- Research
- Open access
- Published:
Altered expression of serum lncRNA CASC2 and miRNA-21-5p in COVID-19 patients
Human Genomics volume 18, Article number: 18 (2024)
Abstract
Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has a high incidence of spread. On January 30, 2020, the World Health Organization proclaimed a public health emergency of worldwide concern. More than 6.9 million deaths and more than 768 million confirmed cases had been reported worldwide as of June 18, 2023. This study included 51 patients and 50 age- and sex-matched healthy subjects. The present study aimed to identify the expression levels of lncRNA CASC2 and miRNA-21-5p (also known as miRNA-21) in COVID-19 patients and their relation to the clinicopathological characteristics of the disease. The expression levels of noncoding RNAs were measured by RT-PCR technique. Results detected that CASC2 was significantly downregulated while miRNA-21-5p was significantly upregulated in COVID-19 patients compared to healthy subjects. A significant negative correlation was found between CASC2 and miRNA-21-5p. ROC curve analysis used to distinguish COVID-19 patients from controls. MiRNA-21-p serum expression level had a significant positive association with temperature and PO2 (p = 0.04 for each). These findings indicate that CASC2 and miRNA-21-p might be used as potential diagnostic and therapeutic biomarkers in COVID-19.
Introduction
The coronavirus disease 2019 (COVID-19) was originated in China in December 2019 as a result of the most recent human-infectious and pathogenic coronavirus which known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1, 2].
Following virus exposure, signaling cascades that result in the release of type I interferons, cytokines, and chemokines start the inflammatory response to COVID-19 [3]. Inflammasomes, multimeric protein complexes that are crucial for causing inflammation with the subsequent start of an adaptive immune response, are also activated by this initial exposure [4].
The effects of SARS-CoV-2 infection can range widely, from asymptomatic illness to potentially fatal lung disease combined with peripheral abnormalities [5]. Acute respiratory distress syndrome (ARDS) is a presenting symptom in severely affected patients who have lung injury, thromboembolic diseases, cardiovascular, cardiac, gastrointestinal dysregulation, and/or liver or kidney dysfunction [6].
LncRNAs are noncoding RNAs (ncRNAs) that are expressed endogenously and have a length greater than 200 nucleotides. LncRNAs act as regulatory molecules that mediate host–virus interactions [7]. Previous researches have demonstrated different lncRNAs that are connected to the occurrence and progression of COVID-19 disease [8,9,10,11,12].
LncRNA cancer susceptibility candidate 2 (CASC2) is located on chromosome 10q26. It functions as a tumor suppressor gene that can prevent cell growth, invasion, and metastasis while encouraging cell death in a variety of human cancers, including stomach cancer, papillary thyroid cancer, and pancreatic carcinoma [13]. Previous research has shown that lncRNA CASC2 prevents inflammation and sepsis-induced multi-organ damage through a variety of signaling pathways [14, 15].
MicroRNAs (miRNAs) are a family of tiny noncoding RNAs that range in length from 18 to 23 nucleotides. They regulate gene expression by attaching to a particular location in the 3′-untranslated region (3′-UTR) or open reading frame (ORF) to either degrade mRNA or prevent its translation [16]. Host-induced miRNAs can operate as pro- or antiviral factors, or they might assist the virus to evade immune response [17]. Studies have shown that SARS-CoV-2 enters host cells through penetration, and then, the virus releases its particles through exocytosis [18]. Additionally, microRNA plays a vital role in the development of both innate and adaptive immune cells by fine-tuning cell activities. Furthermore, host miRNAs have been reported to play a part in the cytokine storm linked to a SARS-CoV-2 infection [19]. A few of these miRNAs may be important regulators of mediators related to inflammation as well as inhibition of SARS-CoV-2 genome expression. [20,21,22].
MiRNA-21-5p (previously known as MiRNA-21) is a common miRNA that participates in numerous regulatory pathways and shows altered circulation levels in cancer and other illnesses, and the knowledge of its functions may help in developing new approaches to therapeutic intervention [23].
