tRNA modifications: insights into their role in human cancers.

Transfer RNA (tRNA) plays a central role in translation by functioning as a biological link between messenger RNA (mRNA) and proteins. One prominent feature of the tRNA molecule is its heavily modified status, which greatly affects its biogenesis and function. Modifications within the anticodon loop are crucial for translation efficiency and accuracy, whereas other modifications in the body region affect tRNA structure and stability. Recent research has revealed that these diverse modifications are critical regulators of gene expression. They are involved in many important physiological and pathological processes, including cancers. In this review we focus on six different tRNA modifications to delineate their functions and mechanisms in tumorigenesis and tumor progression, providing insights into their clinical potential as biomarkers and therapeutic targets.

METTL14 modulates glycolysis to inhibit colorectal tumorigenesis in p53-wild-type cells.

The frequency of p53 mutations in colorectal cancer (CRC) is approximately 40-50%. A variety of therapies are being developed to target tumors expressing mutant p53. However, potential therapeutic targets for CRC expressing wild-type p53 are rare. In this study, we show that METTL14 is transcriptionally activated by wild-type p53 and suppresses tumor growth only in p53-wild-type (p53-WT) CRC cells. METTL14 deletion promotes both AOM/DSS and AOM-induced CRC growth in mouse models with the intestinal epithelial cell-specific knockout of METTL14. Additionally, METTL14 restrains aerobic glycolysis in p53-WT CRC, by repressing SLC2A3 and PGAM1 expression via selectively promoting m6 A-YTHDF2-dependent pri-miR-6769b/pri-miR-499a processing. Biosynthetic mature miR-6769b-3p and miR-499a-3p decrease SLC2A3 and PGAM1 levels, respectively, and suppress malignant phenotypes. Clinically, METTL14 only acts as a beneficial prognosis factor for the overall survival of p53-WT CRC patients. These results uncover a new mechanism for METTL14 inactivation in tumors and, most importantly, reveal that the activation of METTL14 is a critical mechanism for p53-dependent cancer growth inhibition, which could be targeted for therapy in p53-WT CRC.

Sirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability.

In our previous study, we reported that sirtuin5 (SIRT5), a member of the NAD+-dependent class III histone deacetylase family, is highly expressed in colorectal cancer (CRC). Herein we show that SIRT5 knockdown impairs the production of ribose-5-phosphate, which is essential for nucleotide synthesis, resulting in continuous and irreparable DNA damage and consequently leading to cell cycle arrest and enhanced apoptosis in CRC cells. These SIRT5 silencing-induced effects can be reversed by nucleoside supplementation. Mechanistically, SIRT5 activates transketolase (TKT), a key enzyme in the non-oxidative pentose phosphate pathway, in a demalonylation-dependent manner. Furthermore, TKT is essential for SIRT5-induced malignant phenotypes of CRC both in vivo and in vitro. Altogether, SIRT5 silencing induces DNA damage in CRC via post-translational modifications and inhibits tumor growth, suggesting that SIRT5 can serve as a promising target for CRC treatment.

A specific tRNA half, 5'tiRNA-His-GTG, responds to hypoxia via the HIF1α/ANG axis and promotes colorectal cancer progression by regulating LATS2.

BACKGROUND: Currently, tRNA-derived small RNAs (tsRNAs) are recognized as a novel and potential type of non-coding RNAs (ncRNAs), which participate in various cellular processes and play an essential role in cancer progression. However, tsRNAs involvement in colorectal cancer (CRC) progression remains unclear. METHODS: Sequencing analyses were performed to explore the tsRNAs with differential expression in CRC. Gain- and loss-of functions of 5'tiRNA-His-GTG were performed in CRC cells and xenograft tumor to discover its role in the progression of CRC. Hypoxia culture and hypoxia inducible factor 1 subunit alpha (HIF1α) inhibitors were performed to uncover the biogenesis of 5'tiRNA-His-GTG. The regulation of 5'tiRNA-His-GTG for large tumor suppressor kinase 2 (LATS2) were identified by luciferase reporter assay, western blot, and rescue experiments. RESULTS: Here, our study uncovered the profile of tsRNAs in human CRC tissues and confirmed a specific tRNA half, 5'tiRNA-His-GTG, is upregulated in CRC tissues. Then, in vitro and in vivo experiments revealed the oncogenic role of 5'tiRNA-His-GTG in CRC and found that targeting 5'tiRNA-His-GTG can induce cell apoptosis. Mechanistically, the generation of 5'tiRNA-His-GTG seems to be a responsive process of tumor hypoxic microenvironment, and it is regulated via the HIF1α/angiogenin (ANG) axis. Remarkably, LATS2 was found to be an important and major target of 5'tiRNA-His-GTG, which renders 5'tiRNA-His-GTG to "turn off" hippo signaling pathway and finally promotes the expression of pro-proliferation and anti-apoptosis related genes. CONCLUSIONS: In summary, the findings revealed a specific 5'tiRNA-His-GTG-engaged pathway in CRC progression and provided clues to design a novel therapeutic target in CRC.

Relationship between serrated polyps and synchronous and metachronous advanced neoplasia: A retrospective study.

