FOXP3-regulated lncRNA NONHSAT136151 promotes colorectal cancer progression by disrupting QKI interaction with target mRNAs.

The role of lncRNAs in the pathogenesis of cancer, including colorectal cancer (CRC), has repeatedly been demonstrated. However, very few lncRNAs have been well annotated functionally. Our study identified a novel lncRNA upregulated in CRC, NONHSAT136151, which was correlated with clinical progression. In functional assays, NONHSAT136151 significantly enhanced CRC cell proliferation, migration and invasion. Mechanistically, NONHSAT136151 interacted with RNA-binding protein (RBP) QKI (Quaking) to interfere with QKI binding to target mRNAs and regulate their expression. As well, FOXP3 may be causally related to the dysregulation of NONHSAT136151 in CRC cells through its transcriptional activity. In conclusion, our findings identified a novel lncRNA regulated by FOXP3 participates in CRC progression through interacting with QKI, indicating a novel lncRNA-RBP interaction mechanism is involved in CRC pathogenesis.

PRR15 deficiency facilitates malignant progression by mediating PI3K/Akt signaling and predicts clinical prognosis in triple-negative rather than non-triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast neoplasms with a higher risk of recurrence and metastasis than non-TNBC. Nevertheless, the factors responsible for the differences in the malignant behavior between TNBC and non-TNBC are not fully explored. Proline rich 15 (PRR15) is a protein involved in the progression of several tumor types, but its mechanisms are still controversial. Therefore, this study aimed to investigate the biological role and clinical applications of PRR15 on TNBC. PRR15 gene was differentially expressed between TNBC and non-TNBC patients, previously described as an oncogenic factor in breast cancer. However, our results showed a decreased expression of PRR15 that portended a favorable prognosis in TNBC rather than non-TNBC. PRR15 knockdown facilitated the proliferation, migration, and invasive ability of TNBC cells in vitro and in vivo, which was abolished by PRR15 restoration, without remarkable effects on non-TNBC. High-throughput drug sensitivity revealed that PI3K/Akt signaling was involved in the aggressive properties of PRR15 silencing, which was confirmed by the PI3K/Akt signaling activation in the tumors of PRR15Low patients, and PI3K inhibitor reversed the metastatic capacity of TNBC in mice. The reduced PRR15 expression in TNBC patients was positively correlated with more aggressive clinicopathological characteristics, enhanced metastasis, and poor disease-free survival. Collectively, PRR15 down-regulation promotes malignant progression through the PI3K/Akt signaling in TNBC rather than in non-TNBC, affects the response of TNBC cells to antitumor agents, and is a promising indicator of disease outcomes in TNBC.

Identification of MET fusions as novel therapeutic targets sensitive to MET inhibitors in lung cancer.

INTRODUCTION: Alterations in the MET gene, including amplifications and exon 14 skipping mutations, have been identified as actionable oncogenic alterations. However, MET fusions are rarely detected in lung cancer, and their sensitivity to therapeutics has not been systematically analyzed. METHODS: The data from 30876 lung cancer patients from the LAVA database and 7966 patients from cBioPortal database were screened. Basic demographic and clinical information for the patients harboring MET fusions were collected. A lung squamous cell cancer patient harboring a novel EML4-MET fusion was treated with crizotinib. Additionally, a literature review was performed to summarize the cases of patients harboring MET fusions and their treatment information. RESULTS: MET fusions were found in only 0.2% to 0.3% of lung cancer patients and appeared in almost all exons of the MET gene. Intragenic MET fusions were found in 52.6% (41/78) of the included patients. Crizotinib was effective for MET fusions, including a novel identified EML4-MET fusion, even after the failure of multiple lines of treatment. This result suggested that acquired MET fusions become more regionally selective, as they usually occurred in exons encoding the extracellular region. Interestingly, the MET-fused genes in primary MET fusions or acquired MET fusions were very different, which indicated the different functions and influences of the disease. CONCLUSION: MET fusions are rare, and half of the fusion types were intragenic fusions. Lung cancer patients harboring primary or acquired MET fusions could benefit from crizotinib. In addition, EML4-MET was first reported in this study as a novel MET fusion type.

Research progress on the interaction between long non­coding RNAs and RNA­binding proteins to influence the reprogramming of tumor glucose metabolism (Review).

As epigenetic regulators, long non­coding RNAs (lncRNAs) are involved in various important regulatory processes and typically interact with RNA­binding proteins (RBPs) to exert their core functional effects. An increasing number of studies have demonstrated that lncRNAs can regulate the occurrence and development of cancer through a variety of complex mechanisms and can also participate in tumor glucose metabolism by directly or indirectly regulating the Warburg effect. As one of the metabolic characteristics of tumor cells, the Warburg effect provides a large amount of energy and numerous intermediate products to meet the consumption demands of tumor metabolism, providing advantages for the occurrence and development of tumors. The present review article summarizes the regulatory effects of lncRNAs on the reprogramming of glucose metabolism after interacting with RBPs in tumors. The findings discussed herein may aid in the better understanding of the pathogenesis of malignancies, and may provide novel therapeutic targets, as well as new diagnostic and prognostic markers for human cancers.