There is growing evidence suggesting that lncRNAs can function as competing endogenous RNAs (ceRNAs) by sponging miRNAs. They control the ability of miRNAs to prevent mRNAs from being translated into proteins [24]. Prior research has shown that in the colorectal cancer cell line [25] and the cervical cancer cell line [26], lncRNA CASC2 acts as a ceRNA to regulate miR-21. In our study, we revealed the expression profile of lncRNA CASC2 and miRNA-21-5p in cases with COVID-19 and explored their association with each other and with the clinicopathological manifestations of patients.
Materials and method
Subjects
Our study is a case control study conducted on 51 COVID-19 patients [29 males and 22 females]. A healthcare professional took nasopharyngeal samples and analyzed them for COVID-19 by real-time reverse transcription polymerase chain reaction (rRT-PCR). The rRT-PCR detection kits used for the patients in this study were manufactured by Certest Biotec. Co., Spain. Cases were chosen from the Internal Medicine and Chest departments of Egypt’s Fayoum University Hospital. Fifty healthy participants (30 males and 20 females) with negative COVID-19 PCR results made up the study’s negative control group. Before collecting samples, all participants gave their informed agreement, and the study obtained ethics committee approval from Fayoum University (R224).
The CT quantitative assessment was based on adding up the acutely affected areas in each of the five lung lobes, which were graded from 0 to 4 in the following ways:: 0 = (0%), 1 = (1–25%), 2 = (26–50%), 3 = (51–75%), or 4 = (76–100%). The overall score, which varies from 0 to 20, is the sum of the points from each lobe. Four categories of total severity scores (TSS) were analyzed: none (0), mild (1–5), moderate (6–10), and severe (11–20) [27].
Chest X-Ray Scoring System (CXR score 18): the lungs were divided into six regions by two lines. Depending on the degree of the lung lesion, each location received a score ranging from 0 to 3. Score 0 for normal lung; 1 for interstitial infiltrates; 2 for interstitial and alveolar infiltrates combined (interstitial dominant); and 3 for alveolar and interstitial infiltrates combined (alveolar dominant). The six lung zones are scored, with scores ranging from 0 to 18 [28]. Then, patients are divided into 4 groups based on their overall CXR score, as follows: normal (group score of 0), mild (group score of 1–6), moderate (group score of 7–12), and severe (group score of 13–18) [29], by these new scoring system, COVID-19 patients’ disease severity can be determined.
Routine tests
All patients underwent routine laboratory tests, such as complete blood counts (CBC), liver and kidney functions, blood gases, PH, S. Na, S. K, random blood glucose, and lactate dehydrogenase (LDH).
RNA extraction
By utilizing a miRNeasy extraction kit (Qiagen, Valencia, CA, USA), total RNA was isolated from the serum. RNA's quantity and quality were assessed using the NanoDropâ„¢ 2000 (Thermo Scientific, USA).
Reverse transcription reactions
Following the manufacturer's instructions, RT2 first strand kit (Qiagen, Maryland, USA) was utilized for the synthesis of cDNA from the extracted RNA. In Addition, the miScript II RT Kit from Qiagen in Valencia, California, USA, was used to analyze the expression of miRNA in accordance with the protocol rules.
Quantitative Real-time PCR
These reactions were achieved using RT2 SYBR Green PCR kit (Qiagen, Maryland, USA) for LncRNA CASC2 expression while miScript SYBR Green PCR kit (Qiagen, Valencia, CA, USA) for the detection of miRNA-21-5p.
The LncRNA CASC2 RefSeq Accession number was NR_026939. GAPDH served as an internal control for measuring CASC2 expression level [30].
Moreover, the miR-21-5p catalog number was MS0009079. SNORD 68 was used as an internal reference for miR-21-5p. After analysis of the data using the quantification of the cycle threshold (CT), relative expression of LncRNA CASC2 and miR-21-5p was calculated using the Eq. 2−ΔΔCt. Fold change (FC) values less than 1 indicate downregulation, while fold change values more than 1 indicate upregulation of noncoding RNAs [31, 32]. Control FC values were put as 1.
