to L1CAM. IMP3 and L1CAM expression was assessed in tumors from 378 patients treated for EC at 1 of 9 participating European Network for Individualised Treatment of Endometrial Cancer centers. IMP3 was expressed in 24.6% of the tumors. In general, IMP3 was more homogeneously expressed than L1CAM. IMP3 expression was significantly associated with advanced stage, nonendometrioid histology, grade 3 tumors, deep myometrial invasion, lymphovascular space invasion, distant recurrences, overall mortality, and disease-related mortality. Simultaneous absence of IMP3 and L1CAM expression showed the highest accuracy for identifying low-grade carcinomas (area under the curve 0.766), whereas simultaneous expression of IMP3 and L1CAM was strongly associated with high-grade carcinomas (odds ratio 19.7; 95% confidence interval 9.2-42.2). Even within endometrioid carcinomas, this combination remained superior to IMP3 and L1CAM alone (odds ratio 8.6; 95% confidence interval 3.4-21.9). In conclusion, IMP3 has good diagnostic value and together with L1CAM represents the optimal combination of diagnostic markers for discrimination between low- and high-grade ECs compared to IMP3 and L1CAM alone. Because of the homogenous expression of IMP3, this marker might be valuable in preoperative biopsies when compared to the more patchy L1CAM expression.

Insulin-like growth factor-II mRNA-binding protein 3 immunocytochemical expression in direct endometrial brushings: Possible diagnostic help in endometrial cytology.

This study evaluated the immunocytochemical (ICC) expression of IMP3 in direct endometrial brushings processed as liquid-based cytology (LBC) samples of endometrioid adenocarcinoma (EAC), serous carcinoma (ESC) and surface papillary syncytial change (SPSC) with endometrial glandular and stromal breakdown (EGBD) to exploit its possible differential diagnostic aid. In total, 333 samples of LBC samples were obtained from selected outpatients in parallel with Pipelle endometrial sampling. They consisted of 97 EAC (83 grade 1: EAC-1, 14 EAC-3), 35 ESC and 201 benign endometrial samples (51 proliferative, 42 secretory, 38 atrophic, 70 SPSC with EGBD). ICC expression of insulin-like growth factor-II mRNA-binding protein 3 (IMP3) was manually performed on Papanicolaou-stained LBC samples. The ESC samples showed positive staining cells in 100%, EAC-3 in 28.5%, and EAC-1 in 2.4% cases. All the benign endometrium samples were negative. Only ESC cases showed strong immunoreactivity (≥3+) in more than 50% of tumour cells with an average frequency of 80%. IMP3 is a helpful immunomarker to distinguish ESC from EAC and SPSC in endometrial cytology.

IMP2 and IMP3 cooperate to promote the metastasis of triple-negative breast cancer through destabilization of progesterone receptor

Triple-negative breast cancer (TNBC) is one of the most aggressive malignancies and is associated with high mortality rates due to the lack of effective therapeutic targets. In this study, we demonstrated that insulin-like growth factor-II mRNA-binding protein 2 and 3 (IMP2 and IMP3) are specifically overexpressed in TNBC and cooperate to promote cell migration and invasion. Downregulation of both IMP2 and IMP3 in TNBC cells was found to produce a synergistic effect in suppressing cell invasion and invadopodia formation, whereas overexpression of IMP2 and IMP3 in luminal subtype cells enhanced epithelial-mesenchymal transition and metastasis. We also showed that IMP2 and IMP3 are direct targets of microRNA-200a (miR-200a), which is downregulated in TNBC. Conversely, IMP2 and IMP3 suppressed the transcription of miR-200a by destabilizing progesterone receptor (PR) mRNA through recruitment of the CCR4-NOT transcription complex subunit 1 (CNOT1) complex. Together, our findings suggest that IMP2 and IMP3 partially determine the characteristic phenotype and synergistically promote the metastasis of TNBC by downregulating PR. The identified IMP2/3-miR-200a-PR axis represents a novel double-negative feedback loop and serves as a new potential therapeutic target for the treatment of TNBC.

