Glioma is the most common type of primary brain tumors. After standard treatment regimen (surgical section, radiotherapy and chemotherapy), the average survival time remains merely around 14 months for glioblastoma (grade IV glioma). Recent immune therapy targeting to the immune inhibitory checkpoint axis, i.e., programmed cell death protein 1 (PD-1) and its ligand PD-L1 (i.e., CD274 or B7-H1), has achieved breakthrough in many cancers but still not in glioma. PD-L1 is considered a major prognostic biomarker for immune therapy in many cancers, with anti-PD-1 or anti-PD-L1 antibodies being used. However, the expression and subcellular distribution of PD-L1 in glioma cells exhibits great variance in different studies, severely impairing PD-L1's value as therapeutic and prognostic biomarker in glioma. The role of PD-L1 in modulating immune therapy is complicated. In addition, endogenous PD-L1 plays tumorigenic roles in glioma development. In this review, we summarize PD-L1 mRNA expression and protein levels detected by using different methods and antibodies in human glioma tissues in all literatures, and we evaluate the prognostic value of PD-L1 in glioma. We also summarize the relationships between PD-L1 and immune cell infiltration in glioma. The mechanisms regulating PD-L1 expression and the oncogenic roles of endogenous PD-L1 are discussed. Further, the therapeutic results of using anti-PD-1/PD-L1 antibodies or PD-L1 knockdown are summarized and evaluated. In summary, current results support that PD-L1 is not only a prognostic biomarker of immune therapy, but also a potential therapeutic target for glioma.

Hepatocellular carcinoma (HCC) is the fifth most common and the third most deadly malignant tumor worldwide. Hypoxia and related oxidative stress are heavily involved in the process of HCC development and therapies. However, direct and accurate measuring oxygen concentration and evaluating hypoxic effects in HCC prove difficult. Moreover, the hypoxia-mediated mechanisms in HCC remain elusive. Here, we summarize recent major evidence of hypoxia in HCC lesions by measuring pO2, the clinical importance of hypoxic markers in HCC, and recent advances in hypoxia-related mechanisms and therapies in HCC. For the mechanisms, we focus mainly on the roles of oxygen-sensing proteins (i.e., hypoxia inducible factor and neuroglogin) and hypoxia-induced signaling proteins (e.g., matrix metalloproteinases, high mobility group box 1, Beclin 1, glucose metabolism enzymes, and vascular endothelial growth factor). With respect to therapies, we discuss mainly YQ23, Sorafenib, 2-Methoxyestradiol and Celastrol. This review focuses primarily on the results of clinical and animal studies.

Hepatocellular carcinomas (HCC) are highly malignant and aggressive tumors lack of effective therapeutic drugs. Piperlongumine (PL), a natural product isolated from longer pepper plants, is recently identified as a potent cytotoxic compound highly selective to cancer cells. Here, we reported that PL specifically suppressed HCC cell migration/invasion via endoplasmic reticulum (ER)-MAPKs-CHOP signaling pathway. PL selectively killed HCC cells but not normal hepatocytes with an IC50 of 10-20 µM while PL at much lower concentrations only suppressed HCC cell migration/invasion. PL selectively elevated reactive oxygen species (ROS) in HCC cells, which activated or up-regulated downstream PERK/Ire 1α/Grp78, p38/JNK/Erk and CHOP subsequently. Administration of antioxidants completely abolished PL’s effects on cell death and migration/invasion. However, pharmacological inhibition of ER stress-responses or MAPKs signaling pathways with corresponding specific inhibitors only reversed PL’s effect on cell migration/invasion but not on cell death. Consistently, knocking-down of CHOP by RNA interference only reversed PL-suppressed HCC cell migration. Finally, PL significantly suppressed HCC development and activated the ER-MAPKs-CHOP signaling pathway in HCC xenografts in vivo. Taken together, PL selectively killed HCC cells and preferentially inhibited HCC cell migration/invasion via ROS-ER-MAPKs-CHOP axis, suggesting a novel therapeutic strategy for the highly malignant and aggressive HCC clinically.