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 non-coding RNAs (lncRNAs) as crucial determinants of HCC development. In this study, we report the lncRNA HOTTIP as significantly up-regulated in HCC specimens. HOTTIP gene is located in physical contiguity with HOXA13 and directly controls the HOXA locus gene expression via 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 clinico-pathological 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 are obtained from snap-frozen needle HCC biopsies (n=52) matched with their non-neoplastic counterparts collected from patients that 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. Conclusion: our study highlights the key role of HOTTIP and HOXA13 in HCC development by associating their expression to 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 predictive biomarker of HCC.

Long non-coding RNA ANRIL predicts poor prognosis and promotes invasion/metastasis in serous ovarian cancer

“…An increasing number of discoveries of misregulated lncRNA expression across numerous cancer types have suggested that aberrant lncRNA expression may be a major contributor to tumourigenesis. Further, lncRNAs may add another layer to cancer research because their potential usefulness as biomarkers (8)(9)(10)(11)(12)(13)(14)(15). Therefore, to fully understand the complex mechanisms underlying carcinogenesis and cancer metastasis, the role of lncRNAs must be considered.…”

Overexpression of HOXA13 as a Potential Marker for Diagnosis and Poor Prognosis of Hepatocellular Carcinoma

“…In normal adult tissue, HOXA13 has a tendency for high expression in the hindgut region, while its expression is absent or extremely low in anterior areas of the body including liver (Graham et al 1989;Takahashi et al 2004). Latest evidence indicates that HOXA13 is upregulated in HCC and its expression may be associated with clinical progression of HCC and may be predictive of disease outcome (Cillo et al 2011;Quagliata et al 2014). However, its correlation with tumor angiogenesis, diagnostic value and prognostic significance still remains unclear.…”

Long Non-coding RNAs (LncRNA) Regulated by Transforming Growth Factor (TGF) β

“…HOTTIP has been shown to positively regulate the protein coding genes in close proximity, notable HOXA13, through the recruitment of WDR5, a component of the histone methyltransferase protein MLL complex that promotes transcriptional activation (12). It has also recently been reported that elevated levels of human HOTTIP and HOXA13 expression associates with disease progression and poorer survival in hepatocellular carcinoma (29). However, lncRNAs HOTTIP and HOXA11-AS were not induced by TGF␤ in our microarray analysis, suggesting lncRNA-HIT has a unique role in TGF␤-induced EMT.…”