IMP3 Immunoreactivity is More Sensitive Than AMACR in Detecting Dysplastic Epithelium and Early Adenocarcinoma in Barrett Esophagus.

α-methylacyl coenzyme A racemase (AMACR) and insulin-like growth factor-II mRNA-binding protein 3 (IMP3) are 2 markers helpful in detecting difficult cases of dysplasia in Barrett esophagus (BE). However, no comparison studies have been performed to assess their performance in the same patient population. The aim of our study was to compare the immunohistochemical expression of IMP3 and AMACR in dysplastic lesions and early adenocarcinoma (EAC) arising in BE and evaluate their sensitivity and specificity. A total of 98 cases [BE negative for dysplasia, n=24; indefinite for dysplasia (BE-IND), n=18; low-grade dysplasia (LGD), n=24; high-grade dysplasia (HGD), n=16; and EAC, n=16] were immunostained for AMACR and IMP3 and evaluated for the degree, the extent, and the intensity of staining. No immunoreactivity for AMACR or IMP3 was observed in all 24 cases of BE negative for dyplasia. One of 18 (5.5%) cases of BE-IND was positive for IMP3, but all were negative for AMACR. AMACR and IMP3 were positive in 16.7% versus 41.7 % of the cases with BE-LGD, 25% versus 62.5% of BE-HGD, and 62.5% versus 93.7% of EAC, respectively. The sensitivity of AMACR and IMP3 for the detection of dysplasia in BE is 16.7% and 41.7% for LGD, 25% and 62.5% for HGD, and 62.5% and 93.7% in EAC, respectively. The specificity is 100% for both markers. In addition, a comparison of the intensity of reactivity shows a better result with IMP3 (36/98, 36.7%) than with AMACR (18/98, 18.4%) (P<0.001). IMP3 has a similar specificity, but a better sensitivity, intensity, and extent of reactivity in comparison with AMACR, and may be used as an alternative to AMACR, in support of the diagnosis of BE-dysplasia and EAC.

Quantitative analysis and clonal characterization of T-cell receptor β repertoires in patients with advanced non-small cell lung cancer treated with cancer vaccine.

With the development of cancer immunotherapy that may activate T cells, a practical and quantitative method to improve monitoring and/or prediction of immunological response of patients as a predictive biomarker is of importance. To examine possible biomarkers for a therapeutic cancer vaccine containing a mixture of three epitope peptides derived from cell division-associated 1, lymphocyte antigen 6 complex locus K and insulin-like growth factor-II mRNA-binding protein 3, T-cell receptor β (TCRβ) repertoires of blood samples from 24 patients with human leukocyte antigen-A*2402-positive non-small cell lung cancer were characterized prior to and following 8 weeks of the cancer vaccine treatment, by applying a next-generation sequencing method. It was identified that 14 patients with overall survival (OS) times of ≥12 months had significantly lower TCRβ diversity indexes in samples prior to treatment, compared with 10 patients who succumbed within 1 year (P=0.03). In addition, patients with a high level of activated CD8+ T cells that are defined by a high granzyme A/CD8 ratio had favorable OS rates (log-rank test, P=0.04). The TCRβ diversity index and immunogenic gene markers following vaccine administration may serve as predictive or monitoring biomarkers for cancer vaccine treatment.

Clinicopathological Implication of Insulin-like Growth Factor-II mRNA-Binding Protein 3 (IMP3) Expression in Gastric Cancer.

