3,705 research outputs found
NEW INSIGHTS OF MIR-145 FUNCTION AND REGULATION IN HUMAN BREAST CANCER.
No full textmiR-145 is down-regulated in the majority of human cancers, including breast cancer (BC).
However, its role remains largely unknown. Here, I provide evidence for miR-145 induced
anti-proliferative and pro-apoptotic effect in several BC cell lines, which was not detected in
BC cells lacking a functional TP53 gene and exhibiting an estrogen receptor alfa (ESR1)
negative status. I found that miR-145 anti-proliferative effects were dependent upon TP53
activation and that activation of TP53 could in turn stimulates miR-145 expression. I also
found that miR-145 could repress the expression of ESR1 protein by direct interaction with
two sites within its gene coding sequence. My findings support the existence of a positive
regulatory loop where miR-145 directly targets ESR1 and indirectly activates TP53, which in
turn sustains miR-145 expression and reinforces miR-145 overall effects on proliferation and
apoptosis
microRNA expression and function in Embryonic Stem Cells: miR-100, miR-137 and miR-34a are required for ESC differentiation
No full textGiven their capacity to self-renew and differentiate efficiently into the different cell types, Embryonic Stem Cells (ESCs) provide a valid model to understand the complex network of signaling interactions in the mammalian embryo and open up new possibilities for cell therapy. So a deeper understanding of the molecular mechanisms that regulate generation, self-renewal and differentiation of ESCs is become crucial not only to fulfill their clinical promise but also to get insight into the molecular mechanisms controlling early events of mammalian development. The emergence of microRNAs (microRNAs) as potent regulators of gene expression at the post-transcriptional level has broad implications in all facets of biology, including ESCs and early development.
In recent years, the role of microRNAs in ESCs and mammalian embryogenesis has begun to be explored but specific roles of the microRNAs in the regulation of ESC specific fate are still largely unknown. In this context, our interest is to identify microRNAs regulating ESC functions. We performed a systematic comparison of microRNA expression in undifferentiated versus differentiating mouse ESCs. We report that different microRNAs are increased upon the induction of differentiation. We compared the entire list of candidate mRNA targets of upregulated microRNAs with that of mRNA dowregulated in ESCs upon the induction of differentiation. Among the candidate targets emerged from this analysis, we found three genes Smarca5, Jarid1b and Sirt1, previously demonstrated to be necessary to sustain the undifferentiated phenotype in ESCs. On this basis, we first demonstrated that Smarca5 is a direct target of miR-100, Jarid1b of miR-137 and confirmed previously published data demonstrating that Sirt1 is a direct target of miR-34a in a different context. The suppression of these three microRNAs by anti-miRs caused block of ESC differentiation induced by LIF withdrawal. On the other hand, the overexpression of the three microRNAs resulted in an altered expression of differentiation markers. These results demonstrated that miR-100, miR-137 and miR-34a are required for proper differentiation of ESCs, and that they function by targeting, among the others, the mRNAs of Smarca5, Jarid1b and Sirt1.
In conclusion, we have characterized a subset of microRNAs that are necessary for proper differentiation of mouse ESCs. The identification of microRNAs that are up-regulated upon the induction of ESC differentiation suggests that they suppress, directly or indirectly, the expression of genes necessary to maintain ESCs in the undifferentiated state. The identification of targets of the microRNAs that we have studied may provide tools to drive ESC differentiation towards specific lineages
Drosophila mir-9a regulates wing development via fine-tuning expression of the LIM only factor, dLMO.
