Triple-negative breast cancer (TNBC) is currently the most malignant subtype of breast cancer without effective targeted therapies, which makes its pathoge

Despite the overwhelming number of human long non-coding RNAs (lncRNAs) reported so far, little is known about their physiological functions for the majority of them. The present study uses a CRISPR/Cas9-based synergistic activation mediator (SAM) system to identify potential lncRNAs capable of regulating AKT activity. Among lncRNAs identified from this screen, we demonstrate that AK023948 is a positive regulator for AKT. Knockout of AK023948 suppresses, whereas rescue with AK023948 restores the AKT activity. Mechanistically, AK023948 functionally interacts with DHX9 and p85. Importantly, AK023948 is required for the interaction between DHX9 and p85 to hence the p85 stability and promote AKT activity. Finally, AK023948 is upregulated in breast cancer; interrogation of TCGA data set indicates that upregulation of DHX9 in breast cancer is associated with poor survival. Together, this study demonstrates two previously uncharacterized factors AK023948 and DHX9 as important players in the AKT pathway, and that their upregulation may contribute to breast tumour progression.

Acidic microenvironment is a common feature of solid tumors. We have previously shown that neuron specific acid-sensing ion channel 1 (ASIC1) is expressed in breast cancer, and it is responsible for acidosis-induced cellular signaling through AKT, leading to nuclear factor-κB (NF-κB) activation, and cell invasion and metastasis. However, AKT is frequently activated in cancer. Thus, a key question is whether ASIC1-mediated cell signaling still takes place in the cancer cells carrying constitutively active AKT. In the present study, we show that among four prostate cancer cell lines tested, 22Rv1 cells express the highest level of phosphorylated AKT that is not impacted by acidosis. However, acidosis can still induce NF-κB activation during which extracellular signal-regulated kinase (ERK) serves as an alternative pathway for ASIC-mediated cell signaling. Inhibition of ERK by chemical inhibitors or small interfering RNAs suppresses the acidosis-induced NF-κB activity through regulation of the inhibitory subunit IκBα phosphorylation. Furthermore, suppression of ASIC1-mediated generation of reactive oxygen species (ROS) by ROS scavengers, such as glutathione or N-acetyl-cysteine causes a decrease in ERK phosphorylation and degradation of IκBα. Finally, ASIC1 is upregulated in a subset of prostate cancer cases and ASIC1 knockout by CRISPR/Cas9 significantly suppresses cell invasion, and castration resistance both in vitro and in vivo. Together, these results support the significance of ASIC1-ROS-ERK-IκBα-NF-κB axis in prostate tumorigenesis, especially in the constitutively active AKT background.

In this study, we found that let-7c-5p expression was clearly downregulated in breast cancer tissues compared with that of corresponding adjacent tissues. Furthermore, overexpression of let-7c-5p in MCF-7 breast cancer cells could significantly inhibit cell proliferation and induce cell apoptosis. The target genes of let-7c-5p were predicted by the way of bioinformatics, and validated by dual luciferase reporter assay and western blotting demonstrating that excision repair cross complementing 6 (ERCC6) gene was a direct target. Collectively, the present study suggested that let-7c-5p acted as a tumor suppressor in breast cancer possibly by negatively regulating ERCC6, which took an important part in nucleotide excision repair and it may provide a new potential strategy for breast cancer therapy.

Non‑coding RNAs serve important roles in regulating the expression of certain genes and are involved in the principal biological processes of breast cancer. The majority of studies have focused on defining the regulatory functions of long non‑coding RNAs (lncRNAs) and microRNAs (miRNAs/miRs), and few studies have investigated how lncRNAs and miRNAs are transcriptionally regulated. In the present study, based on the breast invasive carcinoma dataset from The Cancer Genome Atlas at cBioPortal, and using a bioinformatics computational approach, an lncRNA‑miRNA‑mRNA network was constructed. The network consisted of 601 nodes and 706 edges, which represented the complex web of regulatory effects between lncRNAs, miRNAs and target genes. The results of the present study demonstrated that miR‑510 was the most potent miRNA controller and regulator of numerous target genes. In addition, it was observed that the lncRNAs PVT1, CCAT1 and linc00861 exhibited possible interactions with clinical biomarkers, including receptor tyrosine‑protein kinase erbB‑2, estrogen receptor and progesterone receptor, demonstrated using RNA‑protein interaction prediction software. The network of lncRNA‑miRNA‑mRNA interactions will facilitate further experimental studies and may be used to refine biomarker predictions for developing novel therapeutic approaches in breast cancer.

The human genome transcribes a large amount of non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs. LncRNAs and microRNAs have been shown to play a critical regulatory role in tumorigenesis and progression. Competitive endogenous RNAs (ceRNAs) affect other RNAs transcription through competitively binding to common microRNAs (miRNAs). MALAT1 is a typical lncRNA that is markedly up-regulated in breast cancer. However, current understanding of the involvement of MALAT1 in breast cancer development and prognosis remains unclear. In the present study, the expression of MALAT1 in clinical samples of breast cancer tissues was found to be significantly up-regulated that was consistent with the result based on the dataset of the Cancer Genome Atlas (TCGA) at cBioportal. A negative correlation between overall survival and the expression of MALAT1 was statistically significant in the group of diagnosis age below 60 or in the group of infiltrating ductal carcinoma analyzed by TCGA database, which declared that MALAT1 might be a potentially useful prognostic factor. Furthermore, the combination of bioinformatics prediction with experimental verifications indicated that lncRNA MALAT1 can regulate BLCAP mRNA expression through binding to miR-339-5p.