The clinicopathological significance of oncofetal mRNA-binding protein, human insulin-like growth factor II mRNA-binding protein 3 (IMP3), in gastric carcinoma (GC) is not fully understood. Tissue microarray blocks with specimens from 346 patients with GC were constructed to evaluate the clinicopathological role of IMP3 expression in GC. These results were validated with an online dataset of 876 patients from the Kaplan-Meier Plotter. Sera from 15 controls and 57 patients with GC were collected in order to compare the levels of serum IMP3 between groups. High expression of IMP3 was significantly associated with poor prognosis. Survival curves from the Kaplan-Meier Plotter showed that high IMP3 expression was significantly related to worse disease-free survival and overall survival. Tissue overexpression of IMP3 might be used as a predictor of advanced disease or lymph node metastasis, and is associated with poorer prognosis in GCs.

Clear cell carcinomas of the ovary: a mono-institutional study of 73 cases in China with an analysis of the prognostic significance of clinicopathological parameters and IMP3 expression.

BackgroundOvarian clear cell carcinoma (CCC) is an uncommon subtype of ovarian epithelial tumor. The prognostic significance of its clinicopathological parameters is discordant, with the exception of stage as the adverse prognostic factor. The present study aimed to evaluate the prognostic significance of its clinicopathological characteristics and the expression of IMP3 (Insulin-like growth factor-II mRNA-binding protein 3, IMP3 or IGF2BP3) in Chinese patients with primary pure CCC.MethodsWe collected clinicopathological data from 73 cases with a minimum of 5 years of follow-up and evaluated the expression of IMP3 by immunohistochemistry.ResultsIn total, 49.3 % of the patients were in stage I. Advanced stages were closely related to poor prognosis of disease-free survival (DFS) and overall survival (OS) (P < 0.005). Patients with CCC coexisting with endometriosis tended to be younger and to have unilateral involvement but did not exhibit differences in prognosis compared with patients with CCC without endometriosis. Other histological features such as growth pattern, mitosis, and necrosis did not have prognostic significance. IMP3 was positive in 63 % of patients (46 of 73 cases); Thus, positive expression of IMP3 is an adverse prognostic marker in terms of OS (P = 0.012), even in stage I patients (P = 0.038).ConclusionsThe present study demonstrates that IMP3 expression is a prognostic marker, with the exception of stage. IMP3 represents a biomarker of unfavorable prognosis even in stage I patients.

Insulin-Like Growth Factor II mRNA-Binding Protein 3 Expression Correlates with Poor Prognosis in Acral Lentiginous Melanoma.

Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3) is an RNA-binding protein expressed in multiple cancers, including melanomas. However, the expression of IMP-3 has not been investigated in acral lentiginous melanoma (ALM). This study sought to elucidate its prognostic value in ALMs. IMP-3 expression was studied in 93 patients diagnosed with ALM via immunohistochemistry. Univariate and multivariate analyses for survival were performed, according to clinical and histologic parameters, using the Cox proportional hazard model. Survival curves were graphed using the Kaplan-Meier method. IMP-3 was over-expressed in 70 out of 93 tumors (75.3%). IMP-3 expression correlated with thick and high-stage tumor and predicted poorer overall, melanoma-specific, recurrence-free and distant metastasis-free survivals (P = 0.002, 0.006, 0.008 and 0.012, respectively). Further analysis showed that patients with tumor thickness ≤ 4.0 mm and positive IMP-3 expression had a significantly worse melanoma-specific survival than those without IMP-3 expression (P = 0.048). IMP-3 (hazard ratio 3.67, 95% confidence intervals 1.35–9.97, P = 0.011) was confirmed to be an independent prognostic factor for melanoma-specific survival in multivariate survival analysis. Positive IMP-3 expression was an important prognostic factor for ALMs.

The role of insulin-like growth factor-II mRNA-binding protein 3, cyclooxygenase-2, and galectin-3 in differentiating malignant melanoma from benign melanocytic lesion

The role of insulin-like growth factor-II mRNA-binding protein 3, cyclooxygenase-2, and galectin-3 in differentiating malignant melanoma from benign melanocytic lesion

Effect of IMP3 on epithelial-to-mesenchymal transition and the function of colon cancer stem cells.

