A Novel RNA-Binding Protein Signature to Predict Clinical Outcomes and Guide Clinical Therapy in Gastric Cancer

Objective: This study aimed to develop an RNA-binding protein (RBP)-based signature for risk stratification and guiding clinical therapy in gastric cancer.Methods: Based on survival-related RBPs, an RBP-based signature was established by LASSO regression analysis in TCGA dataset. Kaplan–Meier curves were drawn between high- and low-risk groups. The predictive efficacy of this signature was assessed via ROCs at 1-, 3-, and 5-year survival. Its generalizability was verified in an external dataset. Following adjustment with other clinicopathological characteristics, the independency of survival prediction was evaluated via multivariate Cox regression and subgroup analyses. GSEA was utilized in identifying activated pathways in two groups. Stromal score, immune score, tumor purity, and infiltration levels of 22 immune cells were determined in each sample via the ESTIMATE and CIBERSORT algorithms. The sensitivity to chemotherapy drugs was assessed through the GDSC database.Results: Data showed that patients with high risk exhibited unfavorable clinical outcomes than those with low risk. This signature possessed good performance in predicting 1-, 3-, and 5-year survival and can be independently predictive of patients' survival. Calcium, ECM receptor interaction, and focal adhesion were highly enriched in high-risk samples. High-risk samples presented increased stromal and immune scores and reduced tumor purity. Moreover, this signature presented close relationships with immune infiltrations. Low-risk specimens were more sensitive to sorafenib, gefitinib, vinorelbine, and gemcitabine than high-risk specimens.Conclusion: This RBP-based signature may be a promising tool for predicting clinical outcomes and guiding clinical therapy in gastric cancer.

Long non-coding RNAs in Epstein–Barr virus-related cancer

Epstein Barr-virus (EBV) is related to several cancers. Long non-coding RNAs (lncRNAs) act by regulating target genes and are involved in tumourigenesis. However, the role of lncRNAs in EBV-associated cancers is rarely reported. Understanding the role and mechanism of lncRNAs in EBV-associated cancers may contribute to diagnosis, prognosis and clinical therapy in the future. EBV encodes not only miRNAs, but also BART lncRNAs during latency and the BHLF1 lncRNA during both the latent and lytic phases. These lncRNAs can be targeted regulate inflammation, invasion, and migration and thus tumourigenesis. The products of EBV also directly and indirectly regulate host lncRNAs, including LINC00312, NORAD CYTOR, SHNG8, SHNG5, MINCR, lncRNA-BC200, LINC00672, MALATI1, LINC00982, LINC02067, IGFBP7‐AS1, LOC100505716, LOC100128494, NAG7 and RP4-794H19.1, to facilitate tumourigenesis using different mechanisms. Additionally, lncRNAs have been previously validated to interact with microRNAs (miRNAs), and lncRNAs and miRNAs mutually suppress each other. The EBV-miR-BART6-3p/LOC553103/STMN1 axis inhibits EBV-associated tumour cell proliferation. Additionally, H. pylori–EBV co-infection promotes inflammatory lesions and results in EMT. HPV–EBV co-infection inhibits the transition from latency to lytic replication. KSHV–EBV co-infection aggravates tumourigenesis in huNSG mice. COVID-19–EBV co-infection may activate the immune system to destroy a tumour, although this situation is rare and the mechanism requires further confirmation. Hopefully, this information will shed some light on tumour therapy strategies tumourigenesis. Additionally, this strategy benefits for infected patients by preventing latency to lytic replication. Understanding the role and expression of lnRNAs in these two phases of EBV is critical to control the transition from latency to the lytic replication phase. This review presents differential expressed lncRNAs in EBV-associated cancers and provides resources to aid in developing superior strategies for clinical therapy.

Extracellular vesicle-derived miRNA as a novel regulatory system for bi-directional communication in gut-brain-microbiota axis

The gut-brain-microbiota axis (GBMAx) coordinates bidirectional communication between the gut and brain, and is increasingly recognized as playing a central role in physiology and disease. MicroRNAs are important intracellular components secreted by extracellular vesicles (EVs), which act as vital mediators of intercellular and interspecies communication. This review will present current advances in EV-derived microRNAs and their potential functional link with GBMAx. We propose that EV-derived microRNAs comprise a novel regulatory system for GBMAx, and a potential novel therapeutic target for modifying GBMAx in clinical therapy.

