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2. Supplementary Figure 5 from Hsa-miR-31-3p Expression Is Linked to Progression-free Survival in Patients with KRAS Wild-type Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

Author

Manceau, Gilles, primary, Imbeaud, Sandrine, primary, Thiébaut, Raphaële, primary, Liébaert, François, primary, Fontaine, Karine, primary, Rousseau, Francis, primary, Génin, Bérengère, primary, Corre, Delphine Le, primary, Didelot, Audrey, primary, Vincent, Marc, primary, Bachet, Jean-Baptiste, primary, Chibaudel, Benoist, primary, Bouché, Olivier, primary, Landi, Bruno, primary, Bibeau, Frédéric, primary, Leroy, Karen, primary, Penault-Llorca, Frédérique, primary, Van Laethem, Jean-Luc, primary, Demetter, Pieter, primary, Tejpar, Sabine, primary, Rossi, Simona, primary, Mosakhani, Neda, primary, Österlund, Pia, primary, Ristamäki, Raija, primary, Sarhadi, Virinder, primary, Knuutila, Sakari, primary, Boige, Valérie, primary, André, Thierry, primary, and Laurent-Puig, Pierre, primary

Published
2023
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3. Supplementary Figure 3 from Hsa-miR-31-3p Expression Is Linked to Progression-free Survival in Patients with KRAS Wild-type Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

Author

Manceau, Gilles, primary, Imbeaud, Sandrine, primary, Thiébaut, Raphaële, primary, Liébaert, François, primary, Fontaine, Karine, primary, Rousseau, Francis, primary, Génin, Bérengère, primary, Corre, Delphine Le, primary, Didelot, Audrey, primary, Vincent, Marc, primary, Bachet, Jean-Baptiste, primary, Chibaudel, Benoist, primary, Bouché, Olivier, primary, Landi, Bruno, primary, Bibeau, Frédéric, primary, Leroy, Karen, primary, Penault-Llorca, Frédérique, primary, Van Laethem, Jean-Luc, primary, Demetter, Pieter, primary, Tejpar, Sabine, primary, Rossi, Simona, primary, Mosakhani, Neda, primary, Österlund, Pia, primary, Ristamäki, Raija, primary, Sarhadi, Virinder, primary, Knuutila, Sakari, primary, Boige, Valérie, primary, André, Thierry, primary, and Laurent-Puig, Pierre, primary

Published
2023
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4. Supplementary Figure 4 from Hsa-miR-31-3p Expression Is Linked to Progression-free Survival in Patients with KRAS Wild-type Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

Author

Manceau, Gilles, primary, Imbeaud, Sandrine, primary, Thiébaut, Raphaële, primary, Liébaert, François, primary, Fontaine, Karine, primary, Rousseau, Francis, primary, Génin, Bérengère, primary, Corre, Delphine Le, primary, Didelot, Audrey, primary, Vincent, Marc, primary, Bachet, Jean-Baptiste, primary, Chibaudel, Benoist, primary, Bouché, Olivier, primary, Landi, Bruno, primary, Bibeau, Frédéric, primary, Leroy, Karen, primary, Penault-Llorca, Frédérique, primary, Van Laethem, Jean-Luc, primary, Demetter, Pieter, primary, Tejpar, Sabine, primary, Rossi, Simona, primary, Mosakhani, Neda, primary, Österlund, Pia, primary, Ristamäki, Raija, primary, Sarhadi, Virinder, primary, Knuutila, Sakari, primary, Boige, Valérie, primary, André, Thierry, primary, and Laurent-Puig, Pierre, primary

Published
2023
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5. Supplementary Figure 2 from Hsa-miR-31-3p Expression Is Linked to Progression-free Survival in Patients with KRAS Wild-type Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