No full textInternational audienceMicroRNAs are short non-coding endogenous RNAs that are implicated in regulating various aspects of plants and animal development, however their functions in organogenesis are largely unknown. Here we report that mir-9a belonging to the mir-9 family, regulates Drosophila wing development through a functional target site in the 3' untranslated region of the Drosophila LIM only protein, dLMO. dLMO is a transcription cofactor, that directly inhibits the activity of Apterous, the LIM-HD factor required for the proper dorsal identity of the wings. Deletions of the 3' untranslated region, including the mir-9a site, generate gain-of-function dLMO mutants (Beadex) associated with high levels of dLMO mRNA and protein. Beadex mutants lack wing margins, a phenotype also observed in null mir-9a mutants. We found that mir-9a and dLMO are co-expressed in wing discs and interact genetically for controlling wing development. Lack of mir-9a results in overexpression of dLMO, while gain-of-function mir-9a mutant suppresses dLMO expression. These data indicate that a function of mir-9a is to ensure the appropriate stoichiometry of dLMO during Drosophila wing development. The mir-9a binding site is conserved in the human counterpart LMO2, the T-cell acute leukemia oncogene, suggesting that mir-9 might apply a similar strategy to maintain LMO2 expression under a detrimental threshold
Serum microRNA-122 predicts survival in patients with liver cirrhosis
No full textBackground: Liver cirrhosis is associated with high morbidity and mortality. MicroRNAs (miRs) circulating in the blood are an emerging new class of biomarkers. In particular, the serum level of the liver-specific miR-122 might be a clinically useful new parameter in patients with acute or chronic liver disease.
Aim: Here we investigated if the serum level of miR-122 might be a prognostic parameter in patients with liver cirrhosis.
Methods: 107 patients with liver cirrhosis in the test cohort and 143 patients in the validation cohort were prospectively enrolled into the present study. RNA was extracted from the sera obtained at the time of study enrollment and the level of miR-122 was assessed. Serum miR-122 levels were assessed by quantitative reverse-transcription PCR (RT-PCR) and were compared to overall survival time and to different complications of liver cirrhosis.
Results: Serum miR-122 levels were reduced in patients with hepatic decompensation in comparison to patients with compensated liver disease. Patients with ascites, spontaneous bacterial peritonitis and hepatorenal syndrome had significantly lower miR-122 levels than patients without these complications. Multivariate Cox regression analysis revealed that the miR-122 serum levels were associated with survival independently from the MELD score, sex and age.
Conclusions: Serum miR-122 is a new independent marker for prediction of survival of patients with liver cirrhosis
Structures and the locations of single nucleotide polymorphisms of <i>pre-miR-146a</i>, <i>miR-149</i>, <i>miR-196a2</i>, and <i>miR-499</i>.
No full textStructures and the locations of single nucleotide polymorphisms of pre-miR-146a, miR-149, miR-196a2, and miR-499.</p
Importancia clínica de los micrornas de la vía de p53 en cáncer de pulmón no microcítico: miR-34a y miR-16
No full text[spa] El cáncer de pulmón no célula pequeña es la neoplasia más frecuente en la actualidad en los países industrializados, siendo la primera causa de mortalidad por cáncer en el varón.
Su incidencia continúa aumentando progresivamente, y su tratamiento, pese a los esfuerzos de investigación de los últimos años, sigue siendo poco efectivo en la mayor parte de los casos, situándose la supervivencia global a los cinco años alrededor del 13%.
La alta tasa de recaída, incluso en estadios iniciales susceptibles de cirugías radicales, justifica el interés de estudiar marcadores pronósticos de supervivencia y recaída. Esto nos ayudaría a distinguir grupos de riesgo, cuyo interés radica en ayudarnos a conocer la necesidad y efecto de los tratamientos adyuvantes, con quimioterapia y radioterapia así como abrir la puerta a posibles nuevas armas terapéuticas.
Dada la alta incidencia de alteraciones en la vía de p53 en el cáncer de pulmón no célula pequeña, y su probable valor pronóstico, nuestra hipótesis es que existen alteraciones en los niveles de expresión de los miRNAs directamente regulados por p53, así como en los reguladores intermedios de la función de p53, con posible valor pronóstico en recaída y supervivencia de pacientes operados de cáncer de pulmón no célula pequeña o no microcítico(CPNCP).
