BRMS1L confers anticancer activity in non-small cell lung cancer by transcriptionally inducing a redox imbalance in the GPX2-ROS pathway.

Low expression levels of breast cancer metastasis suppressor 1 like (BRMS1L) have been associated with the growth of cancer cells. However, the mechanisms underlying the role of BRMS1L as an antitumour transcription factor in the progression of NSCLC have not been explored. Herein, we reveal that BRMS1L plays a key role as a tumour suppressor in inhibiting NSCLC proliferation and metastasis. Mechanistically, BRMS1L overexpression results in the downregulation of glutathione peroxidase 2 (GPX2) expression and consequently causes abnormal glutathione metabolism and increased levels of reactive oxygen species (ROS) in cells, inducing oxidative stress injury and apoptosis. Furthermore, overexpression of GPX2 enhances the growth advantage and oxidative stress repair conferred by knockdown of BRMS1L. Importantly, we show that low expression of BRMS1L in NSCLC cells causes relatively high levels of antioxidant accumulation to maintain cell redox balance and renders cancer cells more sensitive to treatment with piperlongumine as an ROS inducer both in vitro and in vivo. These findings offer new insights into the role of BRMS1L as a transcriptional repressor in NSCLC and suggest that the BRMS1L expression level may be a potential biomarker for predicting the therapeutic response to small molecule ROS inducers, providing new ideas for targeted therapy.

Alpha-2 Heremans Schmid Glycoprotein (AHSG) promotes the proliferation of bladder cancer cells by regulating the TGF-ß signalling pathway.

Bladder cancer (BC) is one of the most common urinary tract malignancies and is the tenth most common cancer globally. Alpha-2 Heremans Schmid Glycoprotein (AHSG) is a multifunctional protein that plays different roles in the progression of multiple tumors. However, the role and mechanism of AHSG in the development and progression of BC are unknown. AHSG expression was assessed in BC cells and tissues using western blot and immunohistochemistry. Using plasmid and siRNA, overexpressed and knocked down AHSG in BC cells were constructed. A series of functional experiments, including CCK8, plate clone formation, and flow cytometry, were performed to evaluate cell proliferation and cycle. AHSG was expressed higher in BC cells and tissues than in normal bladder epithelial cells and non-tumor tissues. Functionally, the overexpression of AHSG significantly increased the proliferation of BC cells and promoted the cell cycle from G1 to the S phase, whereas the knockdown of AHSG gave the opposite result.Additionally, western blot results revealed that AHSG expression level was negatively correlated with the phosphorylation level of Smad2/3 protein, a key downstream molecule of the traditional TGF-ß signaling pathway, suggesting that AHSG could antagonize the traditional TGF-ß signaling pathway. Finally, the expression level of AHSG in the urine of BC patients was significantly higher than that of healthy subjects by ELISA, with specificity. Our study concluded that AHSG might be a novel marker of BC that promotes the proliferation of BC cells by regulating the TGF-ß signaling pathway.

GPX2 suppression of H2O2 stress regulates cervical cancer metastasis and apoptosis via activation of the ß-catenin-WNT pathway.

BACKGROUND: Increasing evidence suggests that glutathione peroxidase 2 (GPX2) plays important roles in the tumorigenesis and progression of various human cancers, such as colorectal carcinomas and lung adenocarcinomas. However, the role of GPX2 in cervical cancer is unclear. In this study, we identified the role of GPX2 in cervical cancer tissues and cell lines. MATERIALS AND METHODS: The basal mRNA and protein expression of GPX2 in cervical cancer cells and a series of key molecules in the epithelial to mesenchymal transition (EMT) and WNT/ß-catenin pathways were examined via real time fluorescence quantitative PCR (qRT-PCR) and Western blot assays. The biological phenotype of the cervical cancer cell lines was detected by the cloning formation and transwell assays, and intracellular reactive oxygen species (ROS) levels were detected by flow cytometry. Finally, the GPX2 expression level in 100 clinical cervical tissues was examined by immunohistochemistry. RESULTS: We found that GPX2 was highly expressed in cervical cancer tissues compared to normal individuals and promoted the proliferation and metastasis of cervical cancer cells, and this promotion correlated with the activation of EMT and WNT/ß-catenin signaling in vitro. GPX2 was determined to reduce apoptotic damage by reducing hydroperoxides. According to the characteristics and verification of GPX2, this series of phenotypes is clearly related to oxidative stress in cells. Furthermore, we verified that GPX2 was highly expressed in cervical cancer tissues and promoted the metastasis of cervical cancer. CONCLUSION: In summary, we found that GPX2 was highly expressed in cervical cancer cells and promoted the proliferation and metastasis of cervical cancer by affecting oxidative stress. Our study provides a new target for the clinical treatment of cervical cancer.