Author

Manceau, Gilles, primary, Imbeaud, Sandrine, primary, Thiébaut, Raphaële, primary, Liébaert, François, primary, Fontaine, Karine, primary, Rousseau, Francis, primary, Génin, Bérengère, primary, Corre, Delphine Le, primary, Didelot, Audrey, primary, Vincent, Marc, primary, Bachet, Jean-Baptiste, primary, Chibaudel, Benoist, primary, Bouché, Olivier, primary, Landi, Bruno, primary, Bibeau, Frédéric, primary, Leroy, Karen, primary, Penault-Llorca, Frédérique, primary, Van Laethem, Jean-Luc, primary, Demetter, Pieter, primary, Tejpar, Sabine, primary, Rossi, Simona, primary, Mosakhani, Neda, primary, Österlund, Pia, primary, Ristamäki, Raija, primary, Sarhadi, Virinder, primary, Knuutila, Sakari, primary, Boige, Valérie, primary, André, Thierry, primary, and Laurent-Puig, Pierre, primary

Published
2023
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6. Supplementary Figure 1 from Hsa-miR-31-3p Expression Is Linked to Progression-free Survival in Patients with KRAS Wild-type Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

Author

Manceau, Gilles, primary, Imbeaud, Sandrine, primary, Thiébaut, Raphaële, primary, Liébaert, François, primary, Fontaine, Karine, primary, Rousseau, Francis, primary, Génin, Bérengère, primary, Corre, Delphine Le, primary, Didelot, Audrey, primary, Vincent, Marc, primary, Bachet, Jean-Baptiste, primary, Chibaudel, Benoist, primary, Bouché, Olivier, primary, Landi, Bruno, primary, Bibeau, Frédéric, primary, Leroy, Karen, primary, Penault-Llorca, Frédérique, primary, Van Laethem, Jean-Luc, primary, Demetter, Pieter, primary, Tejpar, Sabine, primary, Rossi, Simona, primary, Mosakhani, Neda, primary, Österlund, Pia, primary, Ristamäki, Raija, primary, Sarhadi, Virinder, primary, Knuutila, Sakari, primary, Boige, Valérie, primary, André, Thierry, primary, and Laurent-Puig, Pierre, primary

Published
2023
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7. Supplementary Materials and Methods, Figure Legends, Tables 1 - 3 from Hsa-miR-31-3p Expression Is Linked to Progression-free Survival in Patients with KRAS Wild-type Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

Author

Manceau, Gilles, primary, Imbeaud, Sandrine, primary, Thiébaut, Raphaële, primary, Liébaert, François, primary, Fontaine, Karine, primary, Rousseau, Francis, primary, Génin, Bérengère, primary, Corre, Delphine Le, primary, Didelot, Audrey, primary, Vincent, Marc, primary, Bachet, Jean-Baptiste, primary, Chibaudel, Benoist, primary, Bouché, Olivier, primary, Landi, Bruno, primary, Bibeau, Frédéric, primary, Leroy, Karen, primary, Penault-Llorca, Frédérique, primary, Van Laethem, Jean-Luc, primary, Demetter, Pieter, primary, Tejpar, Sabine, primary, Rossi, Simona, primary, Mosakhani, Neda, primary, Österlund, Pia, primary, Ristamäki, Raija, primary, Sarhadi, Virinder, primary, Knuutila, Sakari, primary, Boige, Valérie, primary, André, Thierry, primary, and Laurent-Puig, Pierre, primary

Published
2023
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11. An integrated analysis of miRNA and gene copy numbers in xenografts of Ewing's sarcoma

Author

Mosakhani Neda, Guled Mohamed, Leen Gayle, Calabuig-Fariñas Silvia, Niini Tarja, Machado Isidro, Savola Suvi, Scotlandi Katia, López-Guerrero José, Llombart-Bosch Antonio, and Knuutila Sakari