Tratamos pues de identificar el papel que juegan los miRNAs como marcadores útiles en el pronóstico del CPNCP en estadios iniciales, tras cirugía radical. De forma más específica determinar el posible papel pronóstico en recaída y en supervivencia de los miRNAs de la familia de miR-34: miR-34a, miR-34b y miR-34c, cuya transcripción es activada por p53. También definir el posible papel pronóstico en recaída y en supervivencia de los miRNAs miR-16 y miR-143, cuyos niveles finales en la célula, están modulados por p53. Así como, conocer si existen posibles interacciones entre miR-34a, miR-34b, miR-34c, miR-16 y miR-143 a nivel pronóstico.
Para ello, hemos planteado un estudio retrospectivo, con las muestras de tejido tumoral y normal pareado de 70 pacientes, diagnosticados y tratado, de cáncer de pulmón no microcítico estadios I-III, entre Febrero de 1996 y Septiembre de 2002, en el Hospital Clínic de Barcelona. Se realizaron la extracción y cuantificación de RNA. Determinación de los niveles de los microRNAs mencionados. Determinación del estado de metilación de la región promotora del gen MIR34A. Determinación de la presencia de mutaciones de P53 entre los exones 5-8.
Tras estos estudios los resultado obtenidos se han publicado en dos artículos. El primero de ellos en la revista “Carcinogenesis” y el segundo en la revista “Journal of Surgical Oncology”.
En el primer artículo, titulado “miR-34a as a prognostic marker of relapse in surgically resected non-small-cell lung cancer”, relacionamos los niveles de miR-34a con la recaída tumoral, estableciendo tres grupos en función de esta tasa de recaída: el grupo con niveles bajos de miR34a, con un 67% de recaída, los que tenían niveles altos, con un 43% de recaída y los que tenían los niveles más altos con un 0% de recaída. Además, en el análisis univariado para riesgo de recaída, el estado mutacional de P53, los niveles de miR-34a
y el estadio IA vs el resto, se correlacionaron con probabilidad de recaída. Se realizaron dos análisis mutilvariados, incluyendo o no el estado mutacional de P53, permaneciendo en ambos análisis la expresión de miR-34a, como factor independiente para recaída tumoral. Se observó que los pacientes con mutaciones de P53 presentaban una media de expresión de miR-34a más baja. Se observó que el subgrupo de pacientes en el que los niveles de expresión de miR-34a baja coincidían con presencia de mutaciones de P53, presentaban una alta tasa de recaída. En los pacientes sin mutaciones de de P53, existe una diferencia significativa en los niveles de expresión de miR-34a entre los pacientes que presentaban la región promotora de MIR34A metilada vs los que no. Por todo esto, encontramos que miR-34a se demuestra como un nuevo marcador biológico con significación en el pronóstico de la recaída de pacientes sometidos a cirugía del CPNCP, abriendo la posibilidad de una futura herramienta en el algoritmo de decisiones terapéuticas.
En el segundo artículo, titulado “Prognostic Implications of miR-16 Expression Levels in Resected Non-Small-Cell Lung Cancer”, desde la hipótesis de que P53 activa la transcripción de la familia de miRNAs de miR-34 y regula la maduración de miR-16 y miR143, se estudiaron los niveles de expresión de miR-143 y miR-16 en el tejido normal y tumoral pareado de cada paciente de la serie, antes mencionada, de 70 pacientes.
