Altered expression of serum lncRNA CASC2 and miRNA-21-5p in COVID-19 patients.

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.

POU6F1 promotes ferroptosis by increasing lncRNA-CASC2 transcription to regulate SOCS2/SLC7A11 signaling in gastric cancer.

OBJECTIVE: This study investigated the effect and mechanism of POU6F1 and lncRNA-CASC2 on ferroptosis of gastric cancer (GC) cells. METHODS: GC cells treated with erastin and RSL3 were detected for ferroptosis, reactive oxygen species (ROS) level, and cell viability. The expression levels of POU6F1, lncRNA-CASC2, SOCS2, and ferroptosis-related molecules (GPX4 and SLC7A11) were also measured. The regulations among POU6F1, lncRNA-CASC2, FMR1, SOCS2, and SLC7A11 were determined. Subcutaneous tumor models were established, in which the expressions of Ki-67, SOCS2, and GPX4 were detected by immunohistochemistry. RESULTS: GC patients with decreased expressions of POU6F1 and lncRNA-CASC2 had lower survival rate. Overexpression of POU6F1 or lncRNA-CASC2 decreased cell proliferation and GSH levels in GC cells, in addition to increasing total iron, Fe2+, MDA, and ROS levels. POU6F1 directly binds to the lncRNA-CASC2 promoter to promote its transcription. LncRNA-CASC2 can target FMR1 and increase SOCS2 mRNA stability to promote SLC7A11 ubiquitination degradation and activate ferroptosis signaling. Knockdown of SOCS2 inhibited the ferroptosis sensitivity of GC cells and reversed the effects of POU6F1 and lncRNA-CASC2 overexpression on ferroptosis in GC cells. CONCLUSION: Transcription factor POU6F1 binds directly to the lncRNA-CASC2 promoter to promote its expression, while upregulated lncRNA-CASC2 increases SOCS2 stability and expression by targeting FMR1, thereby inhibiting SLC7A11 signaling to promote ferroptosis in GC cells and inhibit GC progression.

LncRNA CASC2 Alleviates Sepsis-induced Acute Lung Injury by Regulating the miR-152-3p/PDK4 Axis.

BACKGROUND: Acute lung injury (ALI) is an early complication of sepsis and it is also considered as an important cause of high mortality in sepsis patients. This research aimed to explore the potential role and mechanism of long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2) in sepsis-induced ALI. METHODS: The levels of CASC2, microRNA-152-3p (miR-152-3p) and pyruvate dehydrogenase kinase 4 (PDK4) in sepsis patients and LPS-treated HPAEpiC were detected by quantitative real-time PCR and western blot. Cell viability and apoptosis were assessed by Counting Kit-8 (CCK-8) assay and flow cytometry. The concentrations of inflammatory factors were tested by Enzyme-linked immunosorbent assay. Oxidative stress was evaluated by the levels of reactive oxygen species and superoxide dismutase using corresponding commercial kits. The targeting relationship between miR-152-3p and CASC2 or PDK4 was verified by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays. RESULTS: CASC2 and PDK4 were down-regulated, while miR-152-3p was up-regulated in sepsis patients and LPS-stimulated HPAEpiC. Overexpression of CASC2 relieved the LPS-resulted cell viability inhibition, apoptosis promotion, inflammatory and oxidative damages in HPAEpiC. In addition, miR-152-3p was a miRNA target of CASC2 and CASC2 alleviated cell injury in LPS-disposed HPAEpiC by sponging miR-152-3p. Moreover, miR-152-3p directly targeted PDK4 and CASC2 increased the PDK4 expression by depending on the sponge effect on miR-152-3p. Meanwhile, inhibition of miR-152-3p attenuated LPS-triggered HPAEpiC injury by upregulating the level of PDK4. CONCLUSION: These results suggested that CASC2 ameliorated the LPS-induced injury in HPAEpiC via regulating miR-152-3p/PDK4 pathway.

Long noncoding RNA CASC2 protect ROS-induced oxidative stress in myocardial infarction by miR-18a/SIRT2.

