Abstract
Keratin 18 (KRT18), one of the most abundant keratins in epithelial and endothelial cells, has been reported to be aberrantly expressed in many malignancies and extensively regarded as a biomarker and important regulator in multiple cancers, including gastric cancer (GC). But the molecular regulatory mechanisms of KRT18 in GC patients and cells are largely unknown. In the present study, we analyzed the expression level of KRT18 in 450 stomach adenocarcinoma tissue samples from TCGA database and found a significantly higher expression level in tumor tissues. We then explored the potential functions of KRT18 in AGS cells (human gastric adenocarcinoma cell line) by KRT18 knockdown using siRNA and whole transcriptome RNA-seq analysis. Notably, KRT18 selectively regulates expression of cell proliferation and apoptotic genes. Beyond this, KRT18 affects the alternative splicing of genes enriched in apoptosis, cell cycle, and other cancer-related pathways, which were then validated by reverse transcription–quantitative polymerase chain reaction approach. We validated KRT18-KD promoted apoptosis and inhibited proliferation in AGS cells. We then used RNA-seq data of GC samples to further demonstrate the modulation of KRT18 on alternative splicing regulation. These results together support the conclusion that KRT18 extensively modulates diverse alternative splicing events of genes enriched in proliferation and apoptosis processes. And the dysregulated splicing factors at transcriptional or posttranscriptional level by KRT18 may contribute to the alternative splicing change of many genes, which expands the functional importance of keratins in apoptotic and cell cycle pathways at the posttranscriptional level in GC.
Highlights
Gastric cancer (GC) is one of the most common and deadly neoplasms in the world, with the fifth incidence and the third mortality in all cancers around the world, following lung and colorectal cancer (Van Cutsem et al, 2016; Rawla and Barsouk, 2019; Thrift and El-Serag, 2020)
The results showed that keratin 18 (KRT18) selectively regulates expression of cell proliferation and apoptosis genes and affects the alternative splicing (AS) of pre-mRNAs from hundreds of genes, enriched in cancerrelated pathways, which were validated by reverse transcription– quantitative polymerase chain reaction (RT-qPCR) approach
Among the staged 415 tumor tissue samples according to the standard of National Comprehensive Cancer Network stage, the expression of KRT18 was significantly up-regulated in most tumor stages, more pronouncedly in late stages (Supplementary Figure 1A)
Summary
Gastric cancer (GC) is one of the most common and deadly neoplasms in the world, with the fifth incidence and the third mortality in all cancers around the world, following lung and colorectal cancer (Van Cutsem et al, 2016; Rawla and Barsouk, 2019; Thrift and El-Serag, 2020). The main risk factors of GC include dietary factors and Helicobacter pylori infection. Studies have revealed that H. pylori infection is an important cause of the gastritis before most GCs (Loor and Dumitrascu, 2016; Van Cutsem et al, 2016). H. pylori infection was reported to trigger GC by multiple pathogenic mechanisms, including endoplasmic reticulum stress and the unfolded protein response, autophagy, oxidative stress, and inflammation (Amieva and Peek, 2016; Diaz et al, 2018). It was reported that HER2 positivity is associated with worsening prognosis, increased disease invasiveness, and shortened survival time in approximately 12–20% of GCs (Gravalos and Jimeno, 2008; Van Cutsem et al, 2015). It is very important to identify molecular markers and therapeutic targets to improve the effectiveness of GC treatment
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