Current understanding of cancer-intrinsic PD-L1: regulation of expression and its protumoral activity.

In the last decade, we have witnessed an unprecedented clinical success in cancer immunotherapies targeting the programmed cell-death ligand 1 (PD-L1) and programmed cell-death 1 (PD-1) pathway. Besides the fact that PD-L1 plays a key role in immune regulation in tumor microenvironment, recently a plethora of reports has suggested a new perspective of non-immunological functions of PD-L1 in the regulation of cancer intrinsic activities including mesenchymal transition, glucose and lipid metabolism, stemness, and autophagy. Here we review the current understanding on the regulation of expression and intrinsic protumoral activity of cancer-intrinsic PD-L1.

Identification of a tumor-suppressive human-specific microRNA within the FHIT tumor-suppressor gene.

Loss or attenuated expression of the tumor-suppressor gene FHIT is associated paradoxically with poor progression of human tumors. Fhit promotes apoptosis and regulates reactive oxygen species; however, the mechanism by which Fhit inhibits tumor growth in animals remains unclear. In this study, we used a multidisciplinary approach based on bioinformatics, small RNA library screening, human tissue analysis, and a xenograft mouse model to identify a novel member of the miR-548 family in the fourth intron of the human FHIT gene.

Molecular mechanisms involved in tumor repopulation after radiotherapy.

Radiotherapy remains one of most important treatment modalities for solid tumors. Current radiotherapy is mostly based on a set of concepts called the 4"R"s, which were established when there was lack of understanding of the underlying molecular mechanisms. However, progress made in the past two decades are beginning to allow us to see some of the molecular details involved in tumor response to radiation therapy.

MicroRNA-21 modulates the levels of reactive oxygen species by targeting SOD3 and TNFα.

MicroRNA-21 (miR-21) is an oncomir overexpressed in most human tumors in that it promotes malignant growth and progression by acting on multiple targets. Here, we broaden the impact of miR-21 in cancer by showing that it regulates the formation of reactive oxygen species (ROS) that promote tumorigenesis. Key targets of miR-21 in mediating this function were SOD3 and TNFα.

RNAi-mediated targeting of noncoding and coding sequences in DNA repair gene messages efficiently radiosensitizes human tumor cells.

Human tumor cell death during radiotherapy is caused mainly by ionizing radiation (IR)-induced DNA double-strand breaks (DSB), which are repaired by either homologous recombination repair (HRR) or nonhomologous end-joining (NHEJ). Although siRNA-mediated knockdown of DNA DSB repair genes can sensitize tumor cells to IR, this approach is limited by inefficiencies of gene silencing. In this study, we show that combining an artificial miRNA (amiR) engineered to target 3'-untranslated regions of XRCC2 (an HRR factor) or XRCC4 (an NHEJ factor) along with an siRNA to target the gene coding region can improve silencing efficiencies to achieve more robust radiosensitization than a single approach alone.

Radiosensitizing effects of ectopic miR-101 on non-small-cell lung cancer cells depend on the endogenous miR-101 level.

Purpose: Previously, we showed that ectopic miR-101 could sensitize human tumor cells to radiation by targeting ATM and DNA-PK catalytic subunit (DNA-PKcs) to inhibit DNA repair, as the endogenous miR-101 levels are low in tumors in general. However, the heterogeneity of human cancers may result in an exception. The purpose of this study was to test the hypothesis that a few tumor cell lines with a high level of endogenous miR-101 would prove less response to ectopic miR-101.

Over-expression of miR-100 is responsible for the low-expression of ATM in the human glioma cell line: M059J.

M059J and M059K cells were isolated from different portions of the same human malignant glioma. M059J cells are more radiosensitive than M059K cells due to the absence of DNA-PKcs and low-expression of ATM. The mechanism concerning the absence of DNA-PKcs in M059J is due to the frameshift mutation in PRKDC (DNA-PKcs gene); however, the reason for the low-expression of ATM in M059J cells remains unclear.

Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation.

Background: Radiotherapy kills tumor-cells by inducing DNA double strand breaks (DSBs). However, the efficient repair of tumors frequently prevents successful treatment. Therefore, identifying new practical sensitizers is an essential step towards successful radiotherapy.

Transcriptional responses to biologically relevant doses of UV-B radiation in the model archaeon, Halobacterium sp. NRC-1.

Background: Most studies of the transcriptional response to UV radiation in living cells have used UV doses that are much higher than those encountered in the natural environment, and most focus on short-wave UV (UV-C) at 254 nm, a wavelength that never reaches the Earth's surface. We have studied the transcriptional response of the sunlight-tolerant model archaeon, Halobacterium sp. NRC-1, to low doses of mid-wave UV (UV-B) to assess its response to UV radiation that is likely to be more biologically relevant.

UV irradiation induces homologous recombination genes in the model archaeon, Halobacterium sp. NRC-1.

Background: A variety of strategies for survival of UV irradiation are used by cells, ranging from repair of UV-damaged DNA, cell cycle arrest, tolerance of unrepaired UV photoproducts, and shielding from UV light. Some of these responses involve UV-inducible genes, including the SOS response in bacteria and an array of genes in eukaryotes. To address the mechanisms used in the third branch of life, we have studied the model archaeon, Halobacterium sp.

Proteasome inhibition by lactacystin in primary neuronal cells induces both potentially neuroprotective and pro-apoptotic transcriptional responses: a microarray analysis.

Although inhibition of the ubiquitin proteasome system has been postulated to play a key role in the pathogenesis of neurodegenerative diseases, studies have also shown that proteasome inhibition can induce increased expression of neuroprotective heat-shock proteins (HSPs). The global gene expression of primary neurons in response to treatment with the proteasome inhibitor lactacystin was studied to identify the widest range of possible pathways affected. Our results showed changes in mRNA abundance, both at different time points after lactacystin treatment and at different lactacystin concentrations.

Evaluation of advanced reverse transcription-PCR assays and an alternative PCR target region for detection of severe acute respiratory syndrome-associated coronavirus.

First-generation reverse transcription-PCR (RT-PCR) assays for severe acute respiratory syndrome-associated coronavirus (SARS-CoV) gave false-negative results in a considerable fraction of patients. In the present study, we evaluated two second-generation, replicase (R) gene-based, real-time RT-PCR test kits--the RealArt HPA coronavirus LC kit (Artus, Hamburg, Germany) and the LightCycler SARS-CoV quantification kit (Roche, Penzberg, Germany)--and a real-time RT-PCR assay for the nucleocapsid (N) gene. Detecting the N-gene RNA might be advantageous due to its high abundance in cells.