OBJECTIVE: Serrated polyps (SP) are regarded as precursor lesions of colorectal cancer (CRC). We conducted this single-center study aiming to investigate the relationship between SP and synchronous and metachronous advanced neoplasia in the Chinese population. METHODS: The data for this retrospective study were collected from the Endoscopy Center and Department of Gastroenterology of Renji Hospital, School of Medicine, Shanghai Jiao Tong University between May 2012 and May 2019. Altogether 2205 patients were pathologically confirmed with colorectal SP. RESULTS: The detection rate of SP among all polyps has gradually increased since 2014 and reached 8.74% by 2019. Among all the SP cases, 1540 (69.84%) were confirmed as having hyperplasic polyps (HP), 486 (22.04%) were having sessile serrated lesions (SSL), and 171 (7.76%) had traditional serrated adenomas (TSA). Compared with HP (2.14%), SSL and TSA were larger and more likely to be accompanied by synchronous and metachronous advanced neoplasia (6.79% and 6.08%). We next found that large SP (diameter ≥10 mm) (odds ratio [OR] 2.52, 95% confidence interval [CI] 1.40-4.55, P = 0.002) and SSL with high-grade intraepithelial neoplasia (OR 13.85, 95% CI 3.28-58.56, P < 0.001) were associated with an increased risk of synchronous advanced neoplasia. However, we failed to find a relationship between SP and metachronous advanced neoplasia because few patients had developed metachronous advanced neoplasia. CONCLUSION: Large SP and SSL with high-grade intraepithelial neoplasia are associated with synchronous advanced neoplasia and require timely surveillance.

tiRNAs: A novel class of small noncoding RNAs that helps cells respond to stressors and plays roles in cancer progression.

tRNA-derived stress-induced RNAs (tiRNAs), important components of tRNA-derived fragments, are gaining popularity for their functions as small noncoding RNAs involved in cancer progression. Under cellular stress, tiRNAs are generated when mature tRNA is specifically cleaved by angiogenin and suggested to act as transducers or effectors involved in cellular stress responses. tiRNAs facilitate cells to respond to stresses mainly via reprogramming translation, inhibiting apoptosis, degrading mRNA, and generating stress granules. This review introduces the cellular biogenesis, molecular mechanisms, and biological roles of tiRNAs in stress response and disease regulation. A better understanding of their roles in regulating cancer may provide novel biomarkers or therapeutic targets for diagnosis and treatment.

Correction to: Case report of cryptogenic multifocal ulcerous stenosing enteritis (CMUSE): a rare isease may contribute to endoscopy-capsule retention in the small intestine.

Following publication of the original article [1], the author reported the wrong version of Table 1 has been published. The word of 'Capsule' was mistakenly written as 'Capusle'.

Case report of cryptogenic multifocal ulcerous stenosing enteritis (CMUSE): a rare disease may contribute to endoscopy-capsule retention in the small intestine.

BACKGROUND: CMUSE is a rare disease whose diagnosis remains difficult because the lesion is confined to the small bowel. CASE PRESENTATION: Here, we present a case of 43-year-old female patient suffered chronic abdominal pain for 20 years, and finally diagnosed with CMUSE. Capsule endoscopy was performed when general endoscopic investigation failed to find the lesion, but the capsule was stranded in the small intestine. Moreover, capsule retention results in acute intestinal obstruction. Thus, surgery was performed and CMUSE was confirmed. The patient was recovered after partial small intestine resection. CONCLUSIONS: Capsule retention occurred in nearly 60% of patients with CMUSE. Capsule endoscopy should be avoided when the patient is suspected of CMUSE, especially with severe anemia and radiologic finding in the ileum.

The Suppressive Effects of the Petroleum Ether Fraction from Atractylodes lancea (Thunb.) DC. On a Collagen-Induced Arthritis Model.

In Chinese traditional medicine, the rhizome of Atractylodes lancea (Thunb.) DC. (A. lancea) is used extensively for the treatment of several diseases such as rheumatic diseases, but its actions on rheumatoid arthritis have not been clarified. The purpose of this article was to investigate the pharmacological effect of an A. lancea rhizome extract on collagen-induced arthritis (CIA) in rats. The CIA model was induced by the injection of bovine type II collagen. The rats were orally administered the petroleum ether (PE) fraction of the A. lancea rhizome (0.82 and 1.64 mg/kg), methotrexate (0.3 mg/kg body weight), or a vehicle from day 7 to day 15 after the model was established. The histological examination and radiological observation showed that the PE fraction significantly reduced the inflammatory responses and collagen loss in the joints of the rats with CIA. The PE fraction inhibited the production of tumor necrosis factor-α, interleukin (IL)-1ß, IL-17, and IL-6 in the sera. Moreover, the treatment with the PE fraction in vivo was able to reduce the level of Beclin 1 protein in the synovial tissue of the rats. These results highlight the antiarthritic potential of the PE fraction of the A. lancea rhizome and provide further evidence of the involvement of Beclin 1 inhibition in the effects of the PE fraction of the A. lancea rhizome. Copyright © 2016 John Wiley & Sons, Ltd.