Das Mantelzelllymphom (MCL) gehört zu den aggressiven, mit bislang zur Verfügung stehenden Therapien nicht heilbaren, Non-Hodgkin-Lymphomen (NHL). Das MCL weist eine schlechte Prognose auf. Charakteristisch für das MCL ist die t(11,14)- Translokation, die das Cyclin D1- Gen betrifft. Darüber hinaus finden sich zahlreiche weitere genetische Alterationen mit Häufung bestimmter Zugewinne und Verluste von genetischem Material. Einer der am häufigsten chromosomal zugewonnene Abschnitte in MCL ist der kurze Arm von Chromosom 7 (7p). In Fällen mit dieser genetischen Veränderung fand sich das IMP3/IGF2BP3-Gen (Insulin-like growth factor 2 mRNAbinding protein 3) unter den am stärksten differentiell exprimierten Genen. In dieser Arbeit konnte in einer immunhistochemischen Analyse eine stark variable IMP3-Protein-Expression in einer Serie von insgesamt 172 primären MCL gezeigt werden. Darüber hinaus fand sich in diesem Kollektiv eine signifikante Korrelation der IMP3-Expression mit der Proliferationsfraktion (Ki67-Immunhistochemie) sowie auch eine Assoziation mit einer blastoiden Morphologie. Es konnte jedoch letztlich keine statistisch signifikante Assoziation der IMP-3-Protein-Expression mit einem chromosomalen Zugewinn von 7p, dem Genort von IMP3, nachgewiesen werden, so dass hier offenbar auch noch andere Mechanismen für die Regulation eine wichtige Rolle spielen. In einer darüber hinaus untersuchten Vergleichsgruppe von 20 Fällen von Lymphknoten mit Infiltraten durch ein small lymphocytic Lymphoma (SLL) zeigte sich insgesamt nur eine geringe IMP3-Expression. Der Befund einer vermehrten IMP3-Protein-Expression in einer Teilgruppe von MCL mit erhöhter Tumorzellproliferation unterstützt die Idee, dass eine Aktivierung des IGFSignalweges in MCL möglicherweise die Proliferation und biologische Aggressivität begünstigt. Daher könnte eine therapeutische Manipulation dieses Signalweges vermutlich eine zukünftige therapeutische Option für das MCL darstellen. / The mantle cell lymphoma (MCL) is one of the most aggressive non-Hodgkin´s lymphomas (NHL) with poor prognosis. As of today, no therapy is capable to cure this lymphoma. One of the key MCL characteristics is the t(11,14)-translocation, involving the cyclin D1 gene. In addition, there are numerous further genetic alterations, especially gains and losses of genetic material. One of the most commonly affected chromosomal sections is the short arm of chromosome 7 (7p). IMP3/IGF2BP3 gene (insulin-like growth factor 2mRNAbinding protein3) is among the strongest differentially expressed genes in cases with this genetic alteration. This work analyses a series of 172 primary MCL cases with the help of immunohistochemistry. These cases have highly variable IMP3 protein expression. This thesis showed significant correlation between the IMP3 expression and the proliferation levels (Ki67 immunohistochemistry), as well with the blastoid morphology of these cases. However, no statistically significant association was found between the IMP3 protein expression and the chromosomal gains of 7p (the locus of IMP3), suggesting that other mechanisms can be responsible for the regulation of IMP3 in MCL. The analysis of the control group (20 cases of lymphnodes infiltrated with a small lymphocytic lymphoma - SLL) showed overall only a small IMP3 expression. The study of seven secondary MCL cases showed no major differences in IMP3 protein expression between the primary diagnoses and later relapses. The findings of the correlation between the IMP3 protein expression and the increased proliferation support the idea that the activation of the IGF signaling pathway possibly favors proliferation and biological aggressiveness in MCL. Therefore, future MCL therapy research could include therapeutic manipulation of the IGF signaling pathway.

