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

Li Han,Yinuo Liu,Lin Zhao,Yuanyuan Yan,Minjie Wei,Miao He,Liwen Zhang,Xuemei Lv,Yanyun Zhao,Haishan Zhao

doi:10.1111/jcmm.15261

Li Han, Yinuo Liu + Show 8 more

Open Access

https://doi.org/10.1111/jcmm.15261

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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.

Highlights

Breast cancer is the most common cancer in women worldwide with high incidence and mortality rates
These results suggest that HOXA transcript at the distal tip (HOTTIP) modulates the stemness of breast cancer stem cells (BCSCs) by regulating the WNT1 pathway by acting as a ceRNA and sponging miR-148a-3p
The treatment options currently available for breast cancer patients, including surgery, chemotherapy, endocrine therapy, and radiation therapy, have improved,[28] the mortality rate associated with breast cancer remains high

Summary

| INTRODUCTION

Breast cancer is the most common cancer in women worldwide with high incidence and mortality rates. Such as CD44, CD24, ALDH, EpCAM, and HER2.5-7 Considering that BCSCs play a key role in tumour initiation and progression, identifying the underlying mechanism of the maintenance of BCSCs will be useful in the development of novel breast cancer-targeted therapies. LncRNA HOTTIP was reported to be involved in modulating cancer stem cell properties in human pancreatic cancer.[23]. We aimed to investigate the biological function of HOTTIP in modulating the properties of BCSCs. We found that high expression of HOTTIP was associated with poor prognosis and promoted the stemness of BCSCs. Mechanistic studies revealed miR148a-3p to be a target of HOTTIP. We demonstrated that HOTTIP promoted CSC-like properties in BCSCs by sponging miR148a-3p These data may provide a novel target for breast cancer treatment strategies

| MATERIALS AND METHODS

Findings

| DISCUSSION