Cell-cell adhesion molecule cadherin-11(CDH11) is preferentially expressed in basal-like breast cancer cells and facilitates breast cancer cell migration by promoting small GTPase Rac activity. However, how the expression of CDH11 is regulated in breast cancer cells is not understood. Here, we show that CDH11 is transcriptionally controlled by homeobox C8 (HOXC8) in human breast cancer cells. HOXC8 serves as a CDH11-specific transcription factor and binds to the site of nucleotides −196 to −191 in the CDH11 promoter. Depletion of HOXC8 leads to the decrease in anchorage-independent cell growth, cell migration/invasion and spontaneous metastasis of breast cancer cells; however, suppressed tumorigenic events were fully rescued by ectopic CDH11 expression in HOXC8-knockdown cells. These results indicate that HOXC8 impacts breast tumorigenesis through CDH11. The analysis of publically available human breast tumor microarray gene expression database demonstrates a strong positive linear association between HOXC8 and CDH11 expression (ρ = 0.801, p < 0.001). Survival analysis (Kaplan-Meier method, log-rank test) shows that both high HOXC8 and CDH11 expression correlate with poor recurrence-free survival rate of patients. Together, our study suggests that HOXC8 promotes breast tumorigenesis by maintaining high level of CDH11 expression in breast cancer cells.

Programmed death ligand-1 (PD-L1) is expressed on the surface of tumor cells and binds to programmed cell death protein-1 (PD1) on the surface of T cells, leading to cancer immune evasion via inhibition of T cell function. One of the characteristics of small cell lung cancer (SCLC) is its ineffective anti-tumor immune response and highly immunosuppressive status in the tumor microenvironment. SCLC cells have been shown to generate extracellular vesicles (EVs), which may play an important role in tumor progression. We thus hypothesized that SCLC EVs may be important mediators of immunosuppression and that PD-L1 could play a role. Herein, we showed that PD-L1 was expressed on the surface of SCLC-derived EVs, with the potential to directly bind to PD1. Experimentally, we further showed that EVs secreted by SCLC cells can inhibit CD8 + T cell activation and cytokine production in vitro in response to T cell receptor stimulation. Importantly, an anti-PD-L1 blocking antibody significantly reversed the EVs-mediated inhibition of CD8 + T cell activation. Furthermore, we performed a retrospective study of patients with SCLC to determine the prognostic value of PD-L1 harvested from plasm circulating EVs. The results showed that EVs containing PD-L1 was an independent prognostic factor and significantly correlated with progression-free survival (PFS). Together, these results indicate that EVs containing PD-L1 can be served as a diagnostic biomarker for predicting the effectiveness of therapy, as well as a new strategy to enhance T cell-mediated immunotherapy against SCLC cancers.

Long-noncoding RNAs (lncRNAs) play roles in regulating cellular functions. High-throughput sequencing analysis identified a new lncRNA, termed LAMTOR5-AS1, the expression of which was much higher in the chemosensitive osteosarcoma (OS) cell line G-292 than in the chemoresistant cell line SJSA-1. Further investigations revealed that LAMTOR5-AS1 significantly inhibits the proliferation and multidrug resistance of OS cells. In vitro assays demonstrated that LAMTOR5-AS1 mediates the interaction between nuclear factor erythroid 2-related factor 2 (NFE2L2, NRF2) and kelch-like ECH-associated protein 1 (KEAP1), which regulate the oxidative stress. Further mechanistic studies revealed that LAMTOR5-AS1 inhibited the ubiquitination degradation pathway of NRF2, resulting in a higher level of NRF2 but a loss of NRF2 transcriptional activity. High level of NRF2 in return upregulated the downstream gene heme oxygenase 1 (HO-1). Moreover, NRF2 controls its own activity by promoting LAMTOR5-AS1 expression, whereas the feedback regulation is weakened in drug-resistant cells due to high antioxidant activity. Overall, we propose that LAMTOR5-AS1 globally regulates chemotherapy-induced cellular oxidative stress by controlling the expression and activity of NRF2.

The transmembrane glycoprotein embigin (EMB) belongs to the immunoglobulin superfamily (IgSF) and a number of IgSF members have been identified as biomarkers for cancer progression. In this study, we show that embigin is transcriptionally regulated by Homeobox C8 (HOXC8) in breast cancer cells and embigin expression suppresses breast tumorigenesis. With aid of Western blot, luciferase reporter gene assay and chromatin immunoprecipitation, we reveal that HOXC8 binds to the EMB promoter at the region of nucleotides −2303 to −2315 and acts as a transcription inhibitor to suppress embigin expression. Depletion of embigin leads to increase in proliferation, anchorage-independent growth and migration of breast cancer cells, and the inhibitory effects mediated by HOXC8 knockdown on breast tumorigenesis can be largely rescued by depletion of embigin expression in breast cancer cells, suggesting that HOXC8 regulates breast tumorigenesis, at least partly, through regulating embigin expression. Moreover, we show that loss of embigin promotes proliferation, anchorage-independent growth, and migration ability of normal mammary epithelial MCF10A cells. The analyses of publically available human breast tumor microarray gene expression database show that low embigin levels correlate with short survival of breast tumor patients, particularly with basal-like tumor patients, and embigin expression is low specifically in patients with basal-like, ER-/HER2- tumors. Taken together, our study demonstrates that low/loss of embigin plays an important role in the progression of breast tumors.

Resistance to first-line chemotherapy drugs has become an obstacle to improving the clinical prognosis of patients with small cell lung cancer (SCLC). Exosomal microRNAs have been shown to play pro- and anti-chemoresistant roles in various cancers, but their role in SCLC chemoresistance has never been explored. In this study, we observed that the expression of exosomal miR-92b-3p was significantly increased in patients who developed chemoresistance. Luciferase reporter analysis confirmed that PTEN was a target gene of miR-92b-3p. The PTEN/AKT regulatory network was related to miR-92b-3p-mediated cell migration and chemoresistance in vitro and in vivo in SCLC. Importantly, exosomes isolated from the conditioned medium of SBC-3 cells overexpressing miR-92b-3p could promote SCLC chemoresistance and cell migration. Furthermore, we found that plasma miR-92b-3p levels were significantly higher in patients with chemoresistant SCLC than in those with chemosensitive SCLC, but the levels were down-regulated in patients who achieved remission. Kaplan–Meier analysis showed that SCLC patients with high miR-92b-3p expression were associated with shorter progression-free survival. Overall, our results suggested that exosomal miR-92b-3p is a potential dynamic biomarker to monitor chemoresistance in SCLC and represents a promising therapeutic target for chemoresistant SCLC.