Emerging role of RNA modification and long noncoding RNA interaction in cancer.

RNA modification, especially N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine methylation, participates in the occurrence and progression of cancer through multiple pathways. The function and expression of these epigenetic regulators have gradually become a hot topic in cancer research. Mutation and regulation of noncoding RNA, especially lncRNA, play a major role in cancer. Generally, lncRNAs exert tumor-suppressive or oncogenic functions and its dysregulation can promote tumor occurrence and metastasis. In this review, we summarize N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine modifications in lncRNAs. Furthermore, we discuss the relationship between epigenetic RNA modification and lncRNA interaction and cancer progression in various cancers. Therefore, this review gives a comprehensive understanding of the mechanisms by which RNA modification affects the progression of various cancers by regulating lncRNAs, which may shed new light on cancer research and provide new insights into cancer therapy.

Downregulation of PDIA3 inhibits gastric cancer cell growth through cell cycle regulation.

OBJECTIVE: Protein disulfide isomerase A3 (PDIA3) promotes the correct folding of newly synthesized glycoproteins in the endoplasmic reticulum. PDIA3 is overexpressed in most tumors, and it may become a biomarker of cancer prognosis and immunotherapy. Our study aims to detect the expression level of PDIA3 in gastric cancer (GC) and its association with GC development as wells as the underlying mechanisms. METHODS: GC cell lines with PDIA3 knockdown by siRNA, CRISPR-cas9 sgRNAs or a pharmacological inhibitor of LOC14 were prepared and used. PDIA3 knockout GC cells were established by CRISPR-cas9-PDIA3 system. The proliferation, migration, invasion and cell cycle of GC cells were analyzed by cell counting kit-8 assay, wound healing assay, transwell assay and flow cytometry, respectively. Immunodeficient nude mice was used to evaluate the role of PDIA3 in tumor formation. Quantitative PCR and western blot were used for examining gene and protein expressions. RNA sequencing was performed to see the altered gene expression. RESULTS: The expressions of PDIA3 in GC tissues and cells were increased significantly, and its expression was negatively correlated with the three-year survival rate of GC patients. Down-regulation of PDIA3 by siRNA, LOC14 or CRISPR-cas9 significantly inhibited proliferation, invasion and migration of GC cells TMK1 and AGS, with cell cycle arrested at G2/M phase. Meanwhile, decreased PDIA3 significantly inhibited growth of tumor xenograft in vivo. It was found that cyclin G1 (encoded by CCNG1 gene) expression was decreased by downregulation of PDIA3 in GC cells both in vitro and in vivo. In addition, protein levels of other cell cycle related factors including cyclin D1, CDK2, and CDK6 were also significantly decreased. Further study showed that STAT3 was associated with PDIA3-mediated cyclin G1 regulation. CONCLUSION: PDIA3 plays an oncogenic role in GC. Our findings unfolded the functional role of PDIA3 in GC development and highlighted a novel target for cancer therapeutic strategy.

Dysregulation of immunity by cigarette smoking promotes inflammation and cancer: A review.

Smoking is a serious global health issue. Cigarette smoking contains over 7000 different chemicals. The main harmful components include nicotine, acrolein, aromatic hydrocarbons and heavy metals, which play the key role for cigarette-induced inflammation and carcinogenesis. Growing evidences show that cigarette smoking and its components exert a remarkable impact on regulation of immunity and dysregulated immunity promotes inflammation and cancer. Therefore, this comprehensive and up-to-date review covers four interrelated topics, including cigarette smoking, inflammation, cancer and immune system. The known harmful chemicals from cigarette smoking were summarized. Importantly, we discussed in depth the impact of cigarette smoking on the formation of inflammatory or tumor microenvironment, primarily by affecting immune effector cells, such as macrophages, neutrophils, and T lymphocytes. Furthermore, the main molecular mechanisms by which cigarette smoking induces inflammation and cancer, including changes in epigenetics, DNA damage and others were further summarized. This article will contribute to a better understanding of the impact of cigarette smoking on inducing inflammation and cancer.

