Abstract
Long noncoding RNAs (lncRNAs) are recognized as a new area for cancer therapy. B-cell lymphoma-2 (Bcl-2)-mediated suppression of apoptosis is an important molecular hallmark of cancer. However, the influence of lncRNA on the regulation of oncogenic Bcl-2 in cancer stem cells has not been explored. In this study, our findings revealed that the lncRNA LHFPL3-AS1-long, generated from the polypyrimidine tract binding protein 1 (PTBP1)-mediated splicing of the LHFPL3-AS1 precursor, upregulated BCL2 protein to contribute to tumorigenesis of melanoma stem cells. The in vitro and in vivo results showed that LHFPL3-AS1-long directly interacted with miR-181a-5p to inhibit the mRNA degradation of Bcl-2 (the target of miR-181), thus suppressing apoptosis of melanoma stem cells. The splicing factor PTBP1 regulated the alternative splicing of LHFPL3-AS1 transcript by preferentially binding to the motifs located in exon3 of LHFPL3-AS1 precursor, leading to the biogenesis of LHFPL3-AS1-long in melanoma stem cells. In patients with melanoma, the expressions of PTBP1 and LHFPL3-AS1 were significantly upregulated compared with the healthy donors. Therefore, our study revealed a mechanistic crosstalk among an onco-splicing factor, lncRNA and tumorigenesis of melanoma stem cells, enabling PTBP1 and LHFPL3-AS1 to serve as the attractive therapeutic targets for melanoma.
Highlights
Over the last few decades, the survival of patients with cancer has improved significantly and the combined cancer death rate has declined, primarily because of multidisciplinary care, improved chemotherapeutic agents and the incorporation of palliative care services into the management scheme[1]
The results showed that three selected long noncoding RNAs (lncRNAs) were significantly upregulated in melanoma stem cells (Fig. 1B)
The results showed that the Bcl[2] silencing significantly promoted apoptosis of melanoma stem cells compared with the control (Fig. 3L), indicating that B-cell lymphoma-2 (Bcl-2) played a negative role in apoptosis of melanoma stem cells
Summary
Over the last few decades, the survival of patients with cancer has improved significantly and the combined cancer death rate has declined, primarily because of multidisciplinary care, improved chemotherapeutic agents and the incorporation of palliative care services into the management scheme[1]. A significant proportion of patients continue to experience recurrence of cancers after adjuvant treatment, and survival associated with stage IV solid tumors still remains low[2,3]. Recent studies have suggested that tumor activity can be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA (ceRNAs) in humans[7]. Multiple types of endogenous ceRNAs have been reported, including protein-coding transcripts, long noncoding RNAs (lncRNAs), pseudogenes, and circular RNAs (circRNAs)[7].
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