The N6-methyladenosine modification of circALG1 promotes the metastasis of colorectal cancer mediated by the miR-342-5p/PGF signalling pathway.

BACKGROUND: Previous studies have shown that the N6-methyladenosine (m6A) modification enhances the binding ability of mRNAs/long noncoding RNAs (lncRNAs) to microRNAs (miRNAs), but the impact of this modification on the competitive endogenous RNA (ceRNA) function of circular RNAs (circRNAs) is unclear. METHODS: We used a human circRNA microarray to detect the expression profiles of circRNAs in 3 pairs of cancer and paracancerous tissues from patients with colorectal cancer (CRC) and 3 pairs of peripheral blood specimens from patients with CRC and healthy individuals. The circRNAs highly expressed in both peripheral blood and tumour tissues of patients with CRC, including circALG1, were screened. A quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis of an expanded sample size was performed to detect the expression level of circALG1 in peripheral blood and tumour tissues of patients with CRC and determine its correlation with clinicopathological features, and circRNA loop-forming validation and stability assays were then conducted. Transwell assays and a nude mouse cancer metastasis model were used to study the function of circALG1 in CRC and the role of altered m6A modification levels on the regulation of circALG1 function. qRT-PCR, western blot (WB), Transwell, RNA-binding protein immunoprecipitation (RIP), RNA antisense purification (RAP), and dual-luciferase reporter gene assays were performed to analyse the ceRNA mechanism of circALG1 and the effect of the m6A modification of circALG1 on the ceRNA function of this circRNA. RESULTS: CircALG1 was highly expressed in both the peripheral blood and tumour tissues of patients with CRC and was closely associated with CRC metastasis. CircALG1 overexpression promoted the migration and invasion of CRC cells, and circALG1 silencing and reduction of the circALG1 m6A modification level inhibited CRC cell migration and invasion. In vivo experiments further confirmed the prometastatic role of circALG1 in CRC. Further mechanistic studies showed that circALG1 upregulated the expression of placental growth factor (PGF) by binding to miR-342-5p and that m6A modification enhanced the binding of circALG1 to miR-342-5p and promoted its ceRNA function. CONCLUSION: M6A modification enhances the binding ability of circALG1 to miR-342-5p to promote the ceRNA function of circALG1, and circALG1 could be a potential therapeutic target in and a prognostic marker for CRC.

Intergenic CircRNA Circ_0007379 Inhibits Colorectal Cancer Progression by Modulating miR-320a Biogenesis in a KSRP-Dependent Manner.

Circular RNAs (circRNAs) are covalently closed RNA structures that play multiple roles in tumorigenesis and progression. Compared with exon‒intron circRNAs, the biological functions and implications of intergenic circRNAs in human cancer are still poorly understood. Here, we performed circRNA microarray analysis and identified an intergenic circRNA, circ_0007379, that was significantly downregulated in patients with colorectal cancer (CRC). The biogenesis of circ_0007379 was mediated by reverse complementary matches (RCMs) and was negatively regulated by the RNA helicase DHX9. Functionally, circ_0007379 suppressed CRC cell growth and metastasis in cell culture as well as in patient-derived organoid and xenograft models. Mechanistically, circ_0007379 acted as a scaffold to facilitate the processing of both pri-miR-320a and pre-miR-320a in a KSRP-dependent manner, leading to miR-320a maturation and subsequent repression of transcription factor RUNX1 expression. Thus, our findings establish a previously unrecognized function of circRNA in inhibiting CRC progression.

Ursolic Acid Protects Neurons in Temporal Lobe Epilepsy and Cognitive Impairment by Repressing Inflammation and Oxidation.

Temporal lobe epilepsy (TLE) is characterized as an impaired ability of learning and memory with periodic and unpredictable seizures. Status epilepticus (SE) is one of the main causes of TLE. Neuroinflammation and oxidative stress are directly involved in epileptogenesis and neurodegeneration, promoting chronic epilepsy and cognitive deficit. Previous studies have shown that ursolic acid (UA) represses inflammation and oxidative stress, contributing to neuroprotection. Herein, we demonstrated that UA treatment alleviated seizure behavior and cognitive impairment induced by epilepsy. Moreover, UA treatment rescued hippocampal neuronal damage, aberrant neurogenesis, and ectopic migration, which are commonly accompanied by epilepsy occurrence. Our study also demonstrated that UA treatment remarkably suppressed the SE-induced neuroinflammation, evidenced by activated microglial cells and decreased inflammation factors, including TNF-α and IL-1ß. Likewise, the expression levels of oxidative stress damage markers and oxidative phosphorylation (OXPHOS) enzyme complexes of mitochondria were also remarkably downregulated following the UA treatment, suggesting that UA suppressed the damage caused by the high oxidative stress and the defect mitochondrial function induced by SE. Furthermore, UA treatment attenuated GABAergic interneuron loss. In summary, our study clarified the notable anti-seizure and neuroprotective properties of UA in pilocarpine-induced epileptic rats, which is mainly achieved by abilities of anti-inflammation and anti-oxidation. Our study indicates the potential advantage of UA application in ameliorating epileptic sequelae.

Penoscrotal extramammary Paget's disease: a review of 33 cases in a 20-year experience.

Extramammary Paget's disease in men most frequently involves the penoscrotal area. The uncertainty of the outcome and of the relationship to the underlying adnexal carcinoma and associated internal malignancy still exists. From 1982 to 2001, 33 patients with penoscrotal extramammary Paget's disease were treated and followed up. Therapeutic modalities included carbon dioxide laser ablation (two patients) and local wide excision (31 patients). Split-thickness skin graft (22 patients), local scrotal flap (six patients), and primary closure (three patients) were utilized to reconstruct the penoscrotal defects after local wide excision. An underlying adnexal carcinoma occurred in seven of 33 patients (21.2 percent). The incidence of associated internal malignancy was 9.1 percent (three of 33 patients), including one concurrently and two nonconcurrently associated malignancies. Eight of 33 patients had local recurrence, representing an incidence of 24.2 percent. Three patients (9.1 percent) had distant metastasis and ultimately died of metastatic carcinoma. Of these patients, 31 were grouped according to the degrees of involvement: limited to the epidermis (group 1, n = 14), involvement of the adnexal gland and/or hair follicle (group 2, n = 10), and the presence of an underlying adnexal carcinoma (group 3, n = 7). Local wide excision with subsequent reconstruction by split-thickness skin graft was favored in this series. Patients with an underlying adnexal carcinoma or pathological invasion of the dermis (group 2 or 3) had a worse prognosis than patients without. From this study, it is difficult to address the particular relationship between the outcome and the associated internal malignancy.