title: Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients.
abstract: Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death. Despite the advances in diagnosis and management of HCC, the biology of this tumor remains poorly understood. Recent evidence highlighted long noncoding RNAs (lncRNAs) as crucial determinants of HCC development. In this study we report the lncRNA HOXA transcript at the distal tip (HOTTIP) as significantly up-regulated in HCC specimens. The HOTTIP gene is located in physical contiguity with HOXA13 and directly controls the HOXA locus gene expression by way of interaction with the WDR5/MLL complex. HOX genes encode transcription factors regulating embryonic development and cell fate. We previously described HOX genes deregulation to be involved in hepatocarcinogenesis. Indeed, we observed the marked up-regulation of HOXA13 in HCC. Here, by correlating clinicopathological and expression data, we demonstrate that the levels of HOTTIP and HOXA13 are associated with HCC patients' clinical progression and predict disease outcome. In contrast to the majority of similar studies, our data were obtained from snap-frozen needle HCC biopsies (n=52) matched with their nonneoplastic counterparts collected from patients who had not yet received any HCC-tailored therapeutic treatments at the time of biopsy. In addition, taking advantage of gain and loss of function experiments in liver cancer-derived cell lines (HuH-6 and HuH-7), we uncover a novel bidirectional regulatory loop between HOTTIP/HOXA13.
  
  
  CONCLUSIONS
  Our study highlights the key role of HOTTIP and HOXA13 in HCC development by associating their expression with metastasis and survival in HCC patients, provides novel insights on the function of lncRNA-driven hepatocarcinogenesis, and paves the way for further investigation about the possible role of HOTTIP as a predictive biomarker of HCC.
authors.affiliation: Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, Basel, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Quagliata
authors.forename: Matthias S
authors.initials: MS
authors.lastname: Matter
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.forename: Leila
authors.initials: L
authors.lastname: Arabi
authors.forename: Christian
authors.initials: C
authors.lastname: Ruiz
authors.forename: Alfredo
authors.initials: A
authors.lastname: Procino
authors.forename: Michal
authors.initials: M
authors.lastname: Kovac
authors.forename: Francesca
authors.initials: F
authors.lastname: Moretti
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Makowska
authors.forename: Tujana
authors.initials: T
authors.lastname: Boldanova
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Andersen
authors.forename: Monika
authors.initials: M
authors.lastname: Hämmerle
authors.forename: Luigi
authors.initials: L
authors.lastname: Tornillo
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.forename: Sven
authors.initials: S
authors.lastname: Diederichs
authors.forename: Clemente
authors.initials: C
authors.lastname: Cillo
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Terracciano
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D002461:Cell Line, Transformed; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D060787:Neoplasm Grading; D011237:Predictive Value of Tests; D062085:RNA, Long Noncoding / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; C099959:homeobox protein HOXA13