LncRNA RP11-93B14.5 promotes gastric cancer cell growth through PI3K/AKT signaling pathway.

OBJECTIVE: Emerging evidence indicates that long non-coding RNA (lncRNA) RP11-93B14.5 facilitates tumor progression in variety of malignancies. The present study proposed to study the functional effect of lncRNA RP11-93B14.5 in gastric cancer (GC) as well as the underlying mechanism. METHODS: Bioinformatics analysis was utilized to analyze lncRNA expression in GC tissues. siRNA was used for knockdown of RP11-93B14.5 in GC cells MKN45 and KATO III. The stable knockdown cell lines were constructed by CRISPR-Cas9. Cell counting kit-8 (CCK-8) assay and soft agar colony formation assay were used to analyze GC cell viability. Flow cytometry analysis was performed to analyze the cell cycle distribution of MKN45 and KATO III. RNA sequencing (RNA-seq) was employed to detect differential genes after transfection with siRP11-93B14.5. Quantitative PCR (Q-PCR) was used to examine gene expression in GC cell lines. Western-blot assay was used to measure protein levels. RNA fluorescent in situ hybridization (FISH) was conducted for lncRNA cellular location and expression. RESULTS: Based on the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database, RP11-93B14.5 was upregulated in GC tissue, which was also verified in GC cell lines in comparison to the normal gastric epithelial HFE145 cells. Knockdown of RP11-93B14.5 decreased cell viability and the colony number of MKN45 and KATO III cells, and altered cell cycle distribution in vitro. RNA-seq analysis revealed RP11-93B14.5 may modulate genes expression of S100A2 and TIMP2 in MKN45 and KATO III cells. Mechanistically, RP11-93B14.5 may drive the progression of GC via S100A2 related-PI3K/AKT signaling pathway. CONCLUSIONS: LncRNA RP11-93B14.5 knockdown alleviated the malignant phenotypes of GC cells through regulating PI3K/AKT. Our results provide evidence for the role of lncRNAs in regulating tumor progression.

Chemical profiling and investigation of molecular mechanisms underlying anti-hepatocellular carcinoma activity of extracts from Polygonum perfoliatum L.

Polygonum perfoliatum L. is an herbal medicine that has been extensively used in traditional Chinese medicine to treat various health conditions ranging from ancient internal to surgical and gynecological diseases. Numerous studies suggest that P. perfoliatum extract elicits significant anti-tumor, anti-inflammatory, anti-bacterial, and anti-viral effects. Nevertheless, the underlying mechanisms of its anti-liver cancer effects remain poorly understood. Our study suggests that P. perfoliatum stem extract (PPLA) has a favorable safety profile and exhibits a significant anti-liver cancer effect both in vitro and in vivo. We identified that PPLA activates the cGMP-PKG signaling pathway, and key regulatory genes including ADRA1B, PLCB2, PRKG2, CALML4, and GLO1 involved in this activation. Moreover, PPLA modulates the expression of genes responsible for the cell cycle. Additionally, we identified four constituents of PPLA, namely taxifolin, myricetin, eriodictyol, and pinocembrin, that plausibly act via the cGMP-PKG signaling pathway. Both in vitro and in vivo experiments confirmed that PPLA, along with its constituting compounds taxifolin, myricetin, and eriodictyol, exhibit potent anti-cancer activities and hold the promise of being developed into therapeutic agents.

Does each Component of Reactive Oxygen Species have a Dual Role in the Tumor Microenvironment?