Subjects
Ewing's sarcoma xenograft, MicroRNA, Copy number, Microarray, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Xenografts have been shown to provide a suitable source of tumor tissue for molecular analysis in the absence of primary tumor material. We utilized ES xenograft series for integrated microarray analyses to identify novel biomarkers. Method Microarray technology (array comparative genomic hybridization (aCGH) and micro RNA arrays) was used to screen and identify copy number changes and differentially expressed miRNAs of 34 and 14 passages, respectively. Incubated cells used for xenografting (Passage 0) were considered to represent the primary tumor. Four important differentially expressed miRNAs (miR-31, miR-31*, miR-145, miR-106) were selected for further validation by real time polymerase chain reaction (RT-PCR). Integrated analysis of aCGH and miRNA data was performed on 14 xenograft passages by bioinformatic methods. Results The most frequent losses and gains of DNA copy number were detected at 9p21.3, 16q and at 8, 15, 17q21.32-qter, 1q21.1-qter, respectively. The presence of these alterations was consistent in all tumor passages. aCGH profiles of xenograft passages of each series resembled their corresponding primary tumors (passage 0). MiR-21, miR-31, miR-31*, miR-106b, miR-145, miR-150*, miR-371-5p, miR-557 and miR-598 showed recurrently altered expression. These miRNAS were predicted to regulate many ES-associated genes, such as genes of the IGF1 pathway, EWSR1, FLI1 and their fusion gene (EWS-FLI1). Twenty differentially expressed miRNAs were pinpointed in regions carrying altered copy numbers. Conclusion In the present study, ES xenografts were successfully applied for integrated microarray analyses. Our findings showed expression changes of miRNAs that were predicted to regulate many ES associated genes, such as IGF1 pathway genes, FLI1, EWSR1, and the EWS-FLI1 fusion genes.

Published
2012
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12. MicroRNAs as Predictive and Prognostic Biomarkers inHuman Neoplasia : With Specific Focus on Colorectal Cancer, Giant Cell Tumor of Bone, and Leukemias

Author

Mosakhani, Neda, University of Helsinki, Faculty of Medicine, Haartman Institute, Helsingin yliopisto, lääketieteellinen tiedekunta, kliinisteoreettinen laitos, Helsingfors universitet, medicinska fakulteten, Haartman institutet, and Mäkinen, Markus