Así los pacientes se clasificaron de acuerdo a los niveles de expresión de miR-16(alto, normal y bajo). Aquellos pacientes con niveles normales tuvieron la mejor evolución, mientras que aquellos con niveles más altos tuvieron la peor. La supervivencia libre de enfermedad (SLE) era de 22,4 meses para los pacientes con niveles altos de miR-16, 71,8 meses para los de niveles normales y de 55,8 meses para los de niveles bajos. La supervivencia global (SG) fue de 23,9 meses para los que tenían niveles altos de miR-16, de 97,6 meses para los que tenían niveles normales y 63,5 meses para aquellos con niveles bajos. No se observó correlación entre los niveles de miR-143 y la evolución clínica de los pacientes. El análisis multivariado mostró a miR-16 como factor pronóstico independiente de SLE Y SG. En un análisis secundario, examinamos la correlación potencial entre la expresión de miR-16 y miR-34a y el estado mutacional de P53.No hubo correlación entre el estado mutacional de P53 y miR-16, pero si se observó una interacción entre miR-16 y miR-34a. En los pacientes con niveles altos de miR-34a, se observaron diferencias entre SLE Y SG, de acuerdo a los niveles de expresión de miR-16, mientras que en los pacientes con niveles bajos de miR-34a presentaban un pobre pronóstico, independientemente de los niveles de expresión de miR-16. Estos resultados nos indican el posible valor pronóstico de miR-16 en pacientes intervenidos de CPNCP, además del posible sinergismo entre miR-34a y miR16.[eng] Non small cell lung cancer is more common today, in industrialized countries and is the leading cause of cancer death in men. Its incidence continues to increase gradually, and their treatment, despite the research efforts of recent years, it remains ineffective in most cases, putting the overall survival at five years about 13%. The high rate of relapse, even in early stages susceptible to radical surgery, justifies the interest in studying prognostic markers of survival and relapse. This would help us distinguish risk groups, whose interest lies in helping to meet the need and effect of adjuvant treatment with chemotherapy and radiotherapy as well as opening the door to possible new therapeutic tools. Given the high incidence of alterations in the p53 pathway in non small cell lung cancer, and likely its prognostic role, our hypothesis is that there are alterations in the expression levels of miRNAs directly regulated by p53, as well as in intermediate regulators of p53 function with potential prognostic value on relapse and survival of patients undergoing non small cell lung cancer (NSCLC). Then, we try to identify the role of miRNAs as useful markers for the prognosis of NSCLC in initial stages, after radical surgery. More specifically determine the possible prognostic role in relapse and survival of the family miRNAs miR-34: miR-34a, miR-34b and miR-34c, whose transcription is activated by p53. Also define the possible prognostic role in relapse and survival of the miRNAs miR-16 and miR-143, whose final levels in the cell are modulated by p53. And, determine whether there are possible interactions between miR-34a, miR-34b, miR-34c, miR-16 and miR-143 as regards prognosis. To do this, we have proposed a retrospective study, with the tumor tissue and paired normal in 70 patients, diagnosed and treated of non small cell lung cancer stages I-III, between February 1996 and September 2002, at the Hospital Clínic, in Barcelona. We performed RNA extraction and quantification. Determining levels of microRNAs mentioned. Determining the status of methylation of the promoter region of the gene MIR34A. Determining the presence of p53 mutations between exons 5-8. Following, the results obtained from these studies have been published in two articles. The first in the journal "Carcinogenesis" and the second in the "Journal of Surgical Oncology." In the first article, entitled "miR-34a as a Prognostic marker of relapse in surgically resected non-small-cell lung cancer", we relate the levels of miR-34a with the tumor relapse, establishing three groups according to the rate of relapse: the group with low levels of miR34a, with 67% relapse, those with high levels, with 43% relapse and those with the highest levels with a 0% relapse. Furthermore, in univariate analysis for risk