ClustMMRA v2: A Scalable Computational Pipeline for the Identification of MicroRNA Clusters Acting Cooperatively on Tumor Molecular Subgroups.

In recent cancer genomics programs, large-scale profiling of microRNAs has been routinely used in order to better understand the role of microRNAs in gene regulation and disease. To support the analysis of such amount of data, scalability of bioinformatics pipelines is increasingly important to handle larger datasets.Here, we describe a scalable implementation of the clustered miRNA Master Regulator Analysis (clustMMRA) pipeline, developed to search for genomic clusters of microRNAs potentially driving cancer molecular subtyping. Genomically clustered microRNAs can be simultaneously expressed to work in a combined manner and jointly regulate cell phenotypes. However, the majority of computational approaches for the identification of microRNA master regulators are typically designed to detect the regulatory effect of a single microRNA.We have applied the clustMMRA pipeline to multiple pediatric tumor datasets, up to a hundred samples in size, demonstrating very satisfying performances of the software on large datasets. Results have highlighted genomic clusters of microRNAs potentially involved in several subgroups of the different pediatric cancers or specifically involved in the phenotype of a subgroup. In particular, we confirmed the cluster of microRNAs at the 14q32 locus to be involved in multiple pediatric cancers, showing its specific downregulation in tumor subgroups with aggressive phenotype.

The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors.

Most lncRNAs display species-specific expression patterns suggesting that animal models of cancer may only incompletely recapitulate the regulatory crosstalk between lncRNAs and oncogenic pathways in humans. Among these pathways, Sonic Hedgehog (SHH) signaling is aberrantly activated in several human cancer entities. We unravel that aberrant expression of the primate-specific lncRNA HedgeHog Interacting Protein-AntiSense 1 (HHIP-AS1) is a hallmark of SHH-driven tumors including medulloblastoma and atypical teratoid/rhabdoid tumors. HHIP-AS1 is actively transcribed from a bidirectional promoter shared with SHH regulator HHIP. Knockdown of HHIP-AS1 induces mitotic spindle deregulation impairing tumorigenicity in vitro and in vivo. Mechanistically, HHIP-AS1 binds directly to the mRNA of cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2) and attenuates its degradation by hsa-miR-425-5p. We uncover that neither HHIP-AS1 nor the corresponding regulatory element in DYNC1I2 are evolutionary conserved in mice. Taken together, we discover an lncRNA-mediated mechanism that enables the pro-mitotic effects of SHH pathway activation in human tumors.