Subjects
medicine
Abstract

Recently, discovery of microRNA has provided new insights into cancer research, revealing the role of miRNAs in various biological processes, and evidence shows that their deregulation in many cancers has prognostic and predictive significance. Although specific miRNAs have been discovered in the malignancies studied in this thesis: colorectal cancer (CRC), giant cell tumor of bone (GCTB), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML), very little still is known about the association of miRNAs with progression and their response to treatment. By applying novel microarray techniques, we profiled miRNA expression in CRC, GCTB, ALL and, AML. In the study focusing on primary tumors of 60 metastatic CRC (mCRC) patients, we detected BRAF mutations in 5 and KRAS mutations in 15 cases. In addition to 46 altered miRNAs in mCRC patients with and without KRAS mutation vs. normal colon tissue, we observed an miRNA signature associated with KRAS status when we compared 15 patients with mutant KRAS with 40 patients without this mutation. Four differentially expressed miRNAs, over-expressed miR-92a, miR-127-3p, miR-486-5p, and under-expressed miR-378, were evident in the mutated KRAS group vs. wild-type KRAS group. In another study on CRC, miRNA profiling in primary tumors of 33 mCRC patients with wild-type BRAF and KRAS allowed identification of miRNAs related to their response to anti-EGFR monoclonal antibody treatment. We found up-regulated miR-31* and down-regulated miR-592 in progressive disease (PD) compared to that in disease control (DC). Evaluation of mRNA levels of SLC26A3 and ATN1, drug-related genes and of miR-31* target genes showed their lower level of expression in PD vs. DC. Moreover, correlation between overall survival and miRNA expression assessed by two approaches, cluster analysis and the Cox proportional hazard regression model, revealed two common miRNAs, miR-140-3p and miR-1224-5p, to be related to survival in both analyses. As for the study of the metastatic and non-metastatic GCTBs, we found 12 miRNAs as being differentially expressed (miR-136, miR-513a-5p, miR-494, miR-224, miR-542-5p). Expression levels of eight genes such as NFIB, TNC, and FLRT2 correlated inversely with miRNA results. The expression levels of miR-136 and its target gene, NFIB, were verified by use of qRT-PCR. The level of NFIB protein also was higher in metastatic than in non-metastatic GCTBs. Further, we tested the protein expression level of NFIB in an independent validation cohort of 74 primary archival GCTB specimens to assess the power of NFIB as a prognostic marker. Immunodetection showed a higher frequency of NFIB over-expression in primary tumors that developed metastases than in the disease-free group. Moreover, we studied the miRNA expression profiles of primary tumors of 90 bone marrow core biopsies of ALL patients, including 11 patients with paired samples at diagnosis and at relapse. We found a set of miRNAs (miR-1281, miR-1225-3p, miR-877*, miR-423-5p, miR-29c) significantly related to survival (q less than 0.05). Further validation of miR-423-5p expression by qRT-PCR confirmed microarray analysis results and showed a direct correlation with survival. In comparisons between the diagnosis-relapse pairs, expression of miR-654-5p and miR-431 between the two groups significantly differed, and these miRNAs were down-regulated in relapse samples. Comparison of miRNA profiling of 15 chemorefractory and 18 chemosensitive AML patients showed that the differentially expressed miRNAs were miR-363, miR-532-5p, and 342-3p, all of which were over-expressed in chemorefractory vs. chemosensitive patients. Verification by use of qRT-PCR of both miR-363 and miR-532-5p revealed similar results as with microarray. The miR-363 target genes RGS17 and HIPK3 both have been associated with drug response. These studies provide new information about genomic changes involved in progression and resistance to treatment in various types of cancer, and also highlight the power of applying genomic-wide array screening techniques in malignancies. The novel findings in these studies may serve as a useful resource for future studies and aid in development of novel therapeutic targets to increase the survival rates of cancer patients. Mikro.RNA:lla (miRNA) on keskeinen merkitys syövän synnyssä. miRNA-profiilit erottelevat hyvin eri syöpätyypit toisistaan ja niillä on merkitystä arvioitaessa syövän ennustetta ja annettavan hoidon vaikutusta. Omassa työssäni selvitin miRNA:aiden ennusteellista ja hoitotulosta ennakoivaa merkitystä suolistosyövässä, jättisolutuumorissa ja akuuteissa leukemioissa. Nämä syövät valittiin tutkimukseen ensinnäkin, koska mainittuja syöpiä on tutkittu monipuolisesti laboratoriossamme yhteistyössä muiden tutkijoiden kanssa ja toiseksi, koska miRNA:den kliinisestä merkityksestä näissä taudeissa oli vain rajallisesti tietoa. Suolistosyöpätutkimukseen valittiin 60 metastasoitunuttu potilasta. KRAS-mutaatiopositiivisilla potilailla todettiin negatiivisista poikkeava miRNA-profiili: miR-92a, miR-127-3p ja miR-486-5p olivat yliekspressoituneet ja miR-378 oli aliekspressoitunut KRAS-positiivisilla potilailla (osatyö I) Osatyössä II tutkittiin EGFR vasta-ainehoidolle sensitiivisiä ja resistenttejä KRAS-negatiivisia potilaita. Hoitoresistenteillä potilailla miRNA31* oli yliekspressoitunut ja miR-592 aliekspressoitunut. SLC26A3 ja ATN1, miR-31*:n säätelemät kohdegeenit ekspressoituivat käänteisesti miRNA:n ekspressioon nähden. miR-140-3p and ja -1224-5p yliekspressio liittyi huonoon ennusteeseen. Jättisolutuumorissa (osatyö III) Joukko miRNA:ta erotteli metastasoineet tuumorit ei-metastasoineista. NFIB-, TNC- ja FLRT2- geenit ekspressoituivat käänteisesti mRNA:hin nähden. NFIB-proteiinin yliekspressio osoittautui olevan laajennetulla 74 potilaan aineistolla ennusteellisesti huono merkki. Akuutissa lymfaattisessa leukemiassa (osatyö IV) todettiin miR-654-5p:n ja miR-431:n liittyvän tilastollisesti merkittävästi taudin uusiutumiseen. Joukko miRNA:ta (miR-1281, miR-1225-3p, miR-877*, miR-423-5p ja miR-29c) liittyi tilastollisesti merkittävästi taudin ennusteeseen. Viimeisessä osatyössä (V) osoitettiin, että miR-363, miR-532-5p ja 342-3p liittyivät akuutin myelooisen leukemian hoitoresistenssiin. Väitöskirjatutkimuksessani saatiin uutta tietoa miRNA:aiden osuudesta taudin ennusteeseen ja hoitoresistenssiin. Tutkimuksessa osoitettiin uusia biomarkkereita suoloistosyövässä, jättisolutuumorissa ja leukemioissa. Kuvatut molekulaariset muutokset saattavat tulevaisuudessa avata uusia kohteita kohdistetulle henkilökohtaiselle täsmähoidolle.