of relapse, the mutational status of p53, the levels of miR-34a and stage IA vs the rest, were correlated with likelihood of relapse. Two multivariate analyzes were performed, including or not the P53 mutational status, remaining in both analyzes the expression of miR-34a, as an independent factor for tumor relapse. It was observed that patients with p53 mutations had a mean expression of miR-34a lower. It was noted that the subgroup of patients in which the expression levels of miR-34a low coincided with the presence of p53 mutations, had a high rate of relapse. In patients without mutations of p53, there is a significant difference in expression levels of miR-34a between the patients with the methylated promoter region MIR34A vs. those without. For all this, we found that miR-34a is shown as a novel biomarker with prognostic significance in patients relapsed NSCLC undergoing surgery, opening the possibility of a future tool in the therapeutic decision algorithm. In the second article, entitled "Prognostic Implications of miR-16 Expression Levels in Resected Non-Small-Cell Lung Cancer", from the hypothesis that p53 activates transcription of the family of miRNAs miR-34 and regulates the maturation of miR-16 to miR-143, we studied the expression levels of miR-143 and miR-16 in the paired normal and tumor tissue of each patient in the series, mentioned above, in 70 patients. So patients were classified according to the expression levels of miR-16 (high, normal and low). Patients with normal levels had the best clinical course, while those with higher levels had the worst. The disease-free survival (DFS) was 22.4 months for patients with high levels of miR-16, 71.8 months for normal levels of 55.8 months for low levels. Overall survival (OS) was 23.9 months for those with high levels of miR-16, from 97.6 months for those with normal levels and 63.5 months for those with low levels. No correlation was observed between the levels of miR-143 and the clinical course of patients. Multivariate analysis showed miR-16 as an independent prognostic factor for DFS and OS. In a secondary analysis, we examined the potential correlation between the expression of miR-16 and miR-34a and the mutational status of P53. There was no correlation between p53 mutational status and miR-16, but observed an interaction between miR-16 and miR-34a. In patients with high levels of miR-34a, there were differences between DFS and OS, according to the expression levels of miR-16, whereas in patients with low levels of miR-34a had a poor prognosis, regardless of expression levels of miR-16. These results indicate the possible prognostic value of miR-16 in patients operated for NSCLC, as well as possible synergism between miR-34a and miR1
Die Bedeutung von microRNAs für die Funktion von Endothelzellen
No full textDicer and Drosha are the major enzymes involved in microRNA processing. Using siRNA targeting Dicer and Drosha, thereby downregulating a substantial number of microRNAs in EC, we demonstrate a crucial role of both enzymes in angiogenic processes. Interestingly, Dicer inhibition exerts more profound effects on processes like migration and viability of EC in comparison to Drosha inhibition. Moreover, Dicer effects in vivo angiogenesis, a process which is unaffected by Drosha. This discrepancy might be partially due to the involvement of Dicer in other cellular processes like heterochromatin formation and to the fact that Dicer and Drosha target mainly different subsets of microRNAs. In addition, we identified miR-92a as a novel endogenous repressor of the angiogenic program in EC, which impairs their angiogenic functions in vitro and in vivo. Consistent with these data, blocking miR-92a by systemic infusion of antagomirs enhances neovascularization and functional recovery after ischemia in vivo. At first sight, the anti-angiogenic function of miR-92a in EC appears to contradict the previously identified anti-apoptotic and pro-angiogenic activities of the miR-17~92 cluster in tumor cells. However, this apparent discrepancy might be well rationalized by a predominant function of miR-18a and miR-19a in tumor cells, which are responsible for the tumorigenic and non-cell autonomous pro-angiogenic functions of the miR-17~92 cluster. Instead, miR-92a expression is specifically