The Role of Tumor-Derived Exosomes in the Abscopal Effect and Immunotherapy

Exosomes are microvesicles that can be secreted by various cells and carry a variety of contents; thus, they play multiple biological functions. For instance, the tumor-derived exosomes (TEXs) have been proven to have the effect of immunostimulatory in addition to immunosuppression, making TEXs attractive in clinical immunotherapy and targeted therapy for cancer patients. In addition, TEXs as biomarkers have important clinical diagnostic and prognostic value. Recently, TEXs have been recognized to play important roles in the abscopal effect (AbE), a newly discovered mechanism by which the distant tumors are effectively targeted and repressed during immunotherapy and radiotherapy. Therefore, TEXs has demonstrated great clinical potential in the diagnosis, prognosis and treatment of cancer patients in the future. This review summarizes and discusses the role of TEXs in clinical therapy and their role in AbE in recent studies.

MMP-9 Reinforces Radiation-Induced Delayed Invasion and Metastasis of Surviving Neuroblastoma Cells Through Second-Signaling Positive Feedback With NFkB Via Both ERK and IKK Activation

Neuroblastoma (NB) progression is branded with hematogenous metastasis and frequent relapses. Despite intensive multimodal clinical therapy, outcomes for patients with progressive disease remain poor, with negligible long-term survival. Therefore, understanding the acquired molecular rearrangements in surviving cells with therapy pressure and developing improved therapeutic strategies is a critical need to improve the outcomes for high-risk NB patients. We investigated the rearrangement of MMP9 in NB with therapy pressure, and unveiled the signaling that facilitates NB evolution. Radiation-therapy (RT) significantly increased MMP9 expression/activity, and the induced enzyme activity was persistently maintained across NB cell lines. Further, RT-triggered NFkB transcriptional activity and this RT-induced NFkB were required/adequate for MMP9 maintenance. RT-triggered NFkB-dependent MMP9 actuated a second-signaling feedback to NFkB, facilitating a NFkB-MMP9-NFkB positive feedback cycle (PFC). Critically, MMP9-NFkB feedback is mediated by MMP9-dependent activation of IKKβ and ERK phosphotransferase activity. Beyond its tumor invasion/metastasis function, PFC-dependent MMP9 lessens RT-induced apoptosis and favors survival pathway through the activation of NFkB signaling. In addition, PFC-dependent MMP9 regulates 19 critical molecular determinants that play a pivotal role in tumor evolution. Interestingly, seven of 19 genes possess NFkB-binding sites, demonstrating that MMP9 regulates these molecules by activating NFkB. Collectively, these data suggest that RT-triggered NFkB-dependent MMP9 actuates feedback to NFkB though IKKβ- and ERK1/2-dependent IkBα phosphorylation. This RT-triggered PFC prompts MMP9-dependent survival advantage, tumor growth, and dissemination. Targeting therapy-pressure-driven PFC and/or selective inhibition of MMP9 maintenance could serve as promising therapeutic strategies for treatment of progressive NB that defies current clinical therapy.

Therapeutic Effect and Mechanism of Bushen-Jianpi-Jiedu Decoction Combined with Chemotherapeutic Drugs on Postoperative Colorectal Cancer

There is a lack of effective therapeutic drugs in patients with postoperative colorectal cancer (PCRC). This study aimed to investigate the therapeutic effect and mechanisms of Bushen-Jianpi-Jiedu decoction (BSJPJDD) combined with chemotherapeutic drugs (oxaliplatin) on PCRC with liver and kidney yin deficiency and spleen deficiency syndrome (LKYD-SDS) through the therapeutic evaluation of clinical therapy and the integrative analysis of network pharmacology, RNA-seq and label-free data, and experiment verification in vitro. In clinical therapy, the median progression-free survival (PFS) and Karnofsky performance score (KPS) were increased in PCRC patients by the aqueous extract of BSJPJDD combined with oxaliplatin treatment for three months, compared to oxaliplatin alone (p < 0.05). The integrative analysis showed that 559 differentially expressed genes (DEGs) and 11 differentially expressed proteins (DEPs) were regulated by BSJPJDD, among which seven bioactive compounds through 39 potential targets were involved in the regulation of multiple signaling pathways including MAPK, PI3K-Akt, and HIF-1, etc. In the experimental verification, an ELISA assay showed that plasma ZEB2, CAT, and KRT78 were decreased, and IL-1Α, CD5L, FBLN5, EGF, and KRT78 were increased in comparison to the above (p < 0.05). Furthermore, the SW620 cell viability was inhibited and the expressions of MAPK and the p-ERK/ERK ratio were significantly downregulated by the aqueous extract of BSJPJDD combined with oxaliplatin treatment, compared with oxaliplatin treatment alone (p < 0.05). These data suggested that BSJPJDD combined with oxaliplatin prolongs the survival and improves Karnofsky performance status of PCRC patients with LKYD-SDS, and may be associated with the regulation of multiple signaling pathways.