Reactive oxygen species (ROS) are a class of highly reactive oxidizing molecules, including superoxide anion (O2•-) and hydrogen peroxide (H2O2), among others. Moderate levels of ROS play a crucial role in regulating cellular signaling and maintaining cellular functions. However, abnormal ROS levels or persistent oxidative stress can lead to changes in the tumor microenvironment (TME) that favor cancer development. This review provides an overview of ROS generation, structure, and properties, as well as their effects on various components of the TME. Contrary to previous studies, our findings reveal a dual effect of ROS on different components of the TME, whereby ROS can either enhance or inhibit certain factors, ultimately leading to the promotion or suppression of the TME. For example, H2O2 has dual effects on immune cells and non-cellular components within the TME, while O2•- has dual effects on T cells and fibroblasts. Furthermore, each component demonstrates distinct mechanisms of action and ranges of influence. In the final section of the article, we summarize the current clinical applications of ROS in cancer treatment and identify certain limitations associated with existing therapeutic approaches. Therefore, this review aims to provide a comprehensive understanding of ROS, highlighting their dual effects on different components of the TME, and exploring the potential clinical applications that may pave the way for future treatment and prevention strategies.

Targeting hypoxia-inducible factors for breast cancer therapy: A narrative review.

Hypoxia-inducible factors (HIFs), central regulators for cells to adapt to low cellular oxygen levels, are often overexpressed and activated in breast cancer. HIFs modulate the primary transcriptional response of downstream pathways and target genes in response to hypoxia, including glycolysis, angiogenesis and metastasis. They can promote the development of breast cancer and are associated with poor prognosis of breast cancer patients by regulating cancer processes closely related to tumor invasion, metastasis and drug resistance. Thus, specific targeting of HIFs may improve the efficiency of cancer therapy. In this review, we summarize the advances in HIF-related molecular mechanisms and clinical and preclinical studies of drugs targeting HIFs in breast cancer. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for HIF targeting are increasingly being developed. Therefore, we highlight the HIF related DDS, including liposomes, polymers, metal-based or carbon-based nanoparticles.

PROTACs in gastrointestinal cancers.

Proteolysis targeting chimera (PROTAC) presents a powerful strategy for targeted protein degradation (TPD). The heterobifunctional PROTAC molecule consists of an E3 ligase ligand covalently linked to a protein of interest (POI) via a linker. PROTAC can induce ubiquitinated proteasomal degradation of proteins by hijacking the ubiquitin-proteasome degradation system (UPS). This technique has the advantages of broad targeting profile, good cell permeability, tissue specificity, high selectivity, oral bioavailability, and controllability. To date, a growing number of PROTACs targeting gastrointestinal cancers have been successfully developed, and, in many cases, their POIs have been validated as clinical drug targets. To the best of our knowledge, 15 PROTACs against various targets are currently tested in clinical trials, and many more are likely to be added in the near future. Therefore, this paper details the mechanism, research progress, and application in clinical trials of PROTACs, and summarizes the research achievements related to PROTACs in gastrointestinal cancers. Finally, we discuss the advantages and potential challenges of PROTAC for cancer treatment.

Dysregulation of B7 family and its association with tumor microenvironment in uveal melanoma.

Background: Uveal melanoma (UVM) is the most common primary intraocular malignancy in adults with a poor prognosis. B7 family is an important modulator of the immune response. However, its dysregulation and underlying molecular mechanism in UVM still remains unclear. Methods: Data were derived from TCGA and GEO databases. The prognosis was analyzed by Kaplan-Meier curve. The ESTIMATE algorithm, CIBERSORT algorithm, and TIMER database were used to demonstrate the correlation between B7 family and tumor immune microenvironment in UVM. Single-cell RNA sequencing was used to detect the expression levels of the B7 family in different cell types of UVM. UVM was classified into different types by consistent clustering. Enrichment analysis revealed downstream signaling pathways of the B7 family. The interaction between different cell types was visualized by cell chat. Results: The expression level of B7 family in UVM was significantly dysregulated and negatively correlated with methylation level. The expression of B7 family was associated with prognosis and immune infiltration, and B7 family plays an important role in the tumor microenvironment (TME). B7 family members were highly expressed in monocytes/macrophages of UVM compared with other cell types. Immune response and visual perception were the main functions affected by B7 family. The result of cell chat showed that the interaction between photoreceptor cells and immune-related cells was mainly generated by HLA-C-CD8A. CABP4, KCNJ10 and RORB had the strongest correlation with HLA-C-CD8A, and their high expression was significantly correlated with poor prognosis. CABP4 and RORB were specifically expressed in photoreceptor cells. Conclusions: Dysregulation of the B7 family in UVM is associated with poor prognosis and affects the tumor immune microenvironment. CABP4 and RORB can serve as potential therapeutic targets for UVM, which can be regulated by the B7 family to affect the visual perception and immune response function of the eye, thus influencing the prognosis of UVM.