Statistical analysis
The acquired data were statistically analyzed using SPSS software, version 22. For quantitative data, the mean, median, standard deviation (SD), and interquartile range (IQR) were calculated. Unpaired t-test was used to compare basic characteristics between the study groups. The Mann–Whitney-U test or the Kruskal–Wallis test was used to compare CASC2 and miRNA-21 (Log2) between the two groups or the three groups, respectively. The significance of qualitative data, which were presented as numbers and percentages, was assessed using the Chi-square [2] test. Spearman correlation was used to ascertain the association between the research parameters and LncRNA CASC2 and miRNA-21 (Log2). A ROC curve was used to identify the cutoff values for LncRNA CASC2 and miRNA-21 (Log2) as predictors in differentiating between cases and controls that had the maximum sensitivity and specificity. The cutoff for statistical significance was set at P < 0.05.
The sample size was calculated using (G power version 3.0.10). Minimal sample size of patients was at least 45 in each group assuming a power level of 0.80, alpha level of 0.05, and medium effect size of 0.6 between the two groups of the study for the study biomarkers.
Results
Clinical and demographic evaluation of the study groups
In this study, 50 people served as the controls, whereas 51 COVID-19-infected individuals were included. The average age of the patients was 60.63 ± 10.63 years, compared to 57.4 ± 7.39 years as the average age for the control group. Age and sex did not significantly differ between cases and controls (Table 1).
Regarding HB, ALT, AST, and creatinine, COVID-19 patients and the healthy group showed statistically significant differences (all P < 0.05). (Table 1). Table 2 identifies other clinical information about patients. Patients infected with the SARS-CoV-2 virus had median (IQR) serum expression levels of CASC2 of 0.7 (0.26–0.97) and miRNA-21 (log2) of 8.04 (5.06–10.15) (Fig. 1). When compared to controls, patients had significantly lower levels of LncRNA CASC2 and significantly higher levels of miRNA-21, both with a p-value < 0.001.
Relation of the serum levels of LncRNA CASC2 and miR-21-5p with demographic, clinical, and laboratory variables of COVID-19 patients
Table 3 shows that PEEP (positive end-expiratory pressure) versus CPAP (continuous positive airway pressure), and CPAP versus mechanical ventilation were significantly associated with miRNA-21-5p serum expression level, p = 0.01. Furthermore, CXR18 (Chest X-Ray) Scoring System was significantly related to the expression level of miRNA-21-5p, p = 0.009.
Correlation of LncRNA CASC2 and miRNA-21-5p serum expression levels with characteristics of COVID-19 patients
LncRNA CASC2 and miRNA-21-5p serum expression levels had a significant negative association with each other (p = 0.012). miRNA-21-5p level had a significant positive correlation with temperature and PO2 (p = 0.04 for each) (Table 4).
Diagnostic performance of CASC2 and miRNA-21-5p in COVID-19.
ROC curve showed that CASC2 can discriminate COVID-19 patients from healthy people (AUC = 0.784, 95% CI (0.674–0.895), p < 0.001) with a sensitivity of 76.5% and a specificity of 100% at a cutoff > 0.987 (fold). Serum miRNA-21-5p also identify COVID-19 patients from healthy controls (AUC = 1.00, 95% CI (1–1), p < 0.001) with a sensitivity and specificity of 100% for each of them at a cutoff point 1.19 (fold) (Table 5, Fig. 2).
Discussion
In COVID-19 disease, LncRNAs have been implicated in a growing number of biological regulatory processes, including immune disorders, thrombosis, and a severe inflammatory response [33,34,35]. But these lncRNAs’ features and how they work in COVID-19 remain unclear [36].
Previous research have shown that the long noncoding RNA (lncRNA) cancer susceptibility candidate gene 2 (CASC2), which is found on chromosome 10 of the human genome, inhibits inflammation and sepsis-induced multi-organ damage through a variety of signaling pathways, and inflammation caused by the NF-kB signaling pathway was observed to be inhibited by the lncRNA CASC2 in human renal tubular epithelial cells [37]. Similar to the previous study, it was found that miR-545-3p/PPAR axis modulation via the overexpression of lncRNA CASC2 protects against acute lung injury and damage to human or embryonic kidney cells caused by lipopolysaccharides [38, 39]. Based on the aforementioned supporting data, the lncRNA CASC2 was thought to have potential as a biomarker for inflammation control. Nevertheless, few investigations have shown that. Consequently, the purpose of this study aimed to investigate for the first time the involvement of lncRNA CASC2 in COVID-19. We reported that lncRNA CASC2 was significantly downregulated in COVID-19 patients than in healthy controls.
