Long non-coding RNAs: Biogenesis, functions, and clinical significance in gastric cancer

Gastric cancer is one of the most common cancers worldwide, with a bad prognosis associated with late-stage diagnosis, significantly decreasing the overall survival. This highlights the importance of early detection to improve the clinical course of these patients. Although screening programs, based on endoscopic or radiologic approaches, have been useful in countries with high incidence, they are not cost-effective in low-incidence populations as a massive screening strategy. Additionally, current biomarkers used in daily routine are not specific and sensitive enough, and most of them are obtained invasively. Thus, it is imperative to discover new noninvasive biomarkers able to diagnose early-stage gastric cancer. In this context, liquid biopsy is a promising strategy. In this review, we briefly discuss some of the potential biomarkers for gastric cancer screening and diagnosis identified in blood, saliva, urine, stool, and gastric juice.

Biomarkers for Gastric Cancer Screening and Early Diagnosis.

MicroRNAs (miRNAs/miRs) are a class of small non‑coding RNAs that maintain the precise balance of various physiological processes through regulating the function of target mRNAs. Dysregulation of miRNAs is closely associated with various types of human cancer. miR‑222‑3p is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in tumor occurrence and progression. miR‑222‑3p in human biofluids, such as urine and plasma, may be a potential biomarker for the early diagnosis of tumors. In addition, miR‑222‑3p acts as a prognostic factor for the survival of patients with cancer. The present review first summarizes and discusses the role of miR‑222‑3p as a biomarker for diverse types of cancers, and then focuses on its essential roles in tumorigenesis, progression, metastasis and chemoresistance. Finally, the current understanding of the regulatory mechanisms of miR‑222‑3p at the molecular level are summarized. Overall, the current evidence highlights the crucial role of miR‑222‑3p in cancer diagnosis, prognosis and treatment.

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Emerging roles and mechanisms of microRNA‑222‑3p in human cancer (Review)

tRNAs are a group of conventional noncoding RNAs (ncRNAs) with critical roles in the biological synthesis of proteins. Recently, tRNA-derived small RNAs (tsRNAs) were found to have important biological functions in the development of human diseases including carcinomas, rather than just being considered pure degradation material. tsRNAs not only are abnormally expressed in the cancer tissues and serum of cancer patients, but also have been suggested to regulate various vital cancer hallmarks. On the other hand, the application of tsRNAs as biomarkers and therapeutic targets is promising. In this review, we focused on the basic characteristics of tsRNAs, and their biological functions known thus far, and explored the regulatory roles of tsRNAs in cancer hallmarks including proliferation, apoptosis, metastasis, tumor microenvironment, drug resistance, cancer stem cell phenotype, and cancer cell metabolism. In addition, we also discussed the research progress on the application of tsRNAs as tumor biomarkers and therapeutic targets.

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tRNA-derived small RNAs: novel regulators of cancer hallmarks and targets of clinical application.

CircRNAs in gastric cancer: current research and potential clinical implications

Gastric cancer (GC) is one of the most common cancers in the world. Due to the lack of specific symptoms, more than 80% of patients are diagnosed as the advanced stage with a high mortality rate, so the early diagnosis of GC is incredibly essential. Circular RNAs (CircRNAs) are a kind of endogenous non-coding RNA with stable structure, the long half-life, and tumor specificity. It can be used as a diagnostic marker for tumors. Using circRNA sequencing technology screened three pairs of GC and adjacent tissues, and circRNAs with significant expression differences were screened out. The circular structure and characteristics of circPTPN22 were determined by RT-qPCR, agarose gel electrophoresis, Sanger sequencing, RNase R, and actinomycin D assays. Cell Counting Kit‐8, colony formation, Transwell, Wound healing, tumor formation in mice and western blotting assays were used to detect the effects of circPTPN22 on the proliferation, invasion, migration, tumor growth of GC cells in vitro and protein expression. CircPTPN22 is up-regulated and positively correlated with metastasis in GC tissues, cells, and plasma. RT-qPCR results showed that circPTPN22 had good diagnostic efficacy and could be used to predict the prognosis of GC patients. In vitro and vivo experiments showed that the downregulation of circPTPN22 could inhibit cell proliferation, migration, and invasion through the epithelial-mesenchymal transformation (EMT) pathway. CircPTPN22 may regulate GC progression through the competitive binding of miRNAs. CircPTPN22 can be used as a potential diagnostic and prognostic marker for GC and can inhibit cell proliferation and metastasis through the competitive binding of miRNA to inhibit the EMT pathway.

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As a biomarker for gastric cancer, circPTPN22 regulates the progression of gastric cancer through the EMT pathway.

Background: Gastric cancer (GC) is one of the most common malignant tumors globally and the third leading cause of cancer-related death. Currently, the sensitivity and specificity of diagnostic markers for GC are low, so it is urgent to find new biomarkers with higher sensitivity and specificity. tRNA-derived small RNAs are a kind of small non-coding RNAs derived from tRNAs. It is abundant in cancer cells and body fluids. Our goal is to find the differentially expressed tRNA-derived small RNAs in GC to explore their potential as a GC biomarker. Methods: Quantitative real-time PCR was used to detect the expression level of hsa_tsr016141. The molecular characteristics of hsa_tsr016141 were verified by agarose gel electrophoresis, Sanger sequencing, Actinomycin D Assay, and Nuclear and Cytoplasmic RNA Separation Assay. The diagnostic efficiency of hsa_tsr016141 was analyzed through receiver operating characteristic. Results: The expression level of hsa_tsr016141 in GC tissues and serum was significantly increased. The serum expression level showed a gradient change between GC patients, gastritis patients, and healthy donors and was positively correlated with the degree of lymph node metastasis and tumor grade. ROC analysis showed that the serum expression level of hsa_tsr016141 could significantly distinguish GC patients from healthy donors or gastritis patients. Besides, the expression level of hsa_tsr016141 in GC patients decreased significantly after the operation (P<0.0001). Conclusions: Serum hsa_tsr016141 has good stability and specificity and can be used for dynamic monitoring of GC patients, suggesting that serum hsa_tsr016141 can be a novel biomarker for GC diagnosis and postoperative monitoring.

