Hypoxia-Induced MALAT1 Promotes the Proliferation and Migration of Breast Cancer Cells by Sponging MiR-3064-5p

Abstract

Hypoxia, a common process during tumor growth, can lead to tumor aggressiveness and is tightly associated with poor prognosis. Long noncoding RNAs (lncRNAs) are long ribonucleotides (>200 bases) with limited ability to translate proteins, and are known to affect many aspects of cellular function. One of their regulatory mechanisms is to function as a sponge for microRNA (miRNA) to modulate its biological functions. Previously, MALAT1 was identified as a hypoxia-induced lncRNA. However, the regulatory mechanism and functions of MALAT1 in breast cancer are still unclear. Therefore, we explored whether MALAT1 can regulate the functions of breast cancer cells through miRNAs. Our results showed the expression levels of MALAT1 were significantly up-regulated under hypoxia and regulated by HIF-1α and HIF-2α. Next, in contrast to previous reports, nuclear and cytoplasmic fractionation assays and fluorescence in situ hybridization indicated that MALAT1 was mainly located in the cytoplasm. Therefore, the labeling of MALAT1 as a nuclear marker should be done with the caveat. Furthermore, expression levels of miRNAs and RNA immunoprecipitation using antibody against AGO2 showed that MALAT1 functioned as a sponge of miRNA miR-3064-5p. Lastly, functional assays revealed that MALAT1 could promote cellular migration and proliferation of breast cancer cells. Our findings provide evidence that hypoxia-responsive long non-coding MALAT1 could be transcriptionally activated by HIF-1α and HIF-2α, act as a miRNA sponge of miR-3064-5p, and promote tumor growth and migration in breast cancer cells. These data suggest that MALAT1 may be a candidate for therapeutic targeting of breast cancer progression.

HIF-1α Is a Rational Target for Future Ovarian Cancer Therapies

“…Long noncoding RNAs play variable roles in malignant tumours. HIF-1a can regulate the expression of these noncoding RNAs, and noncoding RNAs can interact with mRNA-HIF-1a to regulate the expression of HIF-1a protein and then induce the progression of many types of tumours, including breast cancer (54) and ovarian cancer (55,56).…”

HOTAIR Modulated Pathways in Early-Stage Breast Cancer Progression

“…This lncRNA was initially identified as upregulated in primary non-small cell lung cancer cells with higher metastasis ability and subsequently associated with other tumor types ( 24 , 31 ). Recently, MALAT1 was identified as a hypoxia-induced transcript that could promote cellular migration and proliferation of breast cancer cells ( 32 ). Interestingly, the HIF-1 alpha transcription factor network was among the most significantly enriched pathways in MCF10A HOTAIR transduced cells suggesting a cooperative role between both oncogenic lncRNAs.…”

LMX1B Activated Circular RNA GFRA1 Modulates the Tumorigenic Properties and Immune Escape of Prostate Cancer

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