LncRNAs may behave as ceRNAs that influence the concentration and biological activity of miRNAs, according to previous studies [40, 41]. The function of CASC2 as a ceRNA of miRNA-21 was identified via bioinformatics analysis. It has been established that lncRNA CASC2 is one of miRNA-21’s primary target genes. In a sequence-specific manner, miRNA-21 was able to reduce the expression of CASC2 [42, 43].
When compared to healthy participants, miRNA-21-5p expression levels were markedly increased in COVID-19 patients. Furthermore, a strikingly negative correlation between CASC2 and miRNA-21-5p expression levels in the serum of COVID-19 patients was observed.
The authors revealed increased levels of miRNA-21 in acute COVID-19-infected individuals when compared with patients had Influenza-acute respiratory distress syndrome and healthy subjects [23]. In addition, a positive association was detected between the expression level of miRNA-21 and the number of intensive care unit (ICU) days on extracorporeal membrane oxygenation or ventilation and dialysis. In accordance with a study done by Dingsdag et al. we detected a negative correlation but without significance between miRNA-21 expression level and levels of lactate dehydrogenase enzyme (LDH) [44]. Interestingly, the upregulation of fibrosis associated miRNA-21 in COVID-19 survivors might be a predictor of inflammation and chronic myocardial damage [45].
It was determined that miRNA-21 has binding sites on coronaviruses. Thus, as a result of SARS-CoV-2 infection, the expression levels of miRNA-21 in blood may change [46]. Thus, understanding its behavior could help to develop new approaches to therapeutic interventions [23, 47].
As a result of SARS-CoV-2 lung infection, Nersisyan et al. found that miR-21-3p is eightfold upregulated. According to reports, SARS-CoV-2 properly interacts with host miR-21-3p in the early stages of infection to block the host’s immune response by directly binding to the viral genome, delaying the immune response and enhancing viral survival and reproduction [48]. IL-17, a proinflammatory cytokine involved in the pathophysiology of various autoimmune disorders, can be increased by miRNA-21 [49].
Notably, the expression of miRNA-21 may provide promising SARS-CoV-2 infection diagnostic value. Additionally, because of the presence of antiviral miRNAs and antibodies, it has been shown that patients with COVID-19 can be treated using plasma from persons who have recovered from SARS-CoV-2 infection. Additionally, nasal spray or drops can be utilized to provide nano-based miRNA vaccinations. Due to the respiratory system being the frequent initial site for SARS-CoV-2 viral entry, the nasal spray variant of the nano-vaccine appears to be more effective against COVID-19 illness [50].
Regarding the clinical data, 21.6% of the patients was on PEEP, 37.3% on mask, 7.8% on CPAP, 33.3% on mechanical ventilation, 45% of the patients have ground-glass opacification (GGO). A cytokine storm that damages alveolar structures due to dysregulated immune systems can facilitate the virus’s entry into vascular endothelial cells through the blood–air barrier. Endothelial dysfunction increases the pulmonary arteries' rigidity and vulnerability as the disease progresses, which eventually leads to thrombosis and microvessel obstruction in alveolar capillaries, which may result in hypoxemia or pulmonary hypertension [51].
Multifocal ground-glass opacity (GGO) with rounded morphology with characteristic bilateral peripheral distribution is the classic chest CT result for COVID-19 pneumonia. This finding can be linked to consolidation and crazy-paving patterns [52]. In addition, traction bronchiectasis and vascular dilatation are common GGO findings in COVID-19 patients [53].
Conclusion
We demonstrated for the first time that lncRNA CASC2 is downregulated in the serum of COVID-19 patients, which is probably protective against SARS-CoV-2 infection. According to our research, patients with COVID-19 may benefit from the therapeutic use of the lncRNA CASC2. Despite the relatively limited number of patients included in this research, our study provides a starting point for more extensive research which should be used to examine the long-term prognosis of COVID-19 patients.
Data availability
All relevant data are included in the article.
References
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.
Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, Si H-R, Zhu Y, Li B, Huang C-L, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–3.
