IEEE BIBM 2023 Workshop on Long Non-Coding RNAs: Mechanism, Function, and Computational Analysis (BIBM-LncRNA)

Title: Targeting the long non-coding RNA lnc-HLX-2-7 in group 3 childhood Medulloblastoma

Abstract: Recent studies suggest that long non-coding RNAs (lncRNAs) contribute to medulloblastoma formation and progression. We have identified a lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 (G3) medulloblastomas. lnc-HLX-2-7 RNA specifically accumulates in the promoter region of HLX, its host gene, which activates HLX expression by recruiting multiple factors, including enhancer elements. RNA sequencing and chromatin immunoprecipitation reveal that HLX binds to and activates the promoters of several oncogenes, including TBX2, LIN9, HOXM1, and MYC. Intravenous treatment with cerium oxide nanoparticle-coated antisense oligonucleotides targeting lnc-HLX-2-7 (CNP-lnc-HLX-2-7) inhibits tumor growth by 40-50% in an intracranial medulloblastoma xenograft mouse model (p<0.01). Combining CNP-lnc-HLX-2-7 with standard-of-care cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared with CNP-lnc-HLX-2-7 monotherapy (p<0.01). Thus, the lnc-HLX-2-7-HLX-MYC axis is important for regulating G3 medulloblastoma progression, providing a strong rationale for using lnc-HLX-2-7 as a therapeutic target for G3 MBs in children.

Brief Bio: Dr. Ranjan J. Perera obtained his Ph.D from the Ghent Universit Belgium, and served as a post-doctoral fellow at Massachusetts Institute of Technology at Ethan Signer's lab. He is currently an Associate Professor in the Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, and the Director of the Center for RNA Biology. The Center for RNA Biology seeks advancement in the study of ribonucleic acids (RNA) at the molecular level and how they impact disease and therapy, particularly related to aggressive forms of cancer. Dr. Perera plans to develop the center to focus on abnormal patterns of regulation of certain long non-coding RNA (lncRNA) and microRNA (mRNA) genes and how they determine the aggressiveness of types of cancer. The goal is earlier detection and improved treatments for aggressive forms of cancer. The center hopes to discover new approaches to investigating cancers by considering whether epi-transcriptomics, epigenetic, and genetic processes might be the important underlying molecular mechanism behind them. The current focus of the RNA center is to develop lipid nanoparticle-based RNA therapeutics to treat childhood brain tumor medulloblastomas and prostate cancer in men. Dr. Perera is affiliated with various institutes and units at Johns Hopkins, incuding Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Cancer & Blood Disorders Institute, Johns Hopkins All Children's Hospital Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, The Johns Hopkins University and Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Title: Human Papillomavirus Type 16 Increases Circular RNA Circ-IGF2BP3 Expression Affecting Proliferation and Migration in Cervical Cancer Cells

Abstract: The high-risk HPV type 16 (HPV 16) is responsible for the majority of HPV related cancers. It has recently been discovered that specific noncoding RNAs can contribute to tumor metastasis, proliferation and angiogenesis. Circular RNAs (circRNAs) are a highly stable class of RNA molecules, with closed loops, that have recently been shown to contribute to oncogenesis. Our group conducted a global circRNA expression in primary cervical keratinocytes containing HPV 16 to identify differentially expressed circRNAs upon HPV infection. Interestingly, a circRNA expressed from the insulin like growth factor 2 binding protein 3 gene (circ-IGF2BP3) was found to be significantly overexpressed in HPV 16 cell lines, which led us to hypothesize that overexpression of circ-IGF2BP3 by HPV 16 has a role in tumorigenesis. To examine the function of circ-IGF2BP3 we designed siRNA complementary to the joined 5 and 3 ends of circ-IGF2BP3. Specificity to circ-IGF2BP3 was verified via qRT PCR and Western blotting for linear IGF2BP3 mRNA and protein, respectively. We then performed functional assays with the circ-IGF2BP3 knockdown including transwell migration, cell proliferation, and senescence assays We showed that absence of circ-IGF2BP3 is associated with a decrease in cervical cancer cell migration and an increase in cell proliferation. Circ-IGF2BP3 is a novel circRNA with important implications for the progression of HPV 16 cervical cancer cells.

Brief Bio: Dr. Ivan Martinez is an Associate professor at WVU Cancer Institute and the Department of Microbiology, Immunology and Cellular Biology at WVU. Originally from Mexico City, he graduated with honors form the most important university in Mexico: The National Autonomous University of Mexico. He completed his Ph.D. in Molecular Genetics and Biochemistry at the University of Pittsburgh, and continued his training as a postdoctoral fellow in the Department of Genetics at Yale University School of Medicine for over 5 years. After his training, he was recruited at WVU in 2013. The goal of Dr. Martinez research is to understand the importance of a group of molecules called non-coding RNAs in different types of cancers such as cervical cancer, head and neck cancer, and lung cancer as well as viral infections.