Long non-coding RNA ZEB2-AS1 promotes the proliferation, metastasis and epithelial mesenchymal transition in triple-negative breast cancer by epigenetically activating ZEB2.

Guoxin Zhang,Peirui Li,Zhaoyan Wang,Yuling Yang,Ruimei Sun,Hongli Li,Zhiyi Yang,Chonggao Yin,Yuanyuan Liu

doi:10.1111/jcmm.14213

Guoxin Zhang, Peirui Li + Show 7 more

Open Access

https://doi.org/10.1111/jcmm.14213

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Abstract

The triple‐negative breast cancer is the most malignant type of breast cancer. Its pathogenesis and prognosis remain poor despite the significant advances in breast cancer diagnosis and therapy. Meanwhile, long noncoding RNAs (LncRNAs) play a pivotal role in the progression of malignant tumors. In this study, we found that LncRNA‐ZEB2‐AS1 was dramatically up‐regulated in our breast cancer specimens and cells (MDA231), especially in metastatic tumor specimens and highly invasive cells, and high lncRNA‐ZEB2‐AS1 expression is associated with clinicopathologic features and short survival of breast cancer patients. LncRNA‐ZEB2‐AS1 promotes the proliferation and metastasis of MDA231 cells in SCID mice. Thus, it is regarded as an oncogene in triple‐negative breast cancer. It is mainly endo‐nuclear and situated near ZEB2, positively regulating ZEB2 expression and activating the epithelial mesenchymal transition via the PI3K/Akt/GSK3β/Zeb2 signaling pathway. Meanwhile, EGF‐induced F‐actin polymerization in MDA231 cells can be suppressed by reducing lncRNA‐ZEB2‐AS1 expression. The migration and invasion of triple‐negative breast cancer can be altered through cytoskeleton rearrangement. In summary, we demonstrated that lncRNA‐ZEB2‐AS1 is an important factor affecting the development of triple‐negative breast cancer and thus a potential oncogene target.

Highlights

Breast cancer is a malignancy with high death rate; that is, individu‐ als with this disease, especially women, have a five‐year overall sur‐ vival rate of less than 15%.1 Having high metastasis and recurrence rates, breast cancer is difficult to treat through prophase clinical diagnosis
Major breakthroughs in clinical treatment meth‐ ods have been achieved for breast cancer, approximately 100 in 100 000 women aged 55‐69 years are expected to contract the disease by 2021.2 Inhibiting the invasion and metastasis of malignant tumors
The assay results of transwell and wound healing showed that the mi‐ gration and invasion of MDA231 cells can be inhibited by reducing lncRNA‐ZEB2‐AS1 (Figure 2D,E). These results suggested that the decrease of lncRNA‐ZEB2‐AS1 expression led to the sup‐ pression of the proliferation and invasion of MDA231 cells

Summary

| INTRODUCTION

Breast cancer is a malignancy with high death rate; that is, individu‐ als with this disease, especially women, have a five‐year overall sur‐ vival rate of less than 15%.1 Having high metastasis and recurrence rates, breast cancer is difficult to treat through prophase clinical diagnosis. Major breakthroughs in clinical treatment meth‐ ods have been achieved for breast cancer, approximately 100 in 100 000 women aged 55‐69 years are expected to contract the disease by 2021.2 Inhibiting the invasion and metastasis of malignant tumors. EMT triggers a variety of bio‐ logical changes in normal mammary epithelial cells, which eventu‐ ally obtains the characteristics of mesenchymal cells. This effect enhances the metastasis capacity, invasiveness and resistance of cancer cells, thereby preventing apoptosis and promoting the pro‐ duction of extracellular matrix components.[4]. Despite the significant role lncRNA in malignant tumor development, its regulatory functions and molecular mechanisms remain poorly understood. In the MDA231 cells, LncRNA‐ZEB2‐AS1 pro‐ moted the proliferation and metastasis of tumor cells and triggered EMT via the PI3K/Akt/GSK3β/Zeb[2] signaling pathway and F‐actin polymerization

| MATERIAL AND METHODS

Findings

| DISCUSSION