Research progress in the establishment of pancreatic cancer models and preclinical applications.

Pancreatic cancer (PC) is a highly malignant tumor in the digestive system. The transformation of tissue from normal to pancreatic intraepithelial neoplasm is driven by certain oncogenes, among which the mutation rate of the KRAS gene is as high as 90%. Currently, PC has limited treatment options, low therapeutic effects, and poor prognosis. Thus, more effective methods to combat PC are urgently needed. Some models that can more accurately reflect the biological behaviors and genomic characteristics of PC, such as its morphology, pathology, proliferation, and invasion, are being continuously developed. These include genetic engineering models, orthotopic xenograft models, and heterotopic xenograft models. Using these PC models, scientists have further verified promising drugs and potential therapeutic targets for PC treatment. This is of great significance for limiting the progression of PC with clinical intervention, improving patient outcomes, and improving survival rates.

LAT, HOXD3 and NFE2L3 identified as novel DNA methylation-driven genes and prognostic markers in human clear cell renal cell carcinoma by integrative bioinformatics approaches.

Background: Abnormal DNA methylation of is one of the important mechanisms leading to tumor pathogenesis. The purpose of this study was to explore differentially methylated genes that may drive the development of renal clear cell carcinoma through a comprehensive analysis of the TCGA database. Materials and methods: Methylation data and RNA-seq data for clear cell renal cell carcinoma were downloaded from The Cancer Genome Atlas (TCGA). Differentially methylated genes and the differential genes associated with survival were then screened by MethylMix R package and univariate Cox proportional-hazards model, respectively. Their common genes were then intersected and obtained for further analysis. Correlation of gene expression and methylation levels, gene set enrichment analysis (GSEA) enrichments, survival curve, and ROC curve plotting for DNA methylation-driven genes were finally performed. The methylation alterations of the three genes were validated via two GEO datasets (GSE70303 and GSE113501), and the genes expression level was verified through two GEO datasets (GSE6344 and GSE53757). Results: Three novel DNA methylation-driven genes LAT, HOXD3 and NFE2L3 were identified in clear cell renal cell carcinoma. Expression analysis further revealed that hypomethylation levels of LAT and NFE2L3 showed higher gene expression levels, while HOXD3 exhibited opposite methylation-expression pattern. The CpG sites of LAT (cg16462073), HOXD3 (cg24000528) and NFE2L3 (cg16882373) that may affect respective gene expressions were also identified. For the survival analysis, we found that hypomethylation and over-expression of LAT and NFE2L3 were correlated with poor survival, while hypermethylation and low-expression HOXD3 was correlated with poor survival of clear cell renal cell carcinoma patients. In addition, GSEA KEGG analysis and biological processes of these genes were also enriched for functional analysis. Kaplan-Meier survival and ROC analyses of these genes showed an average risk score of 0.9140593, AUC = 0.692, which suggested a good clinical application value. Finally, the opposite methylation-expression pattern of these three genes were verified in GEO datasets. Conclusions: In this study, we successfully exhibited the potential DNA methylation-driven genes LAT, HOXD3, and NFE2L3 involved in clear cell renal cell carcinoma. Moreover, gene functions and prognostic risk models were also elucidated, which facilitated the expansion of the current study on the role of methylation in the pathology process of clear cell renal cell carcinoma.

Amygdalin inhibits renal fibrosis in chronic kidney disease.

Renal interstitial fibrosis is a common outcome of chronic renal diseases. Amygdalin is one of a number of nitrilosides, the natural cyanide­containing substances abundant in the seeds of plants of the prunasin family that are used to treat cancer and relieve pain. However, whether amygdalin inhibits the progression of renal fibrosis or not remains unknown. The present study aimed to assess the therapeutic potential of amygdalin by investigating its effect and potential mechanism on the activation of renal interstitial fibroblast cells and renal fibrosis in rat unilateral ureteral obstruction (UUO). Treatment of the cultured renal interstitial fibroblasts with amygdalin inhibited their proliferation and the production of transforming growth factor (TGF)­ß1. In the rat model of obstructive nephropathy, following ureteral obstruction, the administration of amygdalin immediately eliminated the extracellular matrix accumulation and alleviated the renal injury on the 21st day. Collectively, amygdalin attenuated kidney fibroblast (KFB) activation and rat renal interstitial fibrosis. These results indicate that amygdalin is a potent antifibrotic agent that may have therapeutic potential for patients with fibrotic kidney diseases.