Dual Effects of miR-181b-2-3p/SOX21 Interaction on Microglia and Neural Stem Cells after Gamma Irradiation.

Ionizing radiation induces brain inflammation and the impairment of neurogenesis by activating microglia and inducing apoptosis in neurogenic zones. However, the causal relationship between microglial activation and the impairment of neurogenesis as well as the relevant molecular mechanisms involved in microRNA (miR) remain unknown. In the present study, we employed immunohistochemistry and real-time RT-PCR to study the microglial activation and miRNA expression in mouse brains. Real-time RT-PCR, western blot, ELISA, cell proliferation and cytotoxicity assay were used in BV2 and mouse neural stem cells (NSCs). In the mouse model, we found the acute activation of microglia at 1 day and an increased number of microglial cells at 1, 7 and 120 days after irradiation at postnatal day 3 (P3), day 10 (P10) and day 21 (P21), respectively. In cell models, the activation of BV2, a type of microglial cell line, was observed after gamma irradiation. Real-time RT-PCR analysis revealed a deceased expression of miR-181b-2-3p and an increased expression of its target SRY-related high-mobility group box transcription factor 21 (SOX21) in a dose- and time-dependent fashion. The results of the luciferase reporter assay confirmed that SOX21 was the target of miR-181b-2-3p. Furthermore, SOX21 knockdown by siRNA inhibited the activation of microglia, thereby suggesting that the direct interaction of 181b-2-3p with SOX21 might be involved in radiation-induced microglial activation and proliferation. Interestingly, the gamma irradiation of NSCs increased miR-181b-2-3p expression but decreased SOX21 mRNA, which was the opposite of irradiation-induced expression in BV2 cells. As irradiation reduced the viability and proliferation of NSCs, whereas the overexpression of SOX21 restored the impaired cell viability and promoted the proliferation of NSCs, the findings suggest that the radiation-induced interaction of miR-181b-2-3p with SOX21 may play dual roles in microglia and NSCs, respectively, leading to the impairment of brain neurogenesis.

Bispecific T cell engagers and their synergistic tumor immunotherapy with oncolytic viruses.

Tumor immunotherapy, especially T cell based therapy, is becoming the main force in clinical tumor therapies. Bispecific T cell engager (BiTE) uses the single chain variable fragments (scFv) of two antibodies to redirect T cells to kill target cells. BiTEs for hematologic tumors has been approved for clinical use, and BiTEs for solid tumors showed therapeutic effects in clinical trials. Oncolytic viruses (OVs) of the adenovirus expressing p53 and herpes simplex virus expressing GM-CSF was approved for clinical use in 2003 and 2015, respectively, while other OVs showed therapeutic effects in clinical trials. However, BiTE and Oncolytic virus (OV) have their own limitations. We propose that OV-BiTE has a synergistic effect on tumor immunotherapy. Feng Yu et al. designed the first OV-BiTE in 2014, which remarkably eradicated tumors in mice. Here we review the latest development of the structure, function, preclinical studies and/or clinical trials of BiTE and OV-BiTE and provide perspective views for optimizing the design of OV-BiTE. There is no doubt that OV-BiTE is becoming an exciting new platform for tumor immunotherapy and will enter clinical trial soon. Exploring the therapeutic effects and safety of OV-BiTE for synergistic tumor immunotherapy will bring new hope to tumor patients.

Cell­cell fusion as an important mechanism of tumor metastasis (Review).

Cell­cell fusion is a dynamic biological phenomenon, which plays an important role in various physiological processes, such as tissue regeneration. Similarly, normal cells, particularly bone marrow­derived cells (BMDCs), may attempt to fuse with cancer cells to rescue them. The rescue may fail, but the fused cells end up gaining the motility traits of BMDCs and become metastatic due to the resulting genomic instability. In fact, cell­cell fusion was demonstrated to occur in vivo in cancer and was revealed to promote tumor metastasis. However, its existence and role may be underestimated, and has not been widely acknowledged. In the present review, the milestones in cell fusion research were highlighted, the evidence for cell­cell fusion in vitro and in vivo in cancer was evaluated, and the current understanding of the molecular mechanisms by which cell­cell fusion occurs was summarized, to emphasize their important role in tumor metastasis. The summary provided in the present review may promote further study into this process and result in novel discoveries of strategies for future treatment of tumor metastasis.

