MPP7 as a Novel Biomarker of Esophageal Cancer: MPP7 Knockdown Inhibits Esophageal Cancer Cell Migration and Invasion.

MAGUK p55 scaffold protein 7 (MPP7) is a member of the stardust family of membrane-associated guanosine kinase protein P55 and plays a role in the establishment of epithelial cell polarity. However, its potential implication in human esophageal cancer is unclear. In this study, we investigated the expression profile of MPP7 and its functional impact on esophagus cancer. Expression analyses of immunohistochemical microarrays with survival and prognostic information of 103 patients with esophageal cancer demonstrated that MPP7 was overexpressed in 52 patients, who showed poor survival rates. The transcriptional expression of MPP7 in esophageal cancer in TCGA database increased successively from normal epithelial, to esophageal adenocarcinoma, to esophageal squamous cell carcinoma. Transcriptome sequencing after MPP7 knockdown in esophageal carcinoma cells showed that wound-healing-associated proteins were down-regulated, and the TGF-ß pathway was one of the important signaling pathways. A loss-of-function study showed that the knockdown of MPP7 inhibited cell migration and invasion. These results could be verified in a model of tumor cells injected into the tail vein and subcutaneous tumor of nude mice. Herein, our results indicated that MPP7 could have an oncogenic role in human esophagus cancer, thus demonstrating its potential as a novel biomarker for the diagnosis and/or treatment of esophagus cancer.

Dihydroartemisinin Reduces Irradiation-Induced Mitophagy and Radioresistance in Lung Cancer A549 Cells via CIRBP Inhibition.

Radiotherapy is a major therapeutic strategy for lung cancer, and radiation resistance (radioresistance) is an important cause of residual and recurring cancer after treatment. However, the mechanism of radioresistance remains unclear. Mitochondrial autophagy (mitophagy), an important selective autophagy, plays an important role in maintaining cell homeostasis and affects the response to therapy. Recent studies have shown that dihydroartemisinin (DHA), a derivative of artemisinin, can increase the sensitivity to treatment in multiple types of cancer, including lung cancer. The purpose of this study was to elucidate the function and molecular mechanisms of DHA-regulating mitophagy and DHA-reducing radioresistance in lung cancer A549 cells. We first constructed the radioresistant lung cancer A549 cells model (A549R) through fractional radiation, then elucidated the function and mechanism of DHA-regulating mitophagy to reduce the radioresistance of lung cancer by genomic, proteomic, and bioinformatic methods. The results showed that fractional radiation can significantly induce radioresistance and mitophagy in A549 cells, DHA can reduce mitophagy and radioresistance, and the inhibition of mitophagy can reduce radioresistance. Protein chip assay and bioinformatics analysis showed the following: Cold-Inducible RNA Binding Protein (CIRBP) might be a potential target of DHA-regulating mitophagy; CIRBP is highly expressed in A549R cells; the knockdown of CIRBP increases the effect of DHA, reduces mitophagy and radioresistance, and inhibits the mitophagy-related PINK1/Parkin pathway. In conclusion, we believe that DHA reduces radiation-induced mitophagy and radioresistance of lung cancer A549 cells via CIRBP inhibition.

2-Methoxyestradiol inhibits the proliferation and migration and reduces the radioresistance of nasopharyngeal carcinoma CNE-2 stem cells via NF-κB/HIF-1 signaling pathway inactivation and EMT reversal.

Accumulating evidence indicates that cancer stem cells (CSCs) are a source of resistance to radiation therapy (RT); however, the mechanism of this resistance remains unclear. 2-Methoxyestradiol (2-ME2) is a metabolic product of estrogen in the body. Recent studies have found that 2-ME2 regulates the activation of transcription factors, including nuclear factor (NF)-κB/hypoxia-inducible factor-1 (HIF-1), thus contributing to tumor cell apoptosis and chemosensitivity. Therefore, 2-ME2 is being studied as a potential anticancer drug. The purpose of this study was to determine the effect and mechanism by which 2-ME2 inhibits nasopharyngeal carcinoma CNE-2 stem-like cell (NPCSC) proliferation and migration and reduces NPCSC radioresistance. This study has important significance for reducing the radioresistance of these cells to improve the cure rate of NPC. First, the NPCSCs were collected in a serum-free culture system and then identified by relevant experiments. The NPCSCs were treated with 2-ME2 (0-8 µM) combined with X-ray exposure and Cell Counting Kit-8 (CCK-8), Transwell assay, colony formation assay, western blot analysis, RT-PCR, flow cytometry and RNA interference technology were used to explore the effect and mechanism of 2-ME2 on NPCSCs. The results showed that the microspheres collected in the serum­free culture system possessed CSC traits and radioresistance. 2-ME2 obviously inhibited NPCSC growth and migration and reduced NPCSC radioresistance. 2-ME2 decreased NF-κB p65 and HIF-1α protein expression, downregulated NF-κB p65 nuclear localization, and reversed epithelial-mesenchymal transition (EMT). NF-κB p65 knockdown reduced HIF-1α expression, reversed EMT, and enhanced the suppressive effect of 2-ME2 on NPCSCs. Collectively, these data indicate that 2-ME2 inhibits NPCSC proliferation and migration and reduces the radioresistance of NPCSCs via NF-κB/HIF-1 signaling pathway inactivation and EMT reversal.

(-)-Epigallocatechin-3-gallate inhibits nasopharyngeal cancer stem cell self-renewal and migration and reverses the epithelial-mesenchymal transition via NF-κB p65 inactivation.

The cancer stem cell (CSC) theory states that many types of cancer, including nasopharyngeal cancer (NPC), are initiated from and maintained by CSCs, which may be responsible for tumor relapse and resistance to therapy. It is imperative that nasopharyngeal cancer stem cells (NPCSCs) be specifically targeted to eradicate NPC and prevent recurrence. Epigallocatechin-3-gallate (EGCG) inhibits cancer progression by attenuating NF-κB p65 activity, which is upregulated in CSCs and plays an important role in epithelial-mesenchymal transition (EMT). The purpose of this study is to confirm the self-renewal and migration inhibitory effects of EGCG toward NPCSCs and to clarify its mechanism of activity. We enriched and characterized NPCSCs by collecting spheroid-derived cells grown in serum-free medium (SFM) and examined the effects of EGCG on the characteristics of NPCSCs and studied the underlying mechanisms using soft agar colony assays, transwell migration assays, reverse transcriptase polymerase chain reaction (RT-PCR), Western blot analysis, immunofluorescence staining, and xenograft studies. NPC spheroids enriched from NPC cell lines acquired CSC traits and underwent EMT. EGCG inhibited the NPCSCs' self-renewal and migration and reversed EMT, and combined treatment with EGCG and cisplatin reduced the growth of CSC tumor xenografts. Moreover, EGCG inhibited NF-κB p65 activity by modulating the cellular localization of p65 and decreasing the transcriptional regulation of NF-κB p65 on Twist1 expression. NF-κB p65 is a novel therapeutic target in NPCSCs, and the inhibition of activated NF-κB p65 in CSCs by EGCG may offer an effective treatment for NPC.