Tumor Infiltrating Lymphocyte (TIL) Therapy for Solid Tumor Treatment: Progressions and Challenges.

Over the past decade, immunotherapy, especially cell-based immunotherapy, has provided new strategies for cancer therapy. Recent clinical studies demonstrated that adopting cell transfer of tumor-infiltrating lymphocytes (TILs) for advanced solid tumors showed good efficacy. TIL therapy is a type of cell-based immunotherapy using the patient's own immune cells from the microenvironment of the solid tumor to kill tumor cells. In this review, we provide a comprehensive summary of the current strategies and challenges in TIL isolation and generation. Moreover, the current clinical experience of TIL therapy is summarized and discussed, with an emphasis on lymphodepletion regimen, the use of interleukin-2, and related toxicity. Furthermore, we highlight the clinical trials where TIL therapy is used independently and in combination with other types of therapy for solid cancers. Finally, the limitations, future potential, and directions of TIL therapy for solid tumor treatment are also discussed.

VEGF/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment.

Non-small cell lung cancer (NSCLC) is the leading cause of death by cancer worldwide. Despite developments in therapeutic approaches for the past few decades, the 5-year survival rate of patients with NSCLC remains low. NSCLC tumor is a complex, heterogeneous microenvironment, comprising blood vessels, cancer cells, immune cells, and stroma cells. Vascular endothelial growth factors (VEGFs) are a major mediator to induce tumor microvasculature and are associated with the progression, recurrence, and metastasis of NSCLC. Current treatment medicines targeting VEGF/VEGF receptor (VEGFR) pathway, including neutralizing antibodies to VEGF or VEGFR and receptor tyrosine kinase inhibitors, have shown good treatment efficacy in patients with NSCLC. VEGF is not only an important angiogenic factor but also an immunomodulator of tumor microenvironment (TME). VEGFs can suppress antigen presentation, stimulate activity of regulatory T (Treg) cells, and tumor-associated macrophages, which in turn promote an immune suppressive microenvironment in NSCLC. The present review focuses on the angiogenic and non-angiogenic functions of VEGF in NSCLC, especially the interaction between VEGF and the cellular components of the TME. Additionally, we discuss recent preclinical and clinical studies to explore VEGF/VEGFR-targeted compounds and immunotherapy as novel approaches targeting the TME for the treatment of NSCLC.

The roles of different photoselective nets in the targeted regulation of metabolite accumulation, wine aroma and sensory profiles in warm viticulture regions.

To improve the quality of grapes and wine in warm viticulture regions, the effects of pearl, red and black photoselective nets on the quality of grapes and wine were systematically investigated. Compared with the CK (open field), three nets improved the microclimate conditions and reduced grape sugar and wine alcohol levels. However, the nets differentially affected other quality profiles of the grapes and wine. The pearl net reduced the total flavanol contents in grapes and total aromatic volatiles in wine. The red net increased the total flavanol, tannin and total aromatic volatile contents in wine by approximately 40%, 95% and 10%, respectively, and the percentages for the black net were 30%, 45% and 3%, respectively. The red and pearl nets were more inclined to improve the taste and aroma sensory qualities of wine than the black net did. The red net had the highest comprehensive scores via principal component analysis.

Postharvest Dehydration Temperature Modulates the Transcriptomic Programme and Flavonoid Profile of Grape Berries.