We aimed to investigate the function and its possible mechanisms of long noncoding RNA (lncRNA) in acute myocardial infarction (AMI) model. Patients with AMI and normal volunteers were selected from our hospital. Sprague-Dawley rats were induced into in vivo model of AMI. H9c2 cells were treated with H2 O2 to generate injury model. A significantly lower serum gene expression of lncRNA CASC2 was detected. In rat models of AMI, lncRNA CASC2 gene expressions in heart tissue of mice with AMI were decreased. In in vitro model, downregulation of lncRNA CASC2 increased reactive oxygen species (ROS)-induced oxidative stress; lncRNA CASC2 induced NADPH oxidase (NOX-2) expression and suppressed miR-18a expression; MiR-18a promoted ROS-induced oxidative stress; downregulation of miR-18a decreased ROS-induced oxidative stress. The inhibition of miR-18a reversed the effects of CASC2 downregulation on ROS-induced oxidative stress in in vitro model of AMI. The activation of miR-18a reversed the effects of CASC2 on ROS-induced oxidative stress in in vitro model of AMI. These data for the first time suggest that lncRNA CASC2 have better protective effects on AMI, which could reduce oxidative stress through their carried miR-18a and subsequently downregulating the SIRT2/ROS pathway.

Potential of circulating lncRNA CASC2 as a biomarker in reflecting the inflammatory cytokines, multi-organ dysfunction, disease severity, and mortality in sepsis patients.

BACKGROUND: Long noncoding RNA (lncRNA) cancer susceptibility candidate gene 2 (CASC2) inhibits inflammation and multi-organ dysfunction in various ways. The present study was intended to explore the potency of blood lncRNA CASC2 as a biomarker for sepsis management. METHODS: Totally, 184 sepsis patients and 30 healthy controls were enrolled. The reverse transcription-quantitative polymerase chain reaction was used to detect lncRNA CASC2 expression in peripheral blood mononuclear cell samples from the subjects. Mortality during 28 days was recorded in sepsis patients. RESULTS: LncRNA CASC2 was decreased in sepsis patients [median (interquartile range [IQR]): 0.473 (0.241-0.773)] by comparison to healthy controls [median (IQR): 1.019 (0.676-1.685)] (p < 0.001). In sepsis patients, lncRNA CASC2 was negatively correlated with Acute Physiology and Chronic Health Evaluation II (APACHE II) (p = 0.001), Sequential Organ Failure Assessment (SOFA) (p < 0.001), SOFA-respiratory system (p = 0.010), SOFA-coagulation (p = 0.020), SOFA-liver (p = 0.019), and SOFA-renal (p = 0.010) scores, but was not related to SOFA-nervous (p = 0.466) and SOFA-cardio vascular system (p = 0.059) scores. Additionally, lncRNA CASC2 was negatively related to tumor necrosis factor-α (p = 0.024), interleukin (IL)-1ß (p = 0.013), and IL-17A (p = 0.002), but was not linked to IL-6 (p = 0.112) or IL-10 (p = 0.074). Furthermore, lncRNA CASC2 was lower in sepsis deaths [median (IQR): 0.286 (0.166-0.475)] than in survivors [median (IQR): 0.534 (0.296-0.811)] (p < 0.001). Simultaneously, Kaplan-Meier (KM) curve analysis also observed that lncRNA CASC2 was inversely related to accumulating mortality in sepsis patients (p = 0.003). While lncRNA CASC2 could independently predict lower mortality risk. CONCLUSION: Circulating lncRNA CASC2 inadequacy indicates the release of inflammatory cytokines, severe multi-organ injuries, and increased mortality in sepsis patients.

Aberrant expression of LncRNA CASC2 mediated the cell viability, apoptosis and autophagy of colon cancer cells by sponging miR-19a via NF-κB signaling pathway.

