HuR up-regulates cell surface PD-L1 via stabilizing CMTM6 transcript in cancer

Despite the well-established role of CMTM6 in the stabilization of cell surface PD-L1 in cancer cells, the mechanisms underlying CMTM6 expression and regulation are still largely unknown. Here we unexpectedly find a strikingly positive correlation between CMTM6 and Hu-Antigen R (HuR) expression in most types of cancer. Mechanistically, we elucidate HuR stabilizes CMTM6 mRNA via direct association with AU-rich elements (AREs) in its 3′UTR and predominantly up-regulates CMTM6, which is readily abolished by HuR-specific inhibitor, MS-444. Phenotypically, we notice abundant cell surface PD-L1 in HuR-high cancer cells, which significantly inhibits immune activation of co-cultured T cells as indicated by IL-2 production. Treatment with MS-444 completely relieves immune suppression imposed by HuR-overexpression and further stimulates immune responses. Ectopic HuR accelerates allograft tumor progression in vivo, which is greatly compromised by simultaneous administration with MS-444. Our study uncovers a novel mechanism in control of CMTM6 and therefore PD-L1 expression, and suggests the potential of combining HuR inhibitor with PD-1/PD-L1 antibodies for cancer immunotherapy.

HuR Protein in Hepatocellular Carcinoma: Implications in Development, Prognosis and Treatment

Hu-antigen R (HuR) is a post-transcriptional regulator that belongs to the embryonic lethal abnormal vision Drosophila-like family (ELAV). HuR regulates the stability, translation, subcellular localization, and degradation of several target mRNAs, which are implicated in carcinogenesis and could affect therapeutic options. HuR protein is consistently highly expressed in hepatocellular carcinoma (HCC) compared to the adjacent normal liver tissue and is involved in the post-transcriptional regulation of various genes implicated in liver malignant transformation. Additionally, HuR protein seems to be a putative prognosticator in HCC, predicting worse survival. This review summarizes the recent evidence regarding the role of HuR in primary liver tumors, as presented in clinical studies, in vitro experiments and in vivo animal models. In conclusion, our review supports the consistent role of HuR protein in the development, prognosis, and treatment of HCC. Additional studies are expected to expand current information and exploit its putative employment as a future candidate for more personalized treatment in these tumors.

MicroRNA-145 suppresses gastric cancer progression by targeting Hu-antigen R

Hu-antigen R (HuR) is involved in the carcinogenesis and progression of multiple types of cancer. However, its precise role in gastric cancer (GC) and the relevant molecular mechanism remain largely unclear. In the present study, we found that HuR expression level was higher in GC tissues and cell lines than in adjacent normal tissues and normal gastric epithelial cell lines, and this elevated expression was found to have a significant association with lymph node metastasis. Moreover, silencing HuR with RNA interference inhibited cell viability and induced cell apoptosis through the apoptosis-related regulators (Bcl-2 and Bax) in GC cells. In addition, bioinformatic analysis revealed that HuR expression was inversely correlated with miR-145 expression in GC tissue samples, and HuR was identified as a direct target of miR-145 with the dual-luciferase reporter. Enforced expression of miR-145 inhibited the HuR expression at both mRNA and protein levels and induced similar biologic effects of silencing HuR in GC cells. Additionally, we also found that restoration of HuR could eliminate the effects induced by miR-145 in GC cells. Taken together, these findings demonstrate the exact role of the miR-145-HuR axis in the progression of GC and indicate a potential target for GC therapy.

Clinical Significance and Biological Role of HuR in Head and Neck Carcinomas

Background. Hu-antigen R (HuR) is a posttranscriptional regulator of several target mRNAs, implicated in carcinogenesis. This review aims to present the current evidence regarding the biological role and potential clinical significance of HuR in head and neck carcinomas. Methods. The existing literature concerning HuR expression and function in head and neck carcinomas is critically presented and summarised. Results. HuR is expressed in the majority of the examined samples, showing higher cytoplasmic levels in malignant or premalignant cases. Moreover, HuR modulates several genes implicated in biological processes important for malignant transformation, growth, and invasiveness. HuR seems to be an adverse prognosticator in patients with OSCCs, whereas a correlation with a more aggressive phenotype is reported in several types of carcinomas. Conclusions. A consistent role of HuR in the carcinogenesis and progression of head and neck carcinomas is suggested; nevertheless, further studies are warranted to expand the present information.

T-Cell Intracellular Antigens and Hu Antigen R Antagonistically Modulate Mitochondrial Activity and Dynamics by Regulating Optic Atrophy 1 Gene Expression

ABSTRACT Mitochondria undergo frequent morphological changes to control their function. We show here that T-cell intracellular antigens (TIA1b/TIARb) and Hu antigen R (HuR) have antagonistic roles in mitochondrial function by modulating the expression of mitochondrial shaping proteins. Expression of TIA1b/TIARb alters the mitochondrial dynamic network by enhancing fission and clustering, which is accompanied by a decrease in respiration. In contrast, HuR expression promotes fusion and cristae remodeling and increases respiratory activity. Mechanistically, TIA proteins downregulate the expression of optic atrophy 1 (OPA1) protein via switching of the splicing patterns of OPA1 to facilitate the production of OPA1 variant 5 (OPA1v5). Conversely, HuR enhances the expression of OPA1 mRNA isoforms through increasing steady-state levels and targeting translational efficiency at the 3′ untranslated region. Knockdown of TIA1/TIAR or HuR partially reversed the expression profile of OPA1, whereas knockdown of OPA1 or overexpression of OPA1v5 provoked mitochondrial clustering. Middle-term expression of TIA1b/TIARb triggers reactive oxygen species production and mitochondrial DNA damage, which is accompanied by mitophagy, autophagy, and apoptosis. In contrast, HuR expression promotes mitochondrion-dependent cell proliferation. Collectively, these results provide molecular insights into the antagonistic functions of TIA1b/TIARb and HuR in mitochondrial activity dynamics and suggest that their balance might contribute to mitochondrial physiopathology.