V’kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol. 2021;19:155–70.
Shanmugam C, Mohammed AR, Ravuri S, Luthra V, Rajagopal N, Karre S. COVID-2019—a comprehensive pathology insight. Pathol Res Pract. 2020;216:153222.
Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol. 2020;92:424–32.
Freeman TL, Swartz TH. Targeting the NLRP3 Inflammasome in Severe COVID-19. Front Immunol. 2020;11:1518. https://doi.org/10.3389/fimmu.2020.01518.
Peng X, Gralinski L, Armour CD, Ferris MT, Thomas MJ, Proll S, et al. Unique signatures of long noncoding RNA expression in response to virus infection and altered innate immune signaling. MBio. 2010;1(5):e00206-e210.
Cheng J, Zhou X, Feng W, Jia M, Zhang X, An T, et al. Risk stratification by long non-coding RNAs profiling in COVID-19 patients. J Cell Mol Med. 2021;25(10):4753–64.
Chattopadhyay P, Mishra P, Mehta P, Soni J, Gupta R, Tarai B, et al. Transcriptomic study reveals lncRNA-mediated downregulation of innate immune and inflammatory response in the SARS-CoV-2 vaccination breakthrough infections. Front Immunol. 2022;13:1035111.
Cheng J, Zhou X, Feng W, Jia M, Zhang X, An T, et al. Risk stratification by long non-coding RNAs profiling in COVID-19. J Cell Mol Med. 2021;25(10):4753–64.
Ding J, Yin X, Chen J, Zhou J. Current understanding on long non-coding RNAs in immune response to COVID-19. Virus Res. 2022;323:198956.
Enguita FJ, Leitão AL, McDonald JT, Zaksas V, et al. The interplay between lncRNAs, RNA-binding proteins and viral genome during SARS-CoV-2 infection reveals strong connections with regulatory events involved in RNA metabolism and immune response. Theranostics. 2022;12(8):3946–62.
Palmieri G, Paliogiannis P, Sini MC, Manca A, Palomba G, Doneddu V, Tanda F, Pascale MR, Cossu A. Long non-coding RNA CASC2 in human cancer. Crit Rev Oncol Hematol. 2017;111:31–8.
Lu F, Hong Y, Liu L, et al. Long noncoding RNAs: a potential target in sepsis-induced cellular disorder. Exp Cell Res. 2021;406(2):112756.
Zhu L, Shi D, Cao J, Song L. LncRNA CASC2 alleviates sepsis-induced acute lung injury by regulating the miR-152-3p/PDK4 Axis. Immunol Invest. 2021;1–15:1–15.
Fani M, Zandi M, Rezayi M, Khodadad N, Langari H, Amiri I. The role of microRNAs in viral infections. Curr Pharm Des. 2018;24(39):4659–67.
Khan MA, Sany MRU, Islam A, Islam MS. Epigenetic regulator miRNA pattern differences among SARS-CoV, SARS-CoV-2, and SARS-CoV-2 worldwide isolates delineated the mystery behind the epic pathogenicity and distinct clinical characteristics of pandemic COVID-19. Front Genet. 2020;11:765.
Tang T, Bidon M, Jaimes JA, Whittaker GR, Daniel S. Coronavirus membrane fusion mechanism offers a potential target for antiviral development. Antivir Res. 2020;178:104792.
Giannella A, Riccetti S, Sinigaglia A, Piubelli C, Razzaboni E, Di Battista P, Agostini M, Molin ED, Manganelli R, Gobbi F, et al. Circulating microRNA signatures associated with disease severity and outcome in COVID-19 patients. Front Immunol. 2022;13:4409.
Fernández-Pato A, Virseda-Berdices A, Resino S, Ryan P, MartÃnez-González O, Pérez-GarcÃa F, Martin-Vicente M, Valle-Millares D, Brochado-Kith O, Blancas R, et al. Plasma miRNA profile at COVID-19 onset predicts severity status and mortality. Emerg Microbes Infect. 2022;11:676–88.
Jankovic M, Nikolic D, Novakovic I, Petrovic B, Lackovic M, Santric-Milicevic M. miRNAs as a potential biomarker in the COVID-19 infection and complications course, severity, and outcome. Diagnostics. 2023;13:1091.
