Breast cancer is an urgent global priority. This disease is the most common cancer in women, accounting for 30% of newly reported cases, and is one of the leading causes of cancer deaths 1. BC is generated via one-of-a-kind elements like age, menarche history, reproductive patterns, bodily activity, breast traits, and physique habitus. Although tremendous advances have been made in the early detection and therapeutics of breast cancer over the last 20 years, the disease remains a significant public health problem 2. In this context, novel therapeutic techniques for BC are in pressing need. We undertook a long non-coding RNA (LncRNA)-based method to apprehend the underlying mechanism in BC development to enhance novel intervention strategies.
LncRNA genes are a significant proportion of non-coding RNAs that play a vital role in normal growth and also in the tumorigenesis process 3. It is estimated that the human genome contains 23,000 LncRNA genes, which is more than 20,000 protein-coding genes 4. Their physiological and pathological functions are mediated by their interactions with microRNAs, mRNAs, proteins, and genomic DNA5. Since the deregulation of gene expression is an important event in carcinogenesis, it has been suggested that a significant proportion of cancer risk may be attributed to transcribed LncRNAs from cancer-related loci 6.
Dysregulation and deficiency, or mutations of LncRNAs, have been reported in complex diseases 7–9, including BC cancer 10. Depending on their functions and pattern of expression, they can be divided into tumor suppressors and oncogene classes 11. In addition, growing exploratory evidence supports the idea that LncRNAs function as competitive endogenous RNAs (ceRNAs), which compete for microRNA (miRNA) binding to their upregulated target genes 12. The ceRNA theory can critically help to understand and identify the function of LncRNA 13. In the case of BC, the LncRNA expression profile is often dysregulated, and numerous LncRNAs have been concerned in BC tumorigenesis, such as LINC01133, ZEB1-AS1, and ABHD11-AS1 14. Due to the improvement of LncRNA-based therapeutic approaches, defining the function of exclusive LncRNAs in a tumorigenic manner is of first-rate importance. Hence, in this study, we intend to elucidate the oncogenic role of LncRNA MALAT1 in BC, which acts as a miR-561 sponge.
Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is a nuclear-enriched long non-coding RNA generally overexpressed in patient tumors and metastases. Overexpression of MALAT1 is positively correlated with tumor progression and metastasis in many tumor types, including breast tumors. MALAT1 was initially identified as an LncRNA whose expression was increased in early human non-small cell lung tumors that were more prone to metastasis. Subsequently, MALAT1 is highly expressed in numerous other human cancers, including, but not limited to, breast, lung, breast, ovarian, prostate, cervical, endometrial, colorectal, gastric, pancreatic, sarcoma, colorectal, bladder, brain, hepatocellular carcinoma, esophageal squamous cell carcinoma, multiple myeloma, renal cell carcinoma, and lymphoma 15,16. As a ceRNA, MALAT1 can interact with miRNAs (miR-205, miR-1297, miR-217, and miR-155), ultimately driving changes in cellular phenotypes such as invasion, metastasis, proliferation, migration, and apoptosis 17. In addition, MALAT1 may affect cancer carcinogenesis by activating the Wnt/-catenin, ERK/MAPK, and PI3K/AKT pathways, while concomitant activation of oncogenic pathways may cause strong carcinogenic effects 18.
Topoisomerase alpha 2 (TOP2A), a gene located in 17 q12–21 and consisting of two subunits, is a marker of proliferation and chemotherapy resistance in various cancer types, including adrenocortical carcinoma and breast carcinoma. In addition, several miRNAs have been reported to play a regulatory role by directly inhibiting the target TOP2A in cancer 19,20.
In this study, MALAT1 overexpression was detected in BC tissues and cells. Loss-of-function experiments suggest that the silence of MALAT1 inhibits BC proliferation and invasion. In addition, the primary mechanism of interaction between MALAT1 and miR-561 has been identified. We found that MALAT1 can cause miR-561 to "sponge" information and impair TOP2A mRNA degradation (as a target of miR-561) by preventing its association with TOP2A mRNA targeting.