Abnormal and rapid proliferation of colon cancer cells is a severe problem that can be regulated by non-coding RNAs. Thus, our study focused on effects of lncRNA CASC2 and miR-19a on colon cancer cells. Expressions of lncRNA CASC2, miR-19a, Bcl-2, Bax and NF-κB/p65 were examined by RT-qPCR. Cell viabilities were detected by CCK-8. A luciferase report assay was used for measuring binding conditions between lncRNA CASC2 and miR-19a. Western blotting was used to evaluate expression of LC3-I, LC3-II and p62 related to autophagy. Expression of lncRNA CASC2 lower in cancer cell lines and the overexpression reduced the cell viability of HT29 and SW480. Furthermore, Bcl-2 was suppressed by overexpressed lncRNA CASC2, while Bax was upregulated. LC3-Ⅰ and p62 were both inhibited, but LC3-Ⅱ was promoted. MiR-19a was predicted to bind lncRNA CASC2 and expressed higher in cancer cell lines. Overexpressed miR-19a reduced expression of lncRNA CASC2 and increased cell viability. This was repressed by upregulated lncRNA CASC2. Bcl-2 and Bax expression and proteins implicated in autophagy that are regulated by lncRNA CASC2 upregulation were reversed by miR-19a overexpression. NF-κB was upregulated in colon cancer cell lines, while inhibition of NF-κB reversed functions of lncRNA CASC2 and magnified roles of miR-19a. Our findings showed that lncRNA CASC2 inhibited cell viability in colon cancer cell lines and miR-19a reversed its functions through the NF-κB signalling pathway, suggesting that these could be factors in treating colon cancer in the future.

Long Non-Coding RNA CASC2 Overexpression Ameliorates Sepsis-Associated Acute Kidney Injury by Regulating MiR-545-3p/PPARA Axis.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been demonstrated to be involved in the progression of sepsis-induced acute kidney injury (AKI). In this study, we aimed to explore the functions of lncRNA cancer susceptibility candidate 2 (CASC2) in sepsis-induced AKI. METHODS: The sepsis cell models were established by exposing HK2 and HEK293 cells into lipopolysaccharide (LPS). Quantitative real-time polymerase chain reaction (qRT-PCR) assay was conducted to determine the expression of CASC2, miR-545-3p and peroxisome proliferator-activated receptor-α (PPARA) mRNA. Cell Counting Kit-8 (CCK-8) assay, flow cytometry analysis and wound healing assay were employed for cell viability, apoptosis and migration, respectively. Western blot assay was conducted for the protein levels of E-cadherin, α-SMA and PPARA. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by specific kits. The relationship between miR-545-3p and CASC2 or PPARA was verified by dual-luciferase reporter assay. RESULTS: CASC2 level was decreased in sepsis patients' serums and LPS-treated HK2 and HEK293 cells. CASC2 overexpression facilitated cell viability and restrained cell apoptosis, migration, epithelial-mesenchymal transition (EMT) and oxidative stress in LPS-triggered HK2 and HEK293 cells. CASC2 was identified as a sponge for miR-545-3p to regulate PPARA expression. MiR-545-3p overexpression restored the impact of CASC2 on LPS-induced injury in HK2 and HEK293 cells. Moreover, miR-545-3p overexpression aggravated LPS-induced cell injury in HK2 and HEK293 cells by targeting PPARA. CONCLUSION: CASC2 overexpression relieved the damage of HK2 and HEK293 cells mediated by LPS treatment through regulating miR-545-3p/PPARA axis.

LncRNA CASC2 targets CAV1 by competitively binding with microRNA-194-5p to inhibit neonatal lung injury.

Long non-coding RNAs (lncRNAs) are vital regulators of different biological processes during bronchopulmonary dysplasia (BPD). This study was conducted to probe the biological roles of lncRNA CASC2 in the pathogenesis of BPD and neonatal lung injury. Firstly, a hyperoxia-induced mouse model with BPD was established. LncRNAs with differential expression in lung tissues of normal and BPD mice were analyzed by microarray. An adenovirus vector overexpressing CASC2 was constructed and its functions on BPD symptoms in model mice were analyzed. Gain- and loss-of function studies of CASC2 were performed in a bronchial epithelial cell line BEAS-2B to determine its role in cell apoptosis and proliferation under normoxic and hyperoxic conditions. The downstream mechanical molecules of lncRNA CASC2 were predicted on bioinformatics systems and confirmed by luciferase assays. The functional interactions among lncRNA CASC2, miR-194-5p, and CAV1 in BPD were determined by rescue experiments. Consequently, lncRNA CASC2 was found to be poorly expressed in BPD mice. Besides, overexpressed CASC2 was found to relieve the symptoms of BPD in neonatal mice and suppress apoptosis as well as promote proliferation in hyperoxia-induced BEAS-2B cells. Importantly, CASC2 was found to regulate CAV1 expression by competitively binding to miR-194-5p and downregulate the activity of the TGF-ß1 signaling pathway, thereby suppressing lung injury. Either miR-194-5p upregulation or CAV1 downregulation blocked the roles of CASC2. To sum up, this study evidenced that CASC2 alleviates hyperoxia-induced lung injury in mouse and cell models with the involvement of a miR-194-5p-CAV1 crosstalk and the TGF-ß1 inactivation.