631 Background: EMT could promote the acquisition of stem-like properties in cancer cells and cancer stem cell (CSC) has EMT properties. However, the underlying mechanism of the interaction between EMT and CSC still remain unclear. We previously identified Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) plays a vital role in colon cancer carcinogenesis. Here, we aimed to identify the gene function between EMT and CSC in colon cancer. Methods: The expression of IMP3 was analyzed in human tumor tissues. Colonospheres were isolated from colon cancer cell lines and the biological features of IMP3 were investigated in the process of EMT and colonoshpere cells. Results: Increased IMP3 levels were significantly correlated with higher clinical stage, T classification, LNM, presence of distant metastasis. Patients with IMP3-positive localized tumors had lower 5-year disease-free survival (DFS) and overall survival (OS) than those with IMP3-negative tumors. Multivariate survival analysis showed that IMP3 was an independent prognostic marker for DFS and OS. Expanded colonospheres contained cells that expressed high levels of CD133 and had the ability to promote migration and activate the epithelial-mesenchymal transition. Down regulation of IMP3 in HCT116 cells inhibited the invasion, migration ability and epithelial-mesenchymal transition and the properties of colonospheres. Conclusions: These findings suggest that IMP3 plays an important role in colon cancer tumorigenesis and metastasis through transactivation of colon CSC with EMT property, which is helpful to identify critical marker and therapeutic target.

Prognostic significance of insulin-like growth factor-II mRNA-binding protein 3 in urological cancers: a systemic review and meta-analysis

Purpose: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein expressed in diverse malignancies. This study aimed to investigate the prognostic value of IMP3 in urological cancers. Methods: Eligible studies were sought in PubMed, Embase, Cochrane Collaboration and Wanfang databases. Pooled hazard ratios (HRs) with their 95% confidence intervals (CIs) were used to assess the prognostic value of IMP3 in patients with urological cancers. Results: Eight studies including 2,219 patients were enrolled in this meta-analysis. The pooled results showed that IMP3 expression was an indicator of poorer prognosis in patients with urological cancers in terms of overall survival (OS) (HR 2.19, 95% CI 1.35-3.55), disease-specific survival (DSS) (HR 2.10, 95% CI 1.53-2.89), disease-free survival (DFS) (HR 1.49, 95% CI 1.18-1.87) and metastasis-free survival (MFS) (HR 3.80, 95% CI 2.27-6.34). Subgroup analyses revealed that IMP3 was significantly correlated with poorer prognosis in patients with kidney cancer or urothelial cancer in terms of OS (HR 2.52; 95% CI 1.55-4.10), DSS (HR 2.11; 95% CI 1.51-2.95), DFS (HR 2.01; 95% CI 1.40-2.88) and MFS (HR 3.80; 95% CI 2.27-6.34), whereas this association was not found in patients with prostate cancer (OS, HR 1.09, 95% CI 0.45-2.63; DSS, HR 2.06, 95% CI 0.73-5.80; DFS, HR 1.20, 95% CI 0.88-1.62). Conclusions: IMP3 expression might be an indicator of poor prognosis in patients with kidney cancer or urothelial cancer. Further large prospective and well- designed studies utilizing better IMP3 expression assessment processes, are needed to confirm these results especially in patients with prostate cancer.

IMP2 expression in the mouse nervous system (727.4)

