Abstract
BackgroundLiver cancer is one of the most deadly cancers in the world. There are various cells in liver tumor bulk, including liver tumor initiating cells (TICs), which account for liver tumorigenesis, drug resistance, relapse and metastasis. The homeobox (HOX) transcription factors play critical roles in many physiological and pathological processes, while, their roles in liver TICs and liver tumorigenesis remain unknown.MethodsAn unbiased screening was performed using online-available datasets. Liver TICs were sorted by FACS using surface markers CD133, CD13 and EPCAM, or enriched by oncosphere formation assay. TIC self-renewal was examined by oncosphere formation and tumor initiation assay. Loss of function and gain of function assays were performed to examine the role of lncRNA. RNA pulldown, RNA immunoprecipitation, ChIP, Western blot and double FISH were used to explore the molecular mechanism of lncRNA.ResultsHere, we examined the expression pattern of HOX transcription factors, and found HOXA10 was overexpressed in liver cancer samples. Moreover, a divergent lncRNA of HOXA10 (termed lncHOXA10 hereafter) was also highly expressed in liver cancer and liver TICs. LncHOXA10 drove liver TIC self-renewal and liver tumorigenesis through HOXA10-dependent manner. LncHOXA10 interacted with SNF2L and recruited NURF chromatin remodeling complex to HOXA10 promoter, and thus initiated the transcription of HOXA10. Through HOXA10 transcriptional regulation, lncHOXA10 activated HOXA10 in liver TICs. LncHOXA10-HOXA10 signaling can be targeted to eliminate liver TICs. Altogether, lncHOXA10 drove HOXA10 expression and thus promoted liver TIC self-renewal.ConclusionHOXA10 was the most highly expressed HOX transcription factor in liver cancer and liver TICs. LncHOXA10 drove the transcriptional activation of HOXA10. This work revealed the important role of HOX transcription factor in liver TIC self-renewal and added a new layer for liver TIC regulation.
Highlights
Liver cancer is one of the most deadly cancers in the world
HOX transcription factors (TF) participate in many biological processes
(See figure on previous page.) Fig. 5 LncHOXA10 interacted with SNF2L. a RNA pulldown was performed and the specific band in lncHOXA10 sample was identified as SNF2L by mass spectrum. b The combination between lncHOXA10 and SNF2L was examined by RNA-pulldown and Western blot. c Diagram showing the procedure of RAP (RNA antisense purification)
Summary
Liver cancer is one of the most deadly cancers in the world. There are various cells in liver tumor bulk, including liver tumor initiating cells (TICs), which account for liver tumorigenesis, drug resistance, relapse and metastasis. The homeobox (HOX) transcription factors play critical roles in many physiological and pathological processes, while, their roles in liver TICs and liver tumorigenesis remain unknown. The self-renewal of liver TICs is finely regulated by many modulators. Some transcription factors (TF) participate in the self-renewal regulation of liver TICs, including Zic, Oct, Sox, Notch2 [12, 14, 15]. Homeobox (HOX) transcription factors participate in many physiological and pathological processes, including vertebrate development [16], neural crest and branchial arch patterning [17], angiogenesis [18] and tumorigenesis [19]. The roles of HOX TFs in liver TIC self-renewal are unclear. Here we examined the expression profile of HOX TFs in liver cancer, and found HOXA10 (homeobox A10) was the most highly expressed HOX transcription factor in liver tumor
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