Long noncoding RNA CASC2 inhibits ox-LDL-mediated vascular smooth muscle cells proliferation and migration via the regulation of miR-532-3p/PAPD5.

BACKGROUND: Studies have demonstrated that long noncoding RNAs (lncRNAs) have essential impacts on the development of atherosclerosis (AS). This study aimed to identify the role and functional mechanism of lncRNA CASC2 in the development and migration of vascular smooth muscle cells (VSMCs). METHOD: The serum of 40 pairs of AS patients and healthy volunteers were collected and the expression of CASC2 was evaluated. qRT-PCR and western blotting were carried out to examine the expression levels of at mRNA and protein level, repectively. Cell proliferation assay, colony formation assay, transwell migration assay, dual-luciferase reporter assay, and wound healing assay were conducted to evaluate cell proliferation, colony formation, migration, transcription, targeting, and self-restoration. RESULTS: The expression levels of CASC2 were decreased, while the expression levels of miR-532-3p were elevated in AS patient samples and VSMCs. Overexpression of CASC2 inhibited the proliferation and migration of VSMCs and enhanced cell apoptosis. CASC2 inhibited the expression of miR-532-3p, and inversely upregulated the expression of PAPD5, which was a target of miR-532-3p. In addition, knockdown of miR-532-3p-mimic and PAPD5 could attenuate the impact of overexpression of CASC2 on proliferation, migration, and apoptosis in ox-LDL-VSMCs. CONCLUSION: CASC2 suppressed cell reproduction and promoted cell apoptosis by regulating the miR-532-3p/PAPD5 axis in ox-LDL-mediated VSMCs. This might be important for AS therapeutics.

lncRNA CASC2 suppresses the growth of hemangioma cells by regulating miR-18a-5p/FBXL3 axis.

Dysregulation of lncRNA cancer susceptibility candidate 2 (CASC2) is involved in the pathogenesis of multiple malignancies. However, the underlying mechanisms by which lncRNA CASC2 regulates the proliferation of hemangiomas (HAs) remain undocumented. Herein, the expression levels of lncRNA CASC2 and VEGF in proliferating or involuting phase HAs were assessed by qRT-PCR analysis, and the effects of lncRNA CASC2 on HAs cell growth were evaluated by MTT, colony formation assays and Western blot analysis. lncRNA CASC2 specific binding with miR-18a-5p was confirmed by luciferase report assay. Consequently, we found that the expression of lncRNA CASC2 was reduced in proliferating phase HAs as compared with the involuting phase HAs or normal tissues, and possessed a negative correlation with VEGF expression in proliferating phase HAs. Restored expression of lncRNA CASC2 repressed cell viability and colony formation and downregulated VEGF expression, while silencing lncRNA CASC2 showed the opposite effects. Moreover, lncRNA CASC2 was confirmed to bind with miR-18a-5p, which could reverse lncRNA CASC2-induced anti-proliferative effects by targeting FBXL3 in HAs cells. Altogether, our findings demonstrated that lncRNA CASC2 suppressed the growth of HAs cells by regulating miR-18a-5p/FBXL3 axis.

Ginsenoside Rg3 suppresses the growth of gemcitabine-resistant pancreatic cancer cells by upregulating lncRNA-CASC2 and activating PTEN signaling.

