Novel Breast-Specific Long Non-coding RNA LINC00993 Acts as a Tumor Suppressor in Triple-Negative Breast Cancer

Abstract

Background: Triple-negative breast cancer (TNBC) was characterized by breast cancers that do not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor (HER)-2 genes. TNBC patients are associated with a shorter median time to relapse and death for the lack of available treatment targets. Long non-coding RNAs (LncRNAs) have been reported to play an important role in the development of TNBC. We identified a novel breast-specific long non-coding RNA LINC00993, but less was known about its expression pattern and functional role in TNBC. Methods: LINC00993 RNA expression was detected across different types of clinical breast cancer samples by using qRT-PCR. Bioinformatic methods "guilt by association" and gene set enrichment analysis (GSEA) were used to predict LINC00993 functions. Subcellular localization of LINC00993 in cells was detected by RNA fluorescence in situ hybridization (FISH). Effect of LINC00993 on cell growth was measured by plate colony formation assays, typical growth curve, and an in vivo tumor model. Cell cycle analysis was done by flow cytometry analysis. Key cell cycle regulators were detected by Western blot. Results: LINC00993 was largely downregulated in TNBC, and higher expression indicated better outcome. LINC00993 located mainly in the nucleus. LINC00993 suppressed TNBC growth both in vitro and in vivo. LINC00993 was predicted to be involved in cell cycle pathways by using "guilt by association" and GSEA methods. Key cell cycle regulators like p16 INK4A , p14 ARF , p53, and p21 were affected by LINC00993 overexpression. Conclusions: A new breast-specific lincRNA LINC00993 was identified with a tumorsuppressive feature and with prognostic value. This is the first research on LINC00993 function. Our results suggest that controlling LINC00993 level may be beneficial for breast cancer treatment.

Bioinformatic Identification of a Breast‐Specific Transcript Profile

“…Moreover, our previous findings suggested that ANKRD30A and LINC00993 were breast-enriched and LINC00993 may be important for breast cancer because it was significantly downregulated in TNBC [24] and acts as a tumor suppressor by inhibiting tumor proliferation and inducing cell apoptosis. [25] Therefore, the breast-specific protein-coding gene ANKRD30A and the LncRNA LINC00993 were selected for further research (Figure 3).…”

An 8-lncRNA signature predicts the survival of triple-negative breast cancer patients without germline BRCA1/2 mutation

“…CCAT2 promotes oncogenesis in triple-negative breast cancer by regulating stemness of cancer cells 16 . LINC00993 suppressed TNBC growth and its higher expression indicated better outcome 17 . lncRNA FAM83H-AS1 promotes triplenegative breast cancer progression by regulating the miR-136-5p/metadherin axis 18 .…”

Downregulation of long non‑coding RNA MR4435‑2HG suppresses breast cancer progression via the Wnt/β‑catenin signaling pathway

“…For example, LINC01121 mediates the expression of HMGA2 to promote breast cancer cell proliferation, migration and invasion by sponging microRNA (miR/miRNA)-150-5p (10). In addition, the nuclear LINC00993, which is downregulated in breast cancer tissue, inhibits triple-negative breast cancer growth both in vitro and in vivo by orchestrating the expression of cell cycle regulators (11). The lncRNA GAEA interacts with MEX3C to enhance the K27-linked polyubiquitination of PTEN, consequently activating the epithelial-to-mesenchymal transition (EMT) process (12).…”