PI3K p110α inhibition sensitizes cervical cancer cells with aberrant PI3K signaling activation to PARP inhibitor BMN673.

Poly(ADP­ribose) polymerase (PARP) inhibitors have little effect on homologous recombination repair (HRR)­proficient tumor types, such as cervical cancer. In addition to catalytic activity, the PARP inhibitor, BMN673, traps PARP1 on damaged DNA and induces cytotoxic effects. The aim of the present study was to evaluate the therapeutic effect of PI3K inhibitors and BMN673 on cervical cancer cells. The Chou­Talalay method was used to assess the synergistic effect of drug combinations on cervical cancer cells. The effect of PI3K inhibitors and BMN673 on cell growth and survival were also assessed via a Cell Counting Kit­8 assay and three­dimensional sphere culture. Cell migration and invasion were assessed via Transwell migration and Matrigel invasion assays, respectively. In addition, DNA damage and HRR competency were assessed via immunofluorescent staining analysis of γH2AX and RAD51 foci, and tail moment in a comet assay. PARP1 binding in chromatin was assessed via a cellular trapping assay. Ex vivo cultured sections of patient­derived cervical tumors were subjected to drug exposure followed by histological and immunohistochemical analyses. The results revealed that the PI3K p110α inhibitor BYL719 and the PARP inhibitor BMN673 synergized to inhibit cervical cancer cell proliferation, migration and invasion in vitro and ex vivo. However, the pan­PI3K inhibitor BKM120 did not produce the aforementioned effects. Additionally, cervical cancer cells exhibiting aberrant PI3K activation were more responsive to the combined inhibition of PI3K p110α and PARP. Mechanistically, BYL719 co­operated with BMN673 to increase PARP1 trapping on chromatin, induce severe DNA damage and exert cytotoxic effects. The combined use of BMN673 and BYL719 may serve as a promising therapeutic strategy for patients with cervical cancer exhibiting aberrant PI3K activation.

BRMS1L suppresses ovarian cancer metastasis via inhibition of the ß-catenin-wnt pathway.

A low level of breast cancer metastasis suppressor 1-like (BRMS1L) has been implicated in tumour metastasis involving breast cancer and other cancers. It remains unclear whether BRMS1L is involved in epithelial ovarian cancer (EOC) metastasis and what the molecular mechanism of BRMS1L is in suppressing EOC metastasis. In this study, we examined the mRNA expression and protein level of BRMS1L by screening EOC patients. Our results show that BRMS1L expression is downregulated in EOC patients compared to that in normal people and negatively correlated to pathological stages of EOC. We further explored examining epithelial to mesenchymal transition (EMT) as the molecular mechanism of BRMS1L in cancer cell metastasis. The overexpression of BRMS1L inhibits EOC cell migration and invasion, and this inhibition is correlated to the inactivation of EMT and Wnt/ß-catenin signalling in vitro. Knockdown of BRMS1L by shRNA promotes EOC metastasis, enhances EMT process and activates Wnt/ß-catenin signalling. These results suggest that BRMS1L plays a critical role in the suppression of ovarian cancer metastasis, and BRMS1L can be considered as a prognostic biomarker and potential therapeutic target for EOC patients.