A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis

MicroRNA-mediated gene regulation has been implicated in various diseases, including cancer. This study examined the role of microRNAs (miRNAs) during tumorigenesis and malignant progression of pancreatic neuroendocrine tumors (PanNETs) in a genetically engineered mouse model. Previously, a set of miRNAs was observed to be specifically up-regulated in a highly invasive and metastatic subtype of mouse and human PanNET. Using functional assays, we now implicate different miRNAs in distinct phenotypes: miR-137 stimulates tumor growth and local invasion, whereas the miR-23b cluster enables metastasis. An algorithm, Bio-miRTa, has been developed to facilitate the identification of biologically relevant miRNA target genes and applied to these miRNAs. We show that a top-ranked miR-137 candidate gene, Sorl1, has a tumor suppressor function in primary PanNETs. Among the top targets for the miR-23b cluster, Acvr1c/ALK7 has recently been described to be a metastasis suppressor, and we establish herein that it is down-regulated by the miR-23b cluster, which is crucial for its prometastatic activity. Two other miR-23b targets, Robot and P2ryl, also have demonstrable antimetastatic effects. Finally, we have used the Bio-miRTa algorithm in reverse to identify candidate miRNAs that might regulate activin B, the principal ligand for ALK7, identifying thereby a third family of miRNAs-miRNA-130/301-that is congruently up-regulated concomitant with down-regulation of activin B during tumorigenesis, suggestive of functional involvement in evasion of the proapoptotic barrier. Thus, dynamic up-regulation of miRNAs during multistep tumorigenesis and malignant progression serves to down-regulate distinctive suppressor mechanisms of tumor growth, invasion, and metastasis.

MicroRNA 21 is a novel oncogene in Notch1-driven acute lymphoblastic T cell leukemia

Fabian Junker

Notch signaling is a conserved cell-to-cell communication pathway essential in the development and maintenance of various tissues. Upon ligand binding, Notch receptors on the cell surface are proteolytically cleaved, generating the intracellular domain of Notch (NICD) which acts as a transcriptional regulator. Signaling through Notch1 is essential for normal T cell development, and de-regulated Notch1 signaling leads to the development of acute lymphoblastic T cell leukemia (T-ALL). Mouse models of retroviral overexpression of N1ICD in hematopoietic progenitors in bone-marrow (BM) chimeric mice clearly show that Notch1 in T-ALL acts as an oncogene. MicroRNAs (miRNAs) are small RNA molecules that function as post-transcriptional negative regulators of gene expression. They have been described to play either oncogenic or tumor suppressive roles in Notch1-driven T-ALL. However, it is currently unknown whether miRNAs are essential in Notch1-driven leukemogenesis or in T-ALL maintenance. Dicer1 is an essential enzyme for the generation of mature, functional miRNAs. In this study, the global requirement for miRNAs in T-ALL was assessed via conditional ablation of Dicer1 during early N1ICD-mediated leukemogenesis and in later stages of established T-ALL in vivo. Interestingly, both T-ALL development and maintenance in N1ICD overexpressing BM chimeras were dependent on Dicer1. This was found to be due to induction of apoptosis in Dicer1-deficient T-ALL cells. Microarray-based expression analysis demonstrated that potentially oncogenic miRNAs were up-regulated in both mouse and human T-ALL samples compared with normal T cell progenitors. Among the abundantly expressed miRNAs, candidates previously linked to T-ALL were detected as well as novel candidates. Among them, miR-21, which has previously been linked to tumor biology in a variety of solid tumors, was found to be the most differentially regulated in T-ALL and early and late T cell progenitors. It was also found to be abundantly expressed in primary mouse T-ALL specimens as well as human T-ALL cell lines and primary patient T-ALL samples. Using a novel lentivirus-based miRNA activity reporter system, I demonstrated that miR-21 is active in T-ALL cell lines both in vitro and in vivo. In addition, KD of miR-21 led to apoptosis in T-ALL cells with high miR-21 activity, consistent with miR-21 target gene de-repression. Taken together, these findings demonstrate for the first time that miR-21, in the context of Notch1-driven T-ALL, acts in an oncogenic fashion. It does so by facilitating T-ALL cell survival, which is, at least in part, due to repression of programmed cell-death protein 4 (Pdcd4), a miR-21 target gene and potential novel tumor suppressor in T-ALL. In summary, this study shows that in Notch1-driven T-ALL, miRNAs play an essential role by facilitating T-ALL cell survival, and that miR-21 is a novel oncogenic miRNA in this disease.

EPFL2014

MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer

Douglas Hanahan, Jun Lu, Hao Zhang

While altered expression of microRNAs (miRs) in tumors has been well documented, it remains unclear how the miR transcriptome intersects neoplastic progression. By profiling the miR transcriptome we identified miR expression signatures associated with steps in tumorigenesis and the acquisition of hallmark capabilities in a prototypical mouse model of cancer. Metastases and a rare subset of primary tumors shared a distinct miR signature, implicating a discrete lineage for metastatic tumors. The miR-200 family is strongly down-regulated in metastases and met-like primary tumors, thereby relieving repression of the mesenchymal transcription factor Zeb1, which in turn suppresses E-cadherin. Treatment with a clinically approved angiogenesis inhibitor normalized angiogenic signature miRs in primary tumors, while altering expression of metastatic signature miRs similarly to liver metastases, suggesting their involvement in adaptive resistance to anti-angiogenic therapy via enhanced metastasis. Many of the miR changes associated with specific stages and hallmark capabilities in the mouse model are similarly altered in human tumors, including cognate pancreatic neuroendocrine tumors, implying a generality.

Cold Spring Harbor Laboratory Press2009

A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

Douglas Hanahan, Anguraj Sadanandam, Ismaël Wafy, Stephan Wullschleger

Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation-enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities. SIGNIFICANCE: This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. (C) 2015 AACR.

Amer Assoc Cancer Research2015

MicroRNA 21 is a novel oncogene in Notch1-driven acute lymphoblastic T cell leukemia

Fabian Junker

EPFL2014