Despite continuous improvements in research and new cancer therapeutics, the goal of eradicating cancer remains elusive because of drug resistance. For a long time, drug resistance research has been focused on tumor cells themselves; however, recent studies have found that the tumor microenvironment also plays an important role in inducing drug resistance. Cancer-associated fibroblasts (CAFs) are a main component of the tumor microenvironment. They cross-talk with cancer cells to support their survival in the presence of anticancer drugs. This review summarizes the current knowledge of the role of CAFs in tumor drug resistance. An in-depth understanding of the mechanisms underlying the cross-talk between CAFs and cancer cells and insight into the importance of CAFs in drug resistance can guide the development of new anticancer strategies.

As the most critical alternative splicing regulator, heterogeneous nuclear ribonucleoproteins (hnRNPs) have been reported to be implicated in various aspects of cancer. However, the comprehensive understanding of hnRNPs in cancer is still lacking. The molecular alterations and clinical relevance of hnRNP genes were systematically analysed in 33 cancer types based on next‐generation sequence data. The expression, mutation, copy number variation, functional pathways, immune cell correlations and prognostic value of hnRNPs were investigated across different cancer types. HNRNPA1 and HNRNPAB were highly expressed in most tumours. HNRNPM, HNRNPUL1, and HNRNPL showed high mutation frequencies, and most hnRNP genes were frequently mutated in uterine corpus endometrial carcinoma (UCEC). HNRNPA2B1 showed widespread copy number amplification across various cancer types. HNRNPs participated in cancer‐related pathways including protein secretion, mitotic spindle, G2/M checkpoint, DNA repair, IL6/JAK/STAT3 signal and coagulation, of which hnRNP genes of HNRNPF, HNRNPH2, HNRNPU and HNRNPUL1 are more likely to be implicated. Significant correlation of hnRNP genes with T help cells, NK cells, CD8 positive T cells and neutrophils was identified. Most hnRNPs were associated with worse survival of adrenocortical carcinoma (ACC), liver hepatocellular carcinoma (LIHC) and lung adenocarcinoma (LUAD), whereas hnRNPs predicted better prognosis in kidney renal clear cell carcinoma (KIRC) and thymoma (THYM). The prognosis analysis of KIRC suggested that hnRNPs gene cluster was significantly associated with overall survival (HR = 0.5, 95% CI = 0.35‐0.73, P = 0.003). These findings provide novel evidence for further investigation of hnRNPs in the development and therapy of cancer in the future.

Background: Aberrant expression of N6-methyladenosine (m6A) RNA modification regulators plays a critical role in a variety of human diseases. However, their implication in abdominal aortic aneurysm (AAA) remains largely unknown. Herein, we sought to explore the general expression pattern and potential functions of m6A regulators in AAA. Methods: We analyzed gene expression data of m6A regulators in human AAA and normal tissues from public GEO database. The R package and other tools such as m6A2Target database, Gene ontology (GO) functional and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses, gene set variation analysis (GSVA), Search Tool for the Retrieval of Interacting Genes (STRING), starBase, miRDB and Cytoscape software were applied for bioinformatics analysis to investigate the downstream molecular mechanisms and upstream regulatory mechanisms for distinctly expressed regulators. Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were performed to validate the expression of key m6A regulators in our collected human AAA specimens. Results: We found that METTL14 and HNRNPC were the downregulated m6A regulators, and RBM15B was the upregulated methylation transferase in human AAA. The modified genes were primarily enriched in RNA catabolic process, regulation of translation, focal adhesion, transcription coregulator activity, ribosome, RNA transport, cell cycle, et al. METTL14, HNRNPC and RBM15B levels were correlated with the immune infiltration degree of Tcm, macrophages, mast cells, Tgd and NK CD56bright cells. A total of 154 and 76 target genes of three regulators were separately involved in body metabolism and autophagy in AAA disease, and their interactive relationships and hub genes were identified. The lncRNA-miRNA-mRNA interaction regulatory networks were also constructed for METTL14, HNRNPC and RBM15B. Based on our clinical tissue and serum samples, METTL14 exhibited lower expression levels in AAA and its rupture type, and low METTL14 expression was associated with high levels of WBC and CRP (all P < 0.05). Conclusion: Our study presents an overview of the expression pattern and functional significance of m6A regulators in human AAA. Our findings will provide a valuable resource that may guide both mechanistic and therapeutic analyses about the role of key m6A regulators in AAA.

Background. Although multiple types of cancers demonstrated favorable outcome after immunotherapy of PD‐1/PD‐L1 blockade, the specific regulatory mechanism of PD genes in gastric cancer (GC) remains largely unknown. Materials and Methods. Expression of RNA, copy number variants, and clinical parameters of GC individuals from TCGA were analyzed. Coexpressed genes for PD‐1, PD‐L1, and PD‐L2 were selected by correlation analysis and confirmed by STRING. Gene Ontology and KEGG pathway analyses were performed by clusterProfiler. The influence of PD‐1/PD‐L1/PD‐L2 on immune cell infiltration was investigated by MCP‐counter. Results. PD‐L2 demonstrated significant relation with clinical stage of GC (P = 0.043). Survival analysis showed that PD‐1 expression was correlated with better prognosis of GC patients (HR = 0.70, P = 0.031), but PD‐L2 expression was related with worse survival (HR = 1.42, P = 0.032). Mutation of PIK3CA could alter the level of PD‐1, PD‐L1, and PD‐L2 (P < 0.001), and TP53 mutation demonstrated significant correlation with PD‐L1 (P = 0.015) and PD‐L2 (P = 0.014) expression. Enrichment analysis of PD‐1/PD‐L1/PD‐L2 coexpressed genes indicated a biological process of mononuclear cell proliferation, leukocyte cell‐cell adhesion, and lymphocyte activation as well as KEGG pathways including cell differentiation of Th1 and Th2, cell differentiation of Th17, and hematopoietic cell landscape. As for immune infiltration analysis, PD‐1 was mainly related with cytotoxic lymphocytes and endothelial cells; PD‐L1 were associated with monocytic lineage; PD‐L2 showed significant correlation with myeloid dendritic cells. Conclusion. PD‐1 expression showed association with better prognosis of GC, and PD‐L2 expression was related with worse survival. Mutations of PIK3CA and TP53 significantly correlated with PD‐1/PD‐L1/PD‐L2 axis. PD‐1/PD‐L1/PD‐L2 coexpressed genes demonstrated enrichment in mononuclear cell proliferation, leukocyte cell‐cell adhesion, and lymphocyte activation as well as KEGG pathways including cell differentiation of Th1, Th2, and Th17.