Published
2013

16. Simultaneous Underexpression of let-7a-5p and let-7f-5p microRNAs in Plasma and Stool Samples from Early Stage Colorectal Carcinoma

Author

Ghanbari, Reza, primary, Mosakhani, Neda, additional, Sarhadi, Virinder K., additional, Armengol, Gemma, additional, Nouraee, Nazila, additional, Mohammadkhani, Ashraf, additional, Khorrami, Samaneh, additional, Arefian, Ehsan, additional, Paryan, Mahdi, additional, Malekzadeh, Reza, additional, and Knuutila, Sakari, additional

Published
2015
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17. Hsa-miR-31-3p expression is linked to progression-free survival in patients with KRAS wild-type metastatic colorectal cancer treated with anti-EGFR therapy.

Author

Manceau, Gilles, Imbeaud, Sandrine, Thiébaut, Raphaële, Liébaert, François, Fontaine, Karine, Rousseau, Francis, Génin, Bérengère, Le Corre, Delphine, Didelot, Audrey, Vincent, Marc, Bachet, Jean-Baptiste, Chibaudel, Benoist, Bouché, Olivier, Landi, Bruno, Bibeau, Frédéric, Leroy, Karen, Pénault-Llorca, Frederique, Van Laethem, Jean-Luc, Demetter, Pieter, Tejpar, Sabine, Rossi, Simona, Mosakhani, Neda, Osterlund, Pia, Ristamäki, Raija, Sarhadi, Virinder, Knuutila, Sakari, Boige, Valérie, André, Thierry, Laurent-Puig, Pierre, Manceau, Gilles, Imbeaud, Sandrine, Thiébaut, Raphaële, Liébaert, François, Fontaine, Karine, Rousseau, Francis, Génin, Bérengère, Le Corre, Delphine, Didelot, Audrey, Vincent, Marc, Bachet, Jean-Baptiste, Chibaudel, Benoist, Bouché, Olivier, Landi, Bruno, Bibeau, Frédéric, Leroy, Karen, Pénault-Llorca, Frederique, Van Laethem, Jean-Luc, Demetter, Pieter, Tejpar, Sabine, Rossi, Simona, Mosakhani, Neda, Osterlund, Pia, Ristamäki, Raija, Sarhadi, Virinder, Knuutila, Sakari, Boige, Valérie, André, Thierry, and Laurent-Puig, Pierre

Abstract

To identify microRNAs (miRNA) that predict response to anti-EGFR antibodies in patients with wild-type KRAS metastatic colorectal cancer (mCRC)., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2014

19. Hsa-miR-31-3p Expression Is Linked to Progression-free Survival in Patients with KRAS Wild-type Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