Pancreatic cancer is one of the most fatal malignancies with high mortality. Gemcitabine (GEM)-based chemotherapy is the most important treatment. However, the development of GEM resistance leads to chemotherapy failure. Previous studies demonstrated the anticancer activity of ginsenoside Rg3 in a variety of carcinomas through modulating multiple signaling pathways. In the present study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, colony formation assay, flow cytometry apoptosis assay, Western blotting assay, xenograft experiment, and immunohistochemistry assay were performed in GEM-resistant pancreatic cancer cell lines. Ginsenoside Rg3 inhibited the viability of GEM-resistant pancreatic cancer cells in a time-dependent and concentration-dependent manner through induction of apoptosis. The level of long noncoding RNA cancer susceptibility candidate 2 (CASC2) and PTEN expression was upregulated by the ginsenoside Rg3 treatment, and CASC2/PTEN signaling was involved in the ginsenoside Rg3-induced cell growth suppression and apoptosis in GEM-resistant pancreatic cancer cells. Ginsenoside Rg3 could be an effective anticancer agent for chemoresistant pancreatic cancer.

LncRNA CASC2 inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation and migration by regulating the miR-222/ING5 axis.

BACKGROUND: Pulmonary arterial hypertension (PAH) is often characterized by cell proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). LncRNA cancer susceptibility candidate 2 (CASC2) has been revealed to be involved in PASMC injury in hypoxia-induced pulmonary hypertension. However, the exact molecular mechanisms whereby CASC2 regulates PASMC proliferation and migration are still incompletely understood. METHODS: The expression levels of CASC2, miR-222 and inhibitor of growth 5 (ING5) were measured using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot, respectively. Cell proliferation was analyzed by Cell Counting Kit-8 (CCK-8) assay. Wound healing assay was used to analyze cell migration ability. The relationship between miR-222 and CASC2 or ING5 was confirmed using bioinformatics analysis, luciferase reporter assay and RNA immunoprecipitation assay. RESULTS: CASC2 was down-regulated in hypoxia-induced PASMCs in a dose- and time-dependent manner. Functional experiments showed that CASC2 overexpression could reverse hypoxia-induced proliferation and migration of PASMCs. Bioinformatics analysis indicated that CASC2 acted as a competing endogenous RNA of miR-222, thereby regulating the expression of ING5, the downstream target of miR-222, in PASMCs. In addition, rescue assay suggested that the inhibition mediated by CASC2 of hypoxia-induced PASMC proliferation and migration could be attenuated by miR-222 inhibition or ING5 overexpression. CONCLUSION: CASC2 attenuated hypoxia-induced PASMC proliferation and migration by regulating the miR-222/ING5 axis to prevent vascular remodeling and the development of PAH, providing a novel insight and therapeutic strategy for hypoxia-induced PAH.

MiR93-5p inhibits chondrocyte apoptosis in osteoarthritis by targeting lncRNA CASC2.

BACKGROUND: It has been reported that miR-93-5p and long non-coding RNA (lncRNA) Cancer Susceptibility 2 (CASC2) play opposite roles in regulating chondrocyte apoptosis, indicating the possible interaction between them. This study aimed to investigate the interaction between miR-93-5p and lncRNA CASC2 in chondrocyte apoptosis, which plays critical roles in osteoarthritis (OA). METHODS: The interaction between CASC2 and miR-93-5p was analyzed by dual luciferase assay and overexpression experiments. Levels of CASC2 and miR-93-5p in plasma sample from OA patients and healthy controls were measured by RT-qPCR. The roles of CASC2 and miR-93-5p in regulating the apoptosis of chondrocyte induced by LPS were analyzed by cell apoptosis assay. RESULTS: Through bioinformatics analysis we observed the potential interaction between CASC2 and miR-93-5p, which was confirmed by dual luciferase assay. In OA patients, miR-93-5p was downregulated, while CASC2 was upregulated, and they were inversely correlated. LPS treatment led to downregulated miR-93-5p and upregulated CASC2. Overexpression of miR-93-5p led to the downregulated CASC2 in chondrocytes. Under LPS treatment, CASC2 overexpression promoted the apoptosis of chondrocyte. MiR-93-5p overexpression played an opposite role and attenuated the effects of CASC2 overexpression. CONCLUSION: MiR-93-5p was downregulated in OA may inhibit LPS-induced chondrocyte apoptosis by targeting lncRNA CASC2.

