title: Aberrant posttranscriptional processing of hyaluronan synthase 1 in malignant transformation and tumor progression.
abstract: It is becoming increasingly apparent that splicing defects play a key role in cancer, and that alterations in genomic splicing elements promote aberrant splicing. Alternative splicing increases the diversity of the human transcriptome and increases the numbers of functional gene products. However, dysregulation that leads to aberrant pre-mRNA splicing can contribute to cancer. Hyaluronan (HA), known to be an important component of cancer progression, is synthesized by hyaluronan synthases (HASs). In cancer cells, hyaluronan synthase 1 (HAS1) pre-mRNA is abnormally spliced to generate a family of aberrant splice variants (HAS1Vs) that synthesize extracellular and intracellular HA. HAS1Vs are clinically relevant, being found almost exclusively in malignant cells. Expression of aberrant HAS1Vs predicts poor survival in multiple myeloma. In this review, we summarize the unusual properties of HAS1Vs and their relationship to cancer. HAS1Vs form heterogeneous multimers with normally spliced HAS1 as well as with each other and with HAS3. Aberrant variants of HAS1 synthesize HA. Extracellular HA synthesized by HAS1Vs is likely to promote malignant spread. We speculate that synthesis of intracellular HA plays a fundamental and early role in oncogenesis by promoting genetic instability and the emergence of viable cancer variants that lead to aggressive disease.
authors: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: sophia_adamia@dfci.harvard.edu.
authors: Sophia
authors: S
authors: Adamia
authors: Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
authors: Jitra
authors: J
authors: Kriangkum
authors: Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
authors: Andrew R
authors: AR
authors: Belch
authors: Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
authors: Linda M
authors: LM
authors: Pilarski
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D000076002:Hyaluronan Synthases; D051379:Mice; D008938:Mitosis; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000473:pathology; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D008941:Spindle Apparatus; D016896:Treatment Outcome
chemical_list: D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases
keywords: Aberrant splicing; Alternative splicing; B cell malignancies; Hyaluronan synthase 1; Intracellular hyaluronan; Mitotic catastrophe; Oncogenic events; RHAMM