Author

Manceau, Gilles, primary, Imbeaud, Sandrine, additional, Thiébaut, Raphaële, additional, Liébaert, François, additional, Fontaine, Karine, additional, Rousseau, Francis, additional, Génin, Bérengère, additional, Corre, Delphine Le, additional, Didelot, Audrey, additional, Vincent, Marc, additional, Bachet, Jean-Baptiste, additional, Chibaudel, Benoist, additional, Bouché, Olivier, additional, Landi, Bruno, additional, Bibeau, Frédéric, additional, Leroy, Karen, additional, Penault-Llorca, Frédérique, additional, Van Laethem, Jean-Luc, additional, Demetter, Pieter, additional, Tejpar, Sabine, additional, Rossi, Simona, additional, Mosakhani, Neda, additional, Österlund, Pia, additional, Ristamäki, Raija, additional, Sarhadi, Virinder, additional, Knuutila, Sakari, additional, Boige, Valérie, additional, André, Thierry, additional, and Laurent-Puig, Pierre, additional

Published
2014
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24. miRNA-34a underexpressed in Merkel cell polyomavirus-negative Merkel cell carcinoma.

Author

Veija, Tuukka, Sahi, Helka, Koljonen, Virve, Bohling, Tom, Knuutila, Sakari, and Mosakhani, Neda

Abstract

Merkel cell polyomavirus (MCV) is frequently detectable in Merkel cell carcinoma (MCC) tumors, but the significance of MCV infection is not yet totally understood. Thus far, no key regulatory miRNA has been identified for MCC tumorigenesis. However, distinct miRNA expression profiles have been suggested for MCV-positive and MCV-negative tumors. We used microarray hybridization to identify miRNA expression differences in MCC tumor samples according to MCV status and further validated these results by quantitative reverse transcription polymerase chain reaction (qRT-PCR). When compared with MCV-negative tumors, we detected overexpression of miR-34a, miR-30a, miR-142-3p, and miR-1539 in those MCV positives. In addition, slight underexpression was detectable in MCV-positive tumors of miR-181d. We confirmed the distinct expression of miRNAs in MCV-positive and MCV-negative tumors and confirmed statistically significant underexpression of miR-34a in MCV-negative tumors by both array analysis and qRT-PCR. Neither tumor location nor development of metastases affected miRNA expression. [ABSTRACT FROM AUTHOR]

Published
2015
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26. MicroRNA expression profiles in metastatic and non-metastatic giant cell tumor of bone

Author

Mosakhani, Neda, Pazzaglia, Laura, Benassi, Maria Serena, Borze, Ioana, Irene Quattrini, Picci, Piero, and Knuutila, Sakari

Subjects
mRNA, 6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología [CDU], miRNA
Abstract

Giant cell tumor of bone (GCTB) is a skeletal neoplasm, a locally aggressive tumor that occasionally metastasizes to the lungs. To identify novel biomarkers associated with GCTB progression and metastasis, we performed a miRNA microarray on ten primary tumors of GCTB, of which five developed lung metastases and the rest remained metastasis-free. Between metastatic and non-metastatic GCTB, 12 miRNAs were differentially expressed (such as miR-136, miR-513a-5p, miR-494, miR-224, and miR-542-5p). A decreased level of miR-136 in metastatic versus nonmetastatic GCTB was significantly confirmed by the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) (p=0.04). To identify potential target genes for the differentially expressed miRNAs, we used three target prediction databases. Then, to functionally validate the potential target genes of the differentially expressed miRNAs, we re-analyzed our previous gene expression data from the same ten patients. Eight genes such as NFIB, TNC, and FLRT2 were inversely expressed relative to their predicted miRNA regulators. NFIB expression correlated in metastatic GCTB with no or low expression of miR-136, and this gene was selected for further verification with qRT-PCR and immunohistochemistry. Verification of NFIB mRNA and protein by qRT-PCR showed elevated expression levels in metastatic GCTBs. Further, the protein expression level of NFIB was tested in an independent validation cohort of 74 primary archival GCTB specimens. In the primary tumors that developed metastases compared to the disease-free group, NFIB protein was moderately to strongly expressed at a higher frequency. Thus, in GCTB, miR-136 and NFIB may serve as prognostic makers.

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