Les protéines se liant à l’ARN de la famille IMP sont les protéines oncofoetales conservées, qui régulent le transport, la stabilité et la traduction de plusieurs ARNm cibles. Les IMPs sont impliqués dans la tumorigenèse et dans le développement embryonnaire par le contrôle de la prolifération cellulaire, la différenciation, la migration, la polarisation et d`autres processus cellulaires. IMP-3 est difficilement détectable dans des tissus adultes normaux, mais il est surexprimé dans les nombreux cancers, où il a été caractérisé comme un marqueur d’agressivité et de la croissance tumorale rapide, ainsi que d’un pronostic défavorable pour les patients. Dans notre étude, nous avons utilisé une lignée cellulaire RD de rhabdomyosarcome (RMS), où IMPs étaient initialement décrits comme des protéines régulatrices de l`ARNm de IGF-2. Nous avons essayé d'élucider le mécanisme par lequel IMP3 régule l’expression des cyclines D1 et D3, contribuant ainsi à la compréhension des processus oncogéniques dans les RMS et autres cancers.Nous avons montré que IMP3 régule l'expression des cyclines D1 et D3 d'une manière significative in vivo. Nous avons également démontré, qu'en absence de IMP3, les ARNm des cyclines sont exportés vers le cytoplasme et s’associent avec les polyribosomes, mais ne sont pas traduits. En outre, l'inhibition d`IMP3 n'a pas d'influence sur la stabilité des ARNm des cyclines. Nous démontrons que dans des cellules cancéreuses humaines, IMP3 interagit avec plusieurs protéines se liant à l'ARN, et que nombre de ces protéines a un effet sul l’expression des cyclines, ce que suggère l'existence d'un complexe régulateur multiprotéique sur les 3'UTR des cyclines D1 et D3. Nos résultat montrent que l'inhibition de deux protéines clés de RNA-induced silencing complex (RISC) (AGO2 et GW182/TNRC6), rétablit les niveaux d'expression des cyclines D1 et D3, qui ont été considérablement diminués en l’absence d’IMP3 ou de ses partenaires protéiques ILF3/NF90 et PTBP1. Nous concluons que les complexes d`IMP3 et RISC peuvent concourir pour la régulation des ARNm des cyclines. Nous avons également identifié les miARNs qui peuvent être impliqués dans ce processus, ainsi que les domaines fonctionnellement importants dans les 3 'UTR des cyclines, où se passe la competition entre les complexes d’IMP-3 et RISC. Nos résultats sont compatibles avec l'existence de IMP3 - contenant complexe multiprotéique, qui est associé à 3'UTRs des cyclines et régule leur traduction en les protégeant contre la répression traductionnelle par miRISC. / RNA-binding proteins of the IMP family (IGF2 mRNA-binding proteins 1-3) are conserved oncofetal proteins, regulating transport, stability and decay of multiple mRNAs. IMPs are involved in embryonic developement and tumorigenesis by controlling cell proliferation, differentation, migration, polarization and many other important aspects of cell function. IMP-3 is hardly detectable in normal adult tissues, but is overexpressed in many cancers, where it has been reported as a marker of tumor aggressiveness, rapid growth, and bad prognosis for patients. In our research we utilized a rhabdomyosarcoma (RMS) cell line RD, where IMPs were first described as IGF-2 mRNA regulating proteins. We aimed to elucidate the mechanism by which IMP3 regulates the expression of cyclins D1 and D3, thereby contributing to the understanding of oncogenic processes in RMS.In this study, we show that IMP3 regulates the expression of cyclin D1 and D3 in a significant manner in vivo. We also demonstrate that in the absence of IMP3, the mRNAs of the cyclins are exported to the cytoplasm and associated with polyribosomes, but not translated. IMP3 inhibition does not influence the stability of cyclin mRNAs. We demonstrate that in human cancer cells, IMP3 interacts with multiple RNA-binding proteins, and that a number of these IMP-3 partners impacts on the expression of cyclins D1 and D3. These observations suggest the existence of a regulatory IMP-3 containing RNP complex on the 3’UTR of mRNAs of cyclin D1 and D3. Our results show that an inhibition of two key proteins of RNA-induced silencing complex (RISC) (AGO2 and GW182/TNRC6) rescues the expression of cyclin D1 and D3 proteins, which is significantly decreased in the absence of IMP3 or its protein partners ILF3/NF90 and PTBP1. Therefore, IMP3 and RISC complexes can compete for cyclin mRNAs translational repression/activation. We also identified a number of miRNAs that can be involved in this process, and characterized functionally important regions within 3’ UTRs of the cyclins, where the competition between IMP-3 and RISC complexes takes place. Our results are consistent with the existence of IMP3 - containing multiprotein complex, which is associated with 3’UTRs of the cyclins and regulates their translation by protecting them from miRISC-dependent translational repression.

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.

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 10years 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.

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