The Role of CASC2 and miR-21 Interplay in Glioma Malignancy and Patient Outcome.

Recently long non-coding RNAs (lncRNAs) were highlighted for their regulatory role in tumor biology. The novel human lncRNA cancer susceptibility candidate 2 (CASC2) has been characterized as a potential tumor suppressor in several tumor types. However, the roles of CASC2 and its interplay with miR-21 in different malignancy grade patient gliomas remain unexplored. Here we screened 99 different malignancy grade astrocytomas for CASC2, and miR-21 gene expression by real-time quantitative polymerase chain reaction (RT-qPCR) in isocitrate dehydrogenase 1 (IDH1) and O-6-methylguanine methyltransferase (MGMT) assessed gliomas. CASC2 expression was significantly downregulated in glioblastomas (p = 0.0003). Gliomas with low CASC2 expression exhibited a high level of miR-21, which was highly associated with the higher glioma grade (p = 0.0001), IDH1 wild type gliomas (p < 0.0001), and poor patient survival (p < 0.001). Taken together, these observations suggest that CASC2 acts as a tumor suppressor and potentially as a competing endogenous RNA (ceRNA) for miR-21, plays important role in IDH1 wild type glioma pathogenesis and patients' outcomes.

LncRNA CASC 2 is upregulated in aphthous stomatitis and predicts the recurrence.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common oral disease with unknown molecular pathogenesis. Our preliminary microarray analysis revealed the altered expression of lncRNA Cancer Susceptibility Gene 2 (CASC2) in RAS. We therefore analyzed the role of CASC2 in RAS. METHODS: In this study, plasma samples were obtained from RAS patients and healthy participants. Plasma levels of CASC2 were measured by RT-qPCR. Plasma levels of IL-6 and IL-18 were measured by enzyme-linked immunosorbent assay (ELISA). A follow-up study was performed to analyze the role of CASC2 in the recurrence of RAS. RESULTS: In the present study, we found that lncRNA Cancer Susceptibility Gene 2 (CASC2), as well as pro-inflammatory factors interleukin 6 (IL-6) and interleukin 18 (IL-18), were upregulated in plasma of RAS patients compared with healthy participants. Plasma levels of lncRNA CASC2 were positively correlated with plasma levels of IL-6 and IL-18 in RAS patients but not in healthy participants. Compared with pre-treatment levels, plasma levels of lncRNA CASC2, IL-6 and IL-18 were reduced after recovery. A follow-up study showed that patients with high levels of lncRNA CASC2 had a significantly higher recurrence rate. CONCLUSION: LncRNA CASC 2 is upregulated in RAS and predicts the recurrence.

Good or not good: Role of miR-18a in cancer biology.

miR-18a is a member of primary transcript called miR-17-92a (C13orf25 or MIR17HG) which also contains five other miRNAs: miR-17, miR-19a, miR-20a, miR-19b and miR-92a. This cluster as a whole shows specific characteristics, where miR-18a seems to be unique. In contrast to the other members, the expression of miR-18a is additionally controlled and probably functions as its own internal controller of the cluster. miR-18a regulates many genes involved in proliferation, cell cycle, apoptosis, response to different kinds of stress, autophagy and differentiation. The disturbances of miR-18a expression are observed in cancer as well as in different diseases or pathological states. The miR-17-92a cluster is commonly described as oncogenic and it is known as 'oncomiR-1', but this statement is a simplification because miR-18a can act both as an oncogene and a suppressor. In this review we summarize the current knowledge about miR-18a focusing on its regulation, role in cancer biology and utility as a potential biomarker.

Overexpression of cancer susceptibility candidate 2 inhibited progression of hepatocellular carcinoma cells.

OBJECTIVE: Our study was aimed to investigate the effect of cancer susceptibility candidate 2 (CASC2) on the proliferation, cell cycle, apoptosis, and metastasis of hepatocellular carcinoma (HCC) cells. METHODS: CASC2 expression in tumor tissues and HCC cells was tested by quantitative real-time polymerase chain reaction. After manipulating the expression of CASC2 in Hep3B and HepG2 cