Abstract

BackgroundTriple-negative breast cancer (TNBC) is a significant cause of patient morbidity. The exactly pathobiological features of this condition has yet to be completely elucidated.MethodsBreast cancer data obtained from The Cancer Genome Atlas (TCGA) database were evaluated for lncRNA SNHG6 expression. Normal human breast epithelial cell line (MCF-10A) and other breast cancer cell lines (BT-549, MDA-MB-231, Hs 578t, ZR-75-30, SK-BR-3, MCF-7) were also assessed for lncRNA SNHG6 expressions. Cellular proliferative ability was evaluated with colony formation and CCK-8 assays. The ability of cells to migrate was scrutinized with the wound healing and Boyden chamber cell migration assays. qRT-PCR enabled for detection of lncRNA SNHG6, miR-125b-5p and BMPR1B mRNA expressions. Protein BMPR1B expressions were further assessed using Western Blotting. Direct binding sites between transcripts were determined using dual-luciferase reporter assays. We also constructed a xenograft mouse model to further dissect the vivo implications of lncRNA SNHG6. Ki-67 and c-Caspase-3 expressions were detected using immunohistochemistry staining.ResultsBreast cancer cell lines demonstrated higher lncRNA SNHG6 expressions, particularly TNBC cell lines, in contrast to normal breast epithelial cell lines. This finding coincided with those noted on analysis of TCGA breast cancer data. lncRNA SNHG6 knockdown inhibited TNBC cell proliferation, migration, while promoted cell apoptosis. Furthermore, suppressed lncRNA SNHG6 expressions resulted in lower tumor weights and volumes in a xenograft mouse model, as evidenced by Ki-67 and c-Caspase-3 expression profiles in tumor tissues. miR-125b-5p and lncRNA SNHG6/BMPR1B both possessed direct binding sites for each other which was validated utilizing a dual-luciferase reporter assay. Decreasing lncRNA SNHG6 expression in TNBC cells upregulated miR-125b-5p expression. Another side, inhibiting miR-125b-5p upregulated BMPR1B expression in these cells. Moreover, knocking down lncRNA SNHG6 downregulated BMPR1B expression in TNBC cells, and the finding was rescued in cells which were exposed to miR-125b-5p inhibitor. Downregulating miR-125b-5p mitigated the effect of suppressing lncRNA SNHG6 on TNBC cell proliferation, migration, and apoptosis.ConclusionDownregulation of lncRNA SNHG6 could inhibit TNBC cell proliferative, migratory capabilities and promote apoptosis capability, likely through modulation of the miR-125b-5p/BMPR1B axis. This axis may be targeted in formulating new therapies for TNBC.

Highlights

  • The second most frequently encountered reason of cancerassociated death in women around the world is due to breast cancer [1]

  • We initially evaluated Long non-coding RNAs (lncRNAs) small nucleolar RNA host gene 6 (SNHG6) transcription levels in breast cancer studies based on data from TCGA with the Gene Expression Profiling Interactive Analysis 2 (GEPIA 2) online tool

  • All breast cancer cell lines were significant for high lncRNA SNHG6 expressions in comparison to normal mammary epithelial cell line. lncRNA SNHG6 expression was found to be elevated in Triple negative breast cancer (TNBC) cell lines (BT-549, MDA-MB231, Hs 578t) in contrast to non-TNBC cell lines (ZR-75-30, SKBR-3, MCF-7) (Figure 1C)

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Summary

Introduction

The second most frequently encountered reason of cancerassociated death in women around the world is due to breast cancer [1]. The exact effects of dysregulated lncRNA expressions have yet to be fully determined. Both breast cancer cell lines and samples, especially those of TNBC, have been found to harbor high expressions of lncRNA H19, which has been implicated to increased rates of metastasis and tumorigenesis [10]. The LncRNA HOX transcript antisense RNA (HOTAIR) is upregulated in breast cancer cell lines and samples, which has been associated to the progression of breast cancer due to its action on the miR-20a-5p/HMGA2 axis [12]. One lncRNA of interest is the oncogenic small nucleolar RNA host gene 6 (SNHG6), which is aberrantly expressed in cancers such as glioma, hepatocellular carcinoma as well as in lung and colorectal cancers [13,14,15,16]. The exactly pathobiological features of this condition has yet to be completely elucidated

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