Mohamed HA, Abdelkafy AE, Khairy RMM, et al. MicroRNAs and cytokines as potential predictive biomarkers for COVID-19 disease progression. Sci Rep. 2023;13:3531.
Garg A, Seeliger B, Derda AA, Xiao K, Gietz A, Scherf K, Sonnenschein K, Pink I, Hoeper MM, Welte T, Bauersachs J, David S, Bär C, Thum T. Circulating cardiovascular microRNAs in critically ill COVID-19 patients. Eur J Heart Fail. 2021;23(3):468–75. https://doi.org/10.1002/ejhf.2096.
Thomson DW, Dinger ME. Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet. 2016;17(5):272–83.
Simonian M, Sharifi M, Nedaeinia R, Mosallaie M, Khosravi S, Avan A, Ghayour-Mobarhan M, Bagheri H, Salehi R. Evaluation of miR-21 inhibition and its impact on cancer susceptibility candidate 2 long noncoding RNA in the colorectal cancer cell line. Adv Biomed Res. 2018;7:14.
Feng Y, Zou W, Hu C, Li G, Zhou S, He Y, Ma F, Deng C, Sun L. Modulation of CASC2/miR-21/PTEN pathway sensitizes cervical cancer to cisplatin. Arch Biochem Biophys. 2017;623–624:20–30.
Chung M, Bernheim A, Mei X, et al. CT imaging features of 2019 novel coronavirus (2019-nCoV). Radiology. 2020. https://doi.org/10.1148/radiol.2020200230.
Borghesi A, Zigliani A, Masciullo R, et al. Radiographic severity index in COVID-19 pneumonia: relationship to age and sex in 783 Italian patients. Radiol Medica. 2020;125(5):461–4. https://doi.org/10.1007/s11547-020-01202-1.
Abo-Hedibah SA, Tharwat N, Elmokadem AH. Is chest X-ray severity scoring for COVID-19 pneumonia reliable? Pol J Radiol. 2021;86:e432–9.
Shaker OG, Abdelaleem OO, Mahmoud RH, Abdelghaffar NK, Ahmed TI, Said OM, et al. Diagnostic and prognostic role of SerummiR-20b, miR-17-3p, HOTAIR, and MALAT1 in diabetic retinopathy. IUBMB Life. 2019;71:310–20.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-DeltaDeltaC(T)) method. Methods. 2001;25:402–8.
Shaker OG, Abdelwahed MY, Ahmed NA, et al. Evaluation of serum long noncoding RNA NEAT and MiR-129–5p in hepatocellular carcinoma. IUBMB Life. 2019;71:1571–8.
Schmitz SU, Grote P, Herrmann BG. Mechanisms of long noncoding RNA function in development and disease. Cell Mol Life Sci. 2016;73(13):2491–509. https://doi.org/10.1007/s00018-016-2174-5.
Beermann J, Piccoli M-T, Viereck J, Thum T. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol Rev. 2016;96(4):1297–325. https://doi.org/10.1152/physrev.00041.2015.
Wang J, Zhang Y, Li Q, Zhao J, Yi D, Ding J, et al. Influenza virus exploits an interferon-independent lncRNA to preserve viral RNA synthesis through stabilizing Viral RNA polymerase PB1. Cell Rep. 2019;27(11):3295-304.e3294. https://doi.org/10.1016/j.celrep.2019.05.036.
Yang Q, Lin F, Wang Y, Zeng M, Luo M. Long noncoding RNAs as emerging regulators of COVID-19. Front Immunol. 2021;12:700184.
Wang M, Wei J, Shang F, Zang K, Ji T. Long non−coding RNA CASC2 ameliorates sepsis−induced acute kidney injury by regulating the miR −155 and NF−kb pathway. Int J Mol Med. 2020;45:1554–62. https://doi.org/10.3892/ijmm.2020.4518.
Li H, Shi H, Gao M, Ma N, Sun R. Long non-coding RNA CASC2 improved acute lung injury by regulating miR-144-3p/AQP1 axis to reduce lung epithelial cell apoptosis. Cell Biosci. 2018;8:15. https://doi.org/10.1186/s13578-018-0205-7.