Raisins are a popular and nutritious snack that is produced through the dehydration of postharvest grape berries under high temperature (HT). However, the response of the endogenous metabolism of white grape varieties to postharvest dehydration under different temperature have not been fully elucidated to date. In this study, the white grape cultivar 'Xiangfei' was chosen to investigate the effect of dehydration at 50 °C, 40 °C, and 30 °C on the transcriptomic programme and metabolite profiles of grape berries. Postharvest dehydration promoted the accumulation of soluble sugar components and organic acids in berries. The content of gallic acid and its derivatives increased during the dehydration process and the temperature of 40 °C was the optimal for flavonoids and proanthocyanidins accumulation. High-temperature dehydration stress might promote the accumulation of gallic acid by increasing the expression levels of their biosynthesis related genes and regulating the production of NADP+ and NADPH. Compared with that at 30 °C, dehydration at 40 °C accelerated the transcription programme of 7654 genes and induced the continuous upregulation of genes related to the heat stress response and redox homeostasis in each stage. The results of this study indicate that an appropriate dehydration temperature should be selected and applied when producing polyphenols-rich raisins.

Long Non-Coding RNAs: Potential Biomarkers and Targets for Hepatocellular Carcinoma Therapy and Diagnosis.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Increasing studies showed that long non-coding RNAs (lncRNAs), a novel class of RNAs that are greater than 200 nucleotides in length but lack the ability to encode proteins, exert crucial roles in the occurrence and progression of HCC. LncRNAs promote the proliferation, migration, invasion, autophagy, and apoptosis of tumor cells by regulating downstream target gene expression and cancer-related signaling pathways. Meanwhile, lncRNA can be used as biomarkers to predict the efficacy of HCC treatment strategies, such as surgery, radiotherapy, chemotherapy, and immunotherapy, and as a potential individualized tool for HCC diagnosis and treatment. In this review, we overview up-to-date findings on lncRNAs as potential biomarkers for HCC surgery, radiotherapy, chemotherapy resistance, target therapy, and immunotherapy, and discuss the potential clinical application of lncRNA as tools for HCC diagnosis and treatment.

Does Having a Usual Primary Care Provider Reduce Polypharmacy Behaviors of Patients With Chronic Disease? A Retrospective Study in Hubei Province, China.

Background: Within China's hierarchical medical system, many patients seek medical care in different hospitals independently without integrated management. As a result, multi-hospital visiting is associated with fragmented service utilization and increased incidence of polypharmacy behaviors, especially for patients with chronic disease. It has been confirmed that factors from the perspective of patients may cause polypharmacy behaviors in Chinese community patients; whether having a usual primary care provider for chronic disease patients could reduce the polypharmacy behaviors and the effect size remains unanswered, and that is what our study aimed to answer. Methods: Our study adopted a cluster sampling method to select 1,196 patients with hypertension or diabetes and measured some information about them. The propensity score weighting method was adopted to eliminate the influence of confounding bias, and then a multivariate logistic regression model was conducted to test the relationship between having a usual primary care provider and polypharmacy behaviors. Results: Patients without usual primary care providers were significantly correlated with polypharmacy behaviors (OR = 2.40, 95%CI: 1.74-3.32, p < 0.001), and the corresponding marginal effect is 0.09 (95%CI: 0.06-0.12). Patients who suffer from two kinds of diseases (OR = 3.05, 95%CI: 1.87-5.10, p < 0.001), with more than three kinds of diseases (OR = 21.03, 95%CI: 12.83-35.65, p < 0.001), with disease history of 20 years and above (OR = 1.66, 95%CI: 1.14-2.42, p = 0.008), who communicate frequently with doctors (OR = 3.14, 95%CI: 1.62-6.19, p < 0.001), alcoholic patients (OR = 2.14, 95%CI: 1.08-4.19, p = 0.027), who used to have meat-based food (OR = 1.42, 95%CI: 1.00-2.00, p = 0.049), and have vegetarian-based diet (OR = 1.42, 95%CI: 1.00-2.00, p = 0.049) are more likely to have polypharmacy behaviors, while patients aged between 65 and 75 years (OR = 0.50, 95%CI: 0.33-0.77, p = 0.020), used to be brain workers (OR = 0.67, 95%CI: 0.45-0.99, p = 0.048), with disease history between 10 and 20 years (OR = 0.56, 95%CI: 0.37-0.83, p = 0.005), have had adverse drug reactions (OR = 0.64, 95%CI: 0.45-0.93, p = 0.019), and participated in medical insurance for urban and rural residents (OR = 0.35, 95%CI: 0.21-0.58, p < 0.001) were less likely to have polypharmacy behaviors. Conclusion: The results suggest that having a usual primary care provider may reduce the incidence of having polypharmacy behaviors; we can take intervention measures to promote establishing a long-term relationship between patients and primary care providers.