upregulated in ischemic tissues and appears to cell-autonomously repress the angiogenic potential of EC. Among the various targets and verified regulated genes identified by microarray, we confirmed the downregulation of Integrin a5 in vitro and in vivo. The relevance of this miR-92a target is evidenced by severe vascular defects in the absence of Integrin a5. In addition, endothelial miR-92a interferes with the expression pattern of genes controlling key EC functions at various levels, some of which, e.g. eNOS, might be secondarily affected by directly targeted genes. Obviously, our data do not formally exclude effects of antagomir-92a on perivascular and other cell types, but surely include effects on EC. Regardless of this, the capacity of miR-92a to target various downstream effectors might be an advantage of miRNA-based therapeutic strategies and may overcome the limited therapeutic capacity of single growth factor or single gene therapies in ischemic diseases, since the highly organized process of vessel growth, maturation and functional maintenance is well known to require the fine-tuned regulation of a set of genes.Angiogenese, die Bildung von Kapillaren aus bereits existierenden Gefäßen, ist ein wichtiger physiologischer Prozess zur Wundheilung und Wiederherstellung des Blutflusses nach Verletzung. Das Ziel der vorliegenden Arbeit war die genaue Untersuchung der Rolle von microRNAs in angiogenen Prozessen. MicroRNAs sind kleine, einzelsträngige RNA Moleküle, welche die Genexpression durch Bindung an die messenger RNA (mRNA) von Zielgenen und darauffolgenden Degradierung der mRNA oder Repression der Translation regulieren. Die Inhibition der microRNA-prozessierenden Enzyme Dicer und Drosha in Endothelzellen führt zu einer Dysregulation der microRNA Expression und zu einer signifikanten Reduktion der Angiogenese in vitro. Im Gegensatz zu Drosha, dessen Inhibition keinen Effekt auf die in vivo Angiogenese zeigt, führt die Inhibition von Dicer auch in einem in vivo Angiogenese-Modell zu einer deutliche reduzierten Einsprossung von Gefäßen. Zusammenfassend sprechen diese Daten für eine wichtige Rolle von microRNAs in der Endothelzellbiologie. Der zweite Teil der vorliegenden Arbeit beschränkte sich auf die Untersuchung einer, in Endothelzellen hoch exprimierten microRNA, miR-92a. MiR-92a ist ein Mitglied des miR-17-92 Clusters, für den bereits eine Rolle in der Tumorangiogenese beschrieben ist. Die Überexpression der miR-92a in Endothelzellen führt zu einer signifikanten Hemmung der Angiogenese, sowie reduzierter Adhäsion und Migration auf Fibronektin. Zudem wird die Einsprossung von Gefäßen in Matrigel Plugs deutlich gehemmt. In Übereinstimmung hierzu führt die systemische Hemmung der miR-92a mit Hilfe von modifizierten antisense Oligoribonukleotiden (Antagomir-92a) im Mausmodell zu einer Stimulation der Einsprossung von Gefäßen in Matrigel Plugs. In klinisch relevanten Modellen, wie dem Hinterlaufischämie-Modell und dem akuten Myokardinfarkt-Modell, führt die Behandlung mit Antagomir-92a zu einer funktionelle Verbesserung. Immunohistologische Analysen ergaben, dass in den Antagomir-92a behandelten Tieren sowohl die Anzahl der Kapillaren als auch der größeren Gefäße deutlich erhöht ist. Obwohl wir einen direkten Effekt der Antagomir-92a Behandlung auf die Myozyten zum jetzigen Zeitpunkt nicht auschließen können, weisen unsere Daten definitiv auf eine Stimulation der Angiogenese hin. Nachdem wir sowohl in vitro als auch in vivo zeigen konnten, dass miR-92a maßgeblich an angiogenen Prozessen beteiligt ist, stellten wir uns die Frage nach den zugrunde liegenden Zielgenen. Es zeigte sich, dass miR-92a neben einer größeren Anzahl pro-angiogener Faktoren die Integrin Untereinheit a5 sowohl in vitro als auch in vivo reguliert. Desweiteren konnten wir mit Hilfe eines Luciferase Assays die direkte Regulation von Integrin a5 durch miR-92a zeigen. Zusammenfassend deuten diese Daten daraufhin, dass Integrin a5 ein Schlüsselregulator der Antagomir-92a-vermittelten Angiogenese ist und somit unmittelbar an der Verbesserung nach Hinterlaufischämie und akutem Myokardinfarkt beteiligt ist
Upregulated sirtuin 1 by miRNA-34a is required for smooth muscle cell differentiation from pluripotent stem cells