Hu Q, Zen W, Zhang M, Wang Z, Cui W, Liu Y, et al. Long non-coding RNA CASC2 overexpression ameliorates sepsis-associated acute kidney injury by regulating MiR-545-3p/PPARA Axis. J Surg Res. 2021;265:223–32. https://doi.org/10.1016/j.jss.2021.03.047.
Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, Tramontano A, Bozzoni I. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 2011;147:358–69.
Liu XH, Sun M, Nie FQ, Ge YB, Zhang EB, Yin DD, Kong R, Xia R, Lu KH, Li JH, et al. Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer. 2014;13:92.
Cao Y, Renfang Xu, Xianlin Xu, Zhou Y, Cui Li, He X. Downregulation of lncRNA CASC2 by microRNA-21 increases the proliferation and migration of renal cell carcinoma cells. Mol Med Rep. 2016;14(1):1019–25.
Pan L, Chen H, Bai Y, Wang Q, Chen L. Long non-coding RNA CASC2 serves as a ceRNA of microRNA21 to promote PDCD4 expression in oral squamous cell carcinoma. Onco Targets Ther. 2019;12:3377–85. https://doi.org/10.2147/OTT.S198970.
Dingsdag SA, Clay OK, Quintero GA. COVID-19 severity, miR-21 targets, and common human genetic variation. Letter regarding the article ‘Circulating cardiovascular microRNAs in critically ill COVID-19 patients.’ Eur J Heart Fail. 2021;23(11):1986–7.
Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Soutschek J, Koteliansky V, Rosenwald A, Basson MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J, Engelhardt S. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signaling in fibroblasts. Nature. 2008;456:980–4.
Zeberg H, Pääbo S. The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature. 2020;587:610–2.
Wang H, Tan Z, Hu H, Liu H, Wu T, Zheng C, Wang X, Luo Z, Wang J, Liu S, Lu Z, Tu J. microRNA21 promotes breast cancer proliferation and metastasis by targeting LZTFL1. BMC Cancer. 2019;19:738.
Nersisyan S, Engibaryan N, Gorbonos A, Kirdey K, Makhonin A, Tonevitsky A. Potential role of cellular miRNAs in coronavirus-host interplay. PeerJ. 2020;8:9994. https://doi.org/10.7717/peerj.9994.
Mai J, Virtue A, Maley E, Tran T, Yin Y, Meng S, Pansuria M, Jiang X, Wang H, Yang XF. MicroRNAs and other mechanisms regulate interleukin-17 cytokines and receptors. Front Biosci. 2012;4:1478–95. https://doi.org/10.2741/474.
Fani M, Zandi M, Ebrahimi S, Soltani S, Abbasi S. The role of miRNAs in COVID-19 disease. Future Virol. 2021. https://doi.org/10.2217/fvl-2020-0389.
Xiang M, et al. Persistent lung injury and prothrombotic state in long COVID. Front Immunol. 2022;13:862522.
Bernheim A, Mei X, Huang M, Yang Y, Fayad Z. CT imaging features of 2019 novel coronavirus (2019-nCoV). Radiology. 2020;295(1):200463.
Zhao W, Zhong Z, Xie X, Yu Q, Liu J. Relation between chest CT findings and clinical conditions of coronavirus disease (COVID-19) pneumonia: a multicenter study. Am J Roentgenol. 2020;214(5):1072–7.
Funding
Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). No financial support is relevant to this study.
Author information
Authors and Affiliations
Contributions
SA and RH were involved in methodology, writing the manuscript, and revision. OS was responsible for design of the work and methodology. MM interpreted the data and wrote the manuscript draft. EH and EE carried out investigation and wrote the manuscript draft. MA and RA collected the samples and wrote the manuscript draft. AA and FA assisted with the methodology and wrote the manuscript draft. AK wrote the manuscript draft.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Additional file 1
. Raw expression data of lncRNA CASC2 and miRNA-21-5p.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Ayoub, S.E., Shaker, O.G., Masoud, M. et al. Altered expression of serum lncRNA CASC2 and miRNA-21-5p in COVID-19 patients. Hum Genomics 18, 18 (2024). https://doi.org/10.1186/s40246-024-00578-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s40246-024-00578-9