Circ-ITCH correlates with less advanced tumor features as well as prolonged survival, and it inhibits cells proliferation but promotes apoptosis in non-small cell lung cancer

Abstract

Background: This study was to investigate the correlation of circ-ITCH expression with tumor features, disease free survival (DFS) and overall survival (OS) in non-small cell lung cancer (NSCLC) patients, and the effect of its dysregulation on cells proliferation and apoptosis of NSCLC cells. Methods: Tumor tissue and paired adjacent normal tissue samples from 190 surgical NSCLC patients were collected and used for detecting circ-ITCH expression by qPCR. Circ-ITCH expression was also measured in normal pulmonary epithelial cell line and 4 NSCLC cell lines by qPCR. Patients' baseline characteristics were recorded and DFS as well as OS were calculated. Blank, circ-ITCH overexpression, blank shRNA, circ-ITCH shRNA plasmids were transferred into NSCLC cell line (A549 cells) as NC(+), Circ-ITCH(+), NC(−) and Circ-ITCH(−) groups. Cells proliferation was measured using CCK-8 and cells apoptosis rate was measured using annexin V (AV)/propidium iodide (PI). Results: Circ-ITCH expression was decreased in tumor tissue compared with paired adjacent tissue, and was negatively correlated with tumor size, lymph node metastasis and TNM stage. And circ-ITCH high expression was associated with favorable DFS and OS. In vitro experiments revealed that compared with normal pulmonary epithelial cell line BEAS-2B, circ-ITCH expression was reduced in NSCLC cell lines HCC827, A549, NCI-H1299 and NCI-H460. And cells proliferation was decreased in Circ-ITCH(+) group and elevated in Circ-ITCH(−) group at 72 h. Cells apoptosis rate was increased in Circ-ITCH(+) group and decreased in Circ-ITCH(−) group at 72 h. Conclusions: Circ-ITCH associates with less advanced tumor features and prolonged survival, and it inhibits cells proliferation while promotes cells apoptosis in NSCLC.

CircRNA ITCH: Insight Into Its Role and Clinical Application Prospect in Tumor and Non-Tumor Diseases

“…These findings imply that reduced circ-ITCH expression was associated with lower overall survival (OS) and disease-free survival (DFS). Specifically, decrease in circ-ITCH was associated with worse OS (p = 0.018) and DFS (p = 0.017) in MM patients (Zhou et al, 2020); in NSLC, its downregulation was correlated with worse OS (p = 0.006) and DFS (p = 0.001) (Li et al, 2019); in PCa, its down-regulation was correlated with worse OS and DFS (both p < 0.001) (Huang et al, 2019); in EOC, its down-regulation was correlated with worse OS (p = 0.003) (Luo et al, 2018a). Furthermore, 1604 patients with various malignancies were included in a meta-analysis, which yielded the same results.…”

“…Furthermore, the expression of circ-ITCH has been linked to tumor size, tumor grade, TNM stage and clinical stage. Specifically, in OC, the expression of circ-ITCH was linked to tumor size (p = 0.0009) and clinical stage (p = 0.0021) (Lin et al, 2020); in TNBC, it was linked to tumor size (p = 0.016), lymphatic metastasis (p = 0.008) and clinical stage (p = 0.002) (Wang S. et al, 2019); in OSCC, it was correlated with clinical stage (p = 0.027) and lymphatic metastasis (p = 0.035) (Hao et al, 2020); in EOC, it was associated with tumor size (p = 0.005) and International Federation of Gynecology and Obstetrics (FIGO) stage (p < 0.001) (Luo et al, 2018a); in GC, it was correlated with tumor grade (p = 0.02), T stage (p = 0.0216) and lymphatic metastasis (p = 0.034) (Ghasemi et al, 2019;Peng and Wang, 2020;Wang et al, 2021); in NPC, it was correlated with lymphatic metastasis (p = 0.0021), clinical stage (p = 0.0028) and bone metastasis (p = 0.0285) (Wang et al, 2022); in non-small cell lung cancer (NSCL), it was linked to tumor size (p < 0.001), lymphatic metastasis (p < 0.001) and clinical stage (p = 0.003) (Li et al, 2019); in MM, it was correlated with international staging system (ISS) stage (p = 0.036) (Zhou et al, 2020). Guo et al (2017), on the other hand, discovered that the single nucleotide polymorphisms rs10485505 and rs4911154 of circ-ITCH were strongly related with an elevated risk of HCC, suggesting that it might be employed as a biomarker for HCC susceptibility.…”

Silencing of circ_0088036 inhibits growth and invasion of lung adenocarcinoma through miR‐203/SP1 axis

“…[ 10 ] For example, circ‐ITCH expressions are reduced in LUAD cells, and overexpression of circ‐ITCH reduces LUAD cell proliferation. [ 11 ] Hsa_circ_0007385 is significantly amplified in LUAD tissues and cells, and restrains LUAD cell metastasis by miR‐181. [ 12 ] Circ_0088036 is a recently discovered circRNAs and is abnormally expressed in rheumatoid arthritis and regulates fibroid synovial cell proliferation and migration.…”

Prognostic and Clinicopathological Significance of Circular RNA circ-ITCH Expression in Cancer Patients: A Meta-analysis

“…Recently, circular RNA Itchy E3 ubiquitin protein ligase (circ-ITCH), a novel circular RNA originated from exons of gene itchy E3 ubiquitin protein ligase (ITCH), located on chromosome 20q11.22, was reported to be lower expressed in several cancers [ 18 ]. So far, circ-ITCH has been proved to be implicated in prostate cancer [ 19 , 20 ], ovarian cancer [ 21 – 24 ], bladder cancer [ 25 ], breast cancer [ 26 ], lung cancer [ 27 ], oral squamous cell carcinoma [ 28 ], gastric cancer [ 29 ], hepatocellular carcinoma [ 30 ], glioma [ 31 ], and multiple myeloma [ 32 ]. Accumulating evidence has implied that circ-ITCH exert tumor-suppressor function in these cancers by acting as a sponge for oncogenic microRNAs.…”