No full text© 2015 Macmillan Publishers Limited. All rights reserved. microRNA-34a (miR-34a) and sirtuin 1 (SirT1) have been extensively studied in tumour biology and longevityaging, but little is known about their functional roles in smooth muscle cell (SMC) differentiation from pluripotent stem cells. Using well-established SMC differentiation models, we have demonstrated that miR-34a has an important role in SMC differentiation from murine and human embryonic stem cells. Surprisingly, deacetylase sirtuin 1 (SirT1), one of the top predicted targets, was positively regulated by miR-34a during SMC differentiation. Mechanistically, we demonstrated that miR-34a promoted differentiating stem cells' arrest at G0G1 phase and observed a significantly decreased incorporation of miR-34a and SirT1 RNA into Ago2-RISC complex upon SMC differentiation. Importantly, we have identified SirT1 as a transcriptional activator in the regulation of SMC gene programme. Finally, our data showed that SirT1 modulated the enrichment of H3K9 tri-methylation around the SMC gene-promoter regions. Taken together, our data reveal a specific regulatory pathway that miR-34a positively regulates its target gene SirT1 in a cellular context-dependent and sequence-specific manner and suggest a functional role for this pathway in SMC differentiation from stem cells in vitro and in vivo
Loss of tumor suppressor mir-203 mediates overexpression of LIM and SH3 Protein 1 (LASP1) in high-risk prostate cancer thereby increasing cell proliferation and migration
No full textSeveral studies have linked overexpression of the LIM and SH3 domain protein 1 (LASP1) to progression of breast, colon, liver, and bladder cancer. However, its expression pattern and role in human prostate cancer (PCa) remained largely undefined. Analysis of published microarray data revealed a significant overexpression of LASP1 in PCa metastases compared to parental primary tumors and normal prostate epithelial cells. Subsequent gene-set enrichment analysis comparing LASP1-high and -low PCa identified an association of LASP1 with genes involved in locomotory behavior and chemokine signaling. These bioinformatic predictions were confirmed in vitro as the inducible short hairpin RNA-mediated LASP1 knockdown impaired migration and proliferation in LNCaP prostate cancer cells. By immunohistochemical staining and semi-quantitative image analysis of whole tissue sections we found an enhanced expression of LASP1 in primary PCa and lymph node metastases over benign prostatic hyperplasia. Strong cytosolic and nuclear LASP1 immunoreactivity correlated with PSA progression. Conversely, qRT-PCR analyses for mir-203, which is a known translational suppressor of LASP1 in matched RNA samples revealed an inverse correlation of LASP1 protein and mir-203 expression. Collectively, our results suggest that loss of mir-203 expression and thus uncontrolled LASP1 overexpression might drive progression of PCa
miR-21 and miR-31 Converge on TIAM1 to Regulate Migration and Invasion of Colon Carcinoma Cells
No full textTGF-β promotes cell migration and invasion, an attribute that is linked to the pro-metastasis function of this cytokine in late stage cancers. The LIM 1863 colon carcinoma organoid undergoes epithelial-mesenchymal transition (EMT) in response to TGF-β. This process is markedly accelerated by TNF-α, and we found that the levels of miR-21 and miR-31 were prominently elevated under the synergistic actions of TGF-β/TNF-α. Consistent with this, overexpression of either miR-21 or miR-31 significantly enhanced the effect of TGF-β alone on LIM 1863 morphological changes. More importantly, transwell assays demonstrated the positive effects of both miR-21 and miR-31 in TGF-β regulation of LIM 1863 motility and invasiveness. Elevated levels of miR-21 and miR-31 also enhanced motility and invasiveness of other colon carcinoma cell lines. We present compelling evidence that TIAM1, a guanidine exchange factor of the Rac GTPase, is a direct target of both miR-21 and miR-31. Indeed in LIM 1863 cells, suppression of TIAM1 is required for miR-21/miR-31 to enhance cell migration and invasion. Therefore, we have uncovered miR-21 and miR-31 as downstream effectors of TGF-β in facilitating invasion and metastasis of colon carcinoma cells
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