Circular RNA LARP4 correlates with decreased Enneking stage, better histological response, and prolonged survival profiles, and it elevates chemosensitivity to cisplatin and doxorubicin via sponging microRNA‐424 in osteosarcoma

Abstract

Background This study aimed to evaluate the association of circular RNA La‐related RNA‐binding protein 4 (circ‐LARP4) with clinical features and prognosis in osteosarcoma patients, and further explore its effect on chemosensitivity in osteosarcoma cells. Methods Seventy‐two osteosarcoma patients with Enneking stage IIA‐IIB who underwent resection were consecutively enrolled, and then, tumor tissues and non‐tumor tissues were obtained. Circ‐LARP4 in tumor tissue/non‐tumor tissue was detected by quantitative polymerase chain reaction. After circ‐LARP4 overexpression and negative control overexpression plasmid transfection, relative cell viability (%) was evaluated by Cell Counting Kit‐8 in MG63 cells treated by different concentrations of cisplatin, methotrexate, and doxorubicin, and IC50 was calculated. Results Circ‐LARP4 was downregulated in tumor tissue compared with non‐tumor tissue and had a good value in distinguishing tumor tissue from non‐tumor tissue with an area under curve of 0.829 (95% CI: 0.762‐0.859). Meanwhile, tumor circ‐LARP4 was negatively correlated with the Enneking stage. After resection, circ‐LARP4 high expression patients showed an increased tumor cell necrosis rate to adjuvant chemotherapy compared to circ‐LARP4 low expression patients, and circ‐LARP4 high expression correlated with prolonged disease‐free survival and overall survival. In vitro experiments revealed that circ‐LARP4 overexpression elevated the chemosensitivity of MG63 cells to cisplatin and doxorubicin but not methotrexate, with decreased cisplatin IC50 and doxorubicin IC50 concentrations than negative control. Besides, miR‐424 overexpression attenuated the chemosensitivity in circ‐LARP4 overexpression‐treated MG63 cells. Conclusion Circ‐LARP4 high expression correlates with decreased Enneking stage and prolonged survival profiles, and it elevates chemosensitivity to cisplatin and doxorubicin via sponging miR‐424 in osteosarcoma.

Diagnostic and Prognostic Significance of Dysregulated Expression of Circular RNAs in Osteosarcoma

“…Moreover, 22 studies were further eliminated with a variety of reasons, including ve studies not related to circRNAs or osteosarcoma, six studies did not report outcomes, two reviews and case reports, four animal studies, and ve lack of extractable data. Finally, 26 studies comprising 1,652 osteosarcoma cases were enrolled in this quantitative study, with 18 on clinicopathological features, ten on diagnosis [13,18,19,21,24,[30][31][32][33][34] [12,14,18,19,[32][33][34][36][37][38][39][40], whereas other two studies on downregulated circRNAs applying ≥ 18 or < 18 years old to separate enrolled patients [13,30]. In consideration of the consistency, only these studies with common cut-off value were included in the following meta-analysis with regard to patients' age.…”

“…CircRNAs were regarded as oncogenes or tumor-suppressor in terms of their expression levels. Speci cally, 21 circRNAs were identi ed as oncogenic circRNAs with upregulated expression pattern [12, 14, 16-23, 31-34, 36, 37, 39-43], while the other ve were recognized as tumor suppressors [13,24,30,35,38] with downregulated expression, respectively. The duration for follow-up ranged from 40 to 125.…”

“…The duration for follow-up ranged from 40 to 125. For diagnostic assay, ten studies with data on sensitivity, speci city and AUC [13,18,19,21,24,[30][31][32][33][34]. The quality of studies was evaluated by QUADAS II and NOS scores.…”

“…Nowadays, circRNAs have attracted the researches attention as potential biomarkers and therapeutic targets in carcinomas, which are attributed to their abundance in tissues, structural stability and tissuespeci c expression pro le [9]. More recently, emerging studies have highlighted the role of circRNAs in osteosarcoma [12][13][14][15][16][17][18][19]. CircRNAs are reported to modulate osteosarcoma malignant properties including cell proliferation, apoptosis, migration and resistance to chemotherapy [12,20,21].…”

“…CircRNAs could interact with cancer-related signaling pathway, such as Akt/GSK-3β, and wnt/β-catenin pathway, or act as a ceRNA to sponge miRNA and consequently regulate target genes in osteosarcoma progression [12,22,23]. Moreover, a growing number of evidences showed that dysregulated circRNAs are closely correlated with survival outcome and clinicopathological parameters including clinical stage, chemo-sensitivity, and metastasis [13,23,24]. However, the clinical prognostic and diagnostic signi cance of circRNAs may be jeopardized due to the controversial results as well as limited sample size in previous studies.…”