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Serum hsa_tsr016141 as a Kind of tRNA-Derived Fragments Is a Novel Biomarker in Gastric Cancer

Abstract Gastric cancer (GC) is one of the most common tumors worldwide and the leading cause of tumor-related mortality. Endoscopy and serological tumor marker testing are currently the main methods of GC screening, and treatment relies on surgical resection or chemotherapy. However, traditional examination and treatment methods are more harmful to patients and less sensitive and accurate. A minimally invasive method to respond to GC early screening, prognosis monitoring, treatment efficacy, and drug resistance situations is urgently needed. As a result, liquid biopsy techniques have received much attention in the clinical application of GC. The non-invasive liquid biopsy technique requires fewer samples, is reproducible, and can guide individualized patient treatment by monitoring patients' molecular-level changes in real-time. In this review, we introduced the clinical applications of circulating tumor cells, circulating free DNA, circulating tumor DNA, non-coding RNAs, exosomes, and proteins, which are the primary markers in liquid biopsy technology in GC. We also discuss the current limitations and future trends of liquid biopsy technology as applied to early clinical biopsy technology. 

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Clinical application and detection techniques of liquid biopsy in gastric cancer

Gastric cancer (GC) is one of the diseases that endanger human health with high morbidity and mortality. The positive rates of traditional biomarkers in the diagnosis of GC are low, so it is necessary to find biomarkers with high sensitivity to increase the detection rate. tRNA-derived small RNAs (tsRNAs) are novel small non-coding RNAs with specific biological functions and aberrant expression in cancer. In this study, we focused on the potential of tRNA-derived small RNAs as GC biomarkers.The differentially expressed tsRNAs in three pairs of GC tissues were screened with high-throughput sequencing and verified using the TCGA database and Quantitative real-time PCR. The methodological evaluation of tRF-23-Q99P9P9NDD was verified by agarose gel electrophoresis, RIN evaluation, and Sanger sequencing. The Chi-square test was used to evaluate the relationship between the tRF-23-Q99P9P9NDD expression and clinicopathological parameters. Kaplan-Meier survival analysis was used to evaluate the effect of the tRF-23-Q99P9P9NDD expression on survival. Additionally, the receiver operating characteristic curve (ROC) was used to evaluate the diagnostic efficacy of tRF-23-Q99P9P9NDD in GC.Differential expression of serum tRF-23-Q99P9P9NDD could distinguish GC patients from gastritis patients and healthy donors. Chi-square test showed that high expression of tRF-23-Q99P9P9NDD was significantly associated with T stage, lymph node metastasis, TNM stage, and nerve/vascular invasion. Kaplan-Meier curve showed that patients with high expression of tRF-23-Q99P9P9NDD had a lower survival rate than patients with low expression of this biomarker. ROC analysis showed that, compared with conventional biomarkers, the efficacy of tRF-23-Q99P9P9NDD was higher, which was improved by the combination of biomarkers, and even in the early stages. Finally, we preliminarily predicted the downstream of tRF-23-Q99P9P9NDD in GC cells.The expression of tRF-23-Q99P9P9NDD in GC serum can identify GC patients, and it has higher efficacy than conventional biomarkers even in the early stages. Furthermore, tRF-23-Q99P9P9NDD can monitor the postoperative conditions of GC patients. 

/pdf/evaluation-of-serum-trf-23-q99p9p9ndd-as-a-potential-l21a24uu.pdf

Evaluation of serum tRF-23-Q99P9P9NDD as a potential biomarker for the clinical diagnosis of gastric cancer

Gastric cancer (GC) is considered one of the most common gastrointestinal malignancies worldwide. Circular RNAs (circRNAs) are a new class of endogenous noncoding RNAs, which can be used as biomarkers and therapeutic targets for many tumors. However, the role and potential regulatory mechanisms of circRNAs in GC remain unclear. In this study, we demonstrated that a specific circRNA, circHAS2, was upregulated in GC tissues and cells and was positively correlated with tumor metastasis. In vitro experiments demonstrated that circHAS2 knockdown or the addition of hsa-miR-944 mimics inhibited the proliferation, migration, and invasion ability of GC cells and affected the epithelial-mesenchymal transition. In addition, hsa-miR-944 interacted with protein phosphatase, Mg2+/Mn2+-dependent 1E (PPM1E), and was found to be a target gene of circHAS2. The upregulation of PPM1E reversed the effects of circHAS2 knockout on GC cells. The circHAS2/hsa-miR-944/PPM1E axis may be involved in the progression of GC; thus, circHAS2 may be a potential biomarker and therapeutic target for GC.

/pdf/circhas2-promotes-the-proliferation-migration-and-invasion-4zn4as51fo.pdf

Xinliang Gu

Papers

As a biomarker for gastric cancer, circPTPN22 regulates the progression of gastric cancer through the EMT pathway.

Serum hsa_tsr016141 as a Kind of tRNA-Derived Fragments Is a Novel Biomarker in Gastric Cancer

Clinical application and detection techniques of liquid biopsy in gastric cancer

Evaluation of serum tRF-23-Q99P9P9NDD as a potential biomarker for the clinical diagnosis of gastric cancer

CircHAS2 promotes the proliferation, migration, and invasion of gastric cancer cells by regulating PPM1E mediated by hsa-miR-944.