Foliar Phenylalanine Application Promoted Antioxidant Activities in Cabernet Sauvignon by Regulating Phenolic Biosynthesis.

The effects of foliar phenylalanine application during veraison (FPV) on phenolic biosynthesis and correlation between phenolic compositions and antioxidant activities in Cabernet Sauvignon grown in field and greenhouse were investigated. Solutions with 69 and 138 mg N/vine phenylalanine (Pe1 and Pe2, respectively) and an aqueous solution without nitrogen (CK) were sprayed three times during veraison. FPV significantly improved antioxidant activities in grapes using the two culture methods. The most contributory phenolic compositions to antioxidant activities were anthocyanins and stilbenes following FPV compared with CK. Phenylalanine metabolism, abscisic acid content, and expression levels of VvPAL, VvCHS, VvF3H, VvUFGT, and VvSTS in the phenolic synthesis pathway were increased from the first FPV to harvest. Although Pe2 significantly increased total phenolic contents than Pe1, antioxidant parameters were not markedly affected by the phenylalanine dose. Our finding revealed that FPV was a useful fertilization method to enhance antioxidant activities in grapes in nitrogen-deficient vineyards.

Metabolic and molecular analysis of nonuniform anthocyanin pigmentation in tomato fruit under high light.

Pigment intensity and patterns are important factors that determine the nutritional and market values of tomato fruits. The acropetal manner of light-dependent anthocyanin accumulation with the highest levels at the stem end of the fruit makes Pro35S:BrTT8 tomato plants an ideal system for investigating the effects of light intensity on anthocyanin biosynthesis. Extensive transcript analyses indicate that anthocyanin pigmentation in Pro35S:BrTT8 plants under high light might be coordinately regulated by the exogenous protein BrTT8 and endogenous proteins SlAN2 and SlMYBL2. Furthermore, yeast two-hybrid assays showed that BrTT8 could interact efficiently with SlAN2, SlMYBL2, and SlAN11. Moreover, the physical interaction between BrTT8 and SlAN2 was validated by FRET. Simultaneous overexpression of SlAN2 and BrTT8 activated significant anthocyanin biosynthesis in infiltrated tobacco leaves. In addition, the ability of SlMYBL2 to suppress anthocyanin accumulation was also demonstrated in infiltrated tobacco leaves. Altogether, these results prove that tissue-specific assemblage of the heterogeneous MYB-bHLH-WD40 complex consisting of SlAN2, BrTT8 and SlAN11 triggers nonuniform anthocyanin accumulation in tomato fruit under high light. Additionally, it is proposed that a negative-feedback loop fulfilled by SlMYBL2 also participates in the regulation of anthocyanin production.

Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment.

Tumor cells along with a small proportion of cancer stem cells exist in a stromal microenvironment consisting of vasculature, cancer-associated fibroblasts, immune cells and extracellular components. Recent epidemiological and clinical studies strongly support that vitamin D supplementation is associated with reduced cancer risk and favorable prognosis. Experimental results suggest that vitamin D not only suppresses cancer cells, but also regulates tumor microenvironment to facilitate tumor repression. In this review, we have outlined the current knowledge on epidemiological studies and clinical trials of vitamin D. Notably, we summarized and discussed the anticancer action of vitamin D in cancer cells, cancer stem cells and stroma cells in tumor microenvironment, providing a better understanding of the role of vitamin D in cancer. We presently re-propose vitamin D to be a novel and economical anticancer agent.