LncRNA HOTTIP facilitates the stemness of breast cancer via regulation of miR‐148a‐3p/WNT1 pathway

Abstract

Emerging evidence suggests that dysregulation of long non‐coding RNA (lncRNA) plays a key role in tumorigenesis. The lncRNA, HOXA transcript at the distal tip (HOTTIP), has been reported to be up‐regulated in multiple cancers, including breast cancer, and is involved in various biological processes, including the maintenance of stemness. However, the biological function and underlying modulatory mechanism of HOTTIP in breast cancer stem cells (BCSCs) remains unknown. In this study, we found that HOTTIP was markedly up‐regulated in BCSCs and had a positive correlation with breast cancer progression. Functional studies revealed that overexpression of HOTTIP markedly promoted cell clonogenicity, increased the expression of the stem cell markers, OCT4 and SOX2, and decreased the expression of the differentiation markers, CK14 and CK18, in breast cancer cells. Knockdown of HOTTIP inhibited the CSC‐like properties of BCSCs. Consistently, depletion of HOTTIP suppressed tumour growth in a humanized model of breast cancer. Mechanistic studies demonstrated that HOTTIP directly binds to miR‐148a‐3p and inhibits the mediation of WNT1, which leads to inactivation of the Wnt/β‐catenin signalling pathway. Our study is the first to report that HOTTIP regulates the CSC‐like properties of BCSCs by as a molecular sponge for miR‐148a‐3p to increase WNT1 expression, offering a new target for breast cancer therapy.

MicroRNA‐148a‐3p suppresses epithelial‐to‐mesenchymal transition and stemness properties via Wnt1‐mediated Wnt/β‐catenin pathway in pancreatic cancer

“…In 2007, Li et al 37 firstly identified pancreatic CSCs using CD44 (+)CD24(+)ESA(+) as surface markers. Since then, pancreatic CSCs have been recognized in succession by using various surface markers, including CD133, 29 CD44, 38 CD24, c‐met and ALDH 39 . In the present study, we identified pancreatic CSCs using CD133 as a surface marker and found that the proportion of CSCs in PC cells was significantly elevated as to normal HPDE cells.…”

“…miR‐148a has been confirmed to be involved in the maintenance of CSC‐like properties of hepatocellular carcinoma 20,21 . Li et al 38 demonstrated that miR‐148a‐3p is dramatically decreased in breast cancer stem cells and could be regulated by HOTTIP to suppress the stemness of breast cancer stem cells. Similarly, our data showed that miR‐148a‐3p was significantly down‐regulated, whereas the CSC markers, including CD133, Nanog, Oct4 and Sox2, were up‐regulated in pancreatic CSCs.…”

The Wnt Signalling Pathway: A Tailored Target in Cancer

“…Overexpression of HOTTIP correlates with the expansion of breast CSCs (BCSCs) and the expression of the stem cell markers, OCT4 and SOX2 . Han et al [ 66 ] demonstrated a reduced expression of differentiation markers, such as CK18 and CK14 and that miR-148a inhibits BC cell migration and invasion by directly targeting Wnt1. Moreover, it has been reported that HOTTIP controls miR-148a-3p by acting as a competing endogenous RNA (ceRNA).…”

“…Moreover, it has been reported that HOTTIP controls miR-148a-3p by acting as a competing endogenous RNA (ceRNA). Thereby, HOTTIP promotes expansion of CSCs in vitro and tumorigenesis in vivo by regulating the miR-148a-3p/Wnt1/β-catenin axis [ 66 ]. These data are summarized in Table 2 .…”

Managing therapeutic resistance in breast cancer: from the lncRNAs perspective

“…Moreover, lncRNA-Hh promotes the activation of the hedgehog signaling molecule Hh to upregulate SOX2 and OCT4 for BCSC maintenance 36 . The lncRNA HOTTIP regulates the miR-148a-3p/WNT1 pathway to maintain the CSC-like properties of BCSCs and facilitate BC growth 49 . Notably, NRAD1 was identified as the first lncRNA which can be activated by a CSC marker 50 .…”