The old CEACAMs find their new role in tumor immunotherapy.

Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) contain 12 family members(CEACAM1、CEACAM3、CEACAM4、CEACAM5、CEACAM6、CEACAM7、CEACAM8、CEACAM16、CEACAM18、CEACAM19、CEACAM20 and CEACAM21)and are expressed diversely in different normal and tumor tissues. CEA (CEACAM5) has been used as a tumor biomarker since 1965. Here we review the latest research and development of the structures, expression, and function of CEACAMs in normal and tumor tissues, and their application in the tumor diagnosis, prognosis, and treatment. We focus on recent clinical studies of CEA targeted cancer immunotherapies, including bispecific antibody (BsAb) for radio-immuno-therapy and imaging, bispecific T cell engager (BiTE) and chimeric antigen receptor T cells (CAR-T). We summarize the promising clinical relevance and challenges of these approaches and give perspective view for future research. This review has important implications in understanding the diversified biology of CEACAMs in normal and tumor tissues, and their new role in tumor immunotherapy.

Correction to: The old CEACAMs find their new role in tumor immunotherapy.

Correction is needed to the original version of this article.

CRISPR/Cas9 genome editing technology significantly accelerated herpes simplex virus research.

Herpes simplex viruses (HSVs) are important pathogens and ideal for gene therapy due to its large genome size. Previous researches on HSVs were hampered because the technology to construct recombinant HSVs were based on DNA homology-dependent repair (HDR) and plaque assay, which are inefficient, laborious, and time-consuming. Fortunately, clustered regularly interspaced short palindromic repeat/CRISPR-associated protein 9 (CRISPR/Cas9) recently provided the possibility to precisely, efficiently, and rapidly edit genomes and indeed is successfully being used in HSVs. Importantly, CRISPR/Cas9 technology increased HSV HDR efficiency exponentially by a 10,000-1,000,000 times when making recombinant HSVs, and its combination with flow cytometric technology made HSV recombination practically automatic. These may have a significant impact on virus and gene therapy researches. This review will summarize the latest development and molecular mechanisms of CRISPR/Cas9 genome editing technology and its recent application in HSVs.

Oncolytic Viruses for Tumor Precision Imaging and Radiotherapy.

In 2003 in China, Peng et al. invented the recombinant adenovirus expressing p53 (Gendicine) for clinical tumor virotherapy. This was the first clinically approved gene therapy and tumor virotherapy drug in the world. An oncolytic herpes simplex virus expressing granulocyte-macrophage colony-stimulating factor (Talimogene laherparepvec) was approved for melanoma treatment in the United States in 2015. Since then, oncolytic viruses have been attracting more and more attention in the field of oncology, and may become novel significant modalities of tumor precision imaging and radiotherapy after further improvement. Oncolytic viruses carrying reporter genes can replicate and express genes of interest selectively in tumor cells, thus improving in vivo noninvasive precision molecular imaging and radiotherapy. Here, the latest developments and molecular mechanisms of tumor imaging and radiotherapy using oncolytic viruses are reviewed, and perspectives are given for further research. Various types of tumors are discussed, and special attention is paid to gastrointestinal tumors.

Oncolytic herpes simplex virus tumor targeting and neutralization escape by engineering viral envelope glycoproteins.

Oncolytic herpes simplex viruses (oHSVs) have been approved for clinical usage and become more and more popular for tumor virotherapy. However, there are still many issues for the oHSVs used in clinics and clinical trials. The main issues are the limited anti-tumor effects, intratumor injection, and some side effects. To overcome such challenges, here we review the genetic engineering of the envelope glycoproteins for oHSVs to target tumors specifically, and at the same time we summarize the many neutralization antibodies against the envelope glycoproteins and align the neutralization epitopes with functional domains of the respective glycoproteins for future identification of new functions of the glycoproteins and future engineering of the epitopes to escape from host neutralization.