The three homologs of insulin like growth factor‐II (IGF‐II) mRNA binding protein (IMP) play an essential role in the posttranscriptional regulation of gene expression in nervous tissue. IMP1/ZBP1 (zipcode binding protein) regulates the localization and translation of specific mRNAs allowing for axon guidance and regeneration. Additionally, previous studies show that IMP1 and IMP3 expression decreases dramatically after birth, whereas IMP2 is sustained in in brain, liver and other organs throughout life (Leeds et al., 1997; Mueller‐Pillasch et al., 1999; Nielsen et al., 1999; Hansen et al., 2004; Gu et al., 2004; Hammer et al., 2005). Of the three homologs, IMP2 is least understood. Our pilot data implicates that IMP2 may play a role in axon regeneration by localizing specific mRNAs. Understanding IMP2 expression pattern is fundamental to further investigation of its functions. We hypothesized that IMP2 is present in both the central and peripheral nervous systems throughout life. Using a custom made IMP2‐specific antibody, along with immunohistochemistry, Western Blot, and primary dorsal root ganglion (DRG) culture we examined the expression of IMP2 in the spinal cord and DRG of the mouse at embryonic, postnatal, and adult stages of life. We found that IMP2 expression is present in both the spinal cord and DRG through all developmental stages of life. Ongoing experiments are focused on the role of IMP2 in axon regeneration in the adult nervous system.

Insulin-Like Growth Factor-II mRNA-Binding Protein 3 Expression in Effusion Cytology: A Marker for Metastatic Adenocarcinoma Cells and a Potential Prognostic Indicator in Gastric Adenocarcinoma

Objective: The aim of our study was to identify the diagnostic value of insulin-like growth factor-II mRNA-binding protein 3 (IMP3) in distinguishing metastatic adenocarcinoma cells (MAC) from reactive mesothelial cells (RMC) in effusions. We also investigated the role of IMP3 as a prognostic indicator for patients with malignant effusion. Study Design: A total of 156 cell block specimens, including 116 malignant effusions with MAC and 40 benign effusions with RMC, were subjected to immunocytochemical staining for IMP3. Results: Immunocytochemical studies showed positive staining for IMP3 in 91 of 116 (78.4%) cases of MAC and in 3 of 40 (7.5%) cases of RMC. With regard to distinguishing MAC from RMC, the IMP3 reactivity was found to be 78.4% sensitive and 92.5% specific with a positive predictive value of 96.8% and a negative predictive value of 59.7%. Diffuse IMP3 expression (>25%) in MAC from patients with gastric adenocarcinoma was associated with shorter survival (p = 0.001). Conclusion: Our data suggest that IMP3 is a helpful marker for differentiating MAC from RMC, and that diffuse IMP3 expression is a poor prognostic indicator in patients with gastric adenocarcinoma and malignant effusion.

An Immunohistochemical Panel to Distinguish Ovarian From Uterine Serous Papillary Carcinomas

Serous papillary carcinomas (SPCs) share a similar morphology regardless of whether they originate from the ovary or the uterus. Identification of the site of origin of the tumor can be a challenging and a diagnostic dilemma, particularly, in the setting of a pelvic mass or peritoneal carcinomatosis. Recognition of the site of origin influences the staging, management, and prognosis of these malignancies. The purpose of this study is to identify a panel of markers to distinguish the ovarian serous papillary carcinomas (OSPC) from the uterine serous papillary carcinomas (USPC). Formalin-fixed, paraffin-embedded archival tissue from 46 cases of SPCs (33 uterine and 13 ovarian) were stained using antibodies for estrogen receptor (ER), WT1, insulin-like growth factor-II mRNA-binding protein 3 (IMP3), p53, and p16. The OSPC expressed ER (92%), WT1 (100%), IMP3 (92%), p53 (92%), and p16 (92%). The USPCs expressed ER (30%), WT1 (64%), IMP3 (85%), p53 (64%), and p16 (76%). Only ER expression was significantly higher in OSPC compared with USPCs (P<0.001). The combined ER(+)WT1(+) phenotype was present in 92% of the OSPC, whereas only 18% of the USPCs had the same phenotype (P<0.001). Furthermore, 71% of the OSPCs expressed ER(+), p53(+), WT1(+), IMP3(+), and p16(+) immunophenotype, whereas in USPCs, the tumor cells showed immunophenotypic diversity, with only 6% of the USPCs expressing reactivity to all the 5 markers (P<0.001). This study suggests that ER alone or in combination with a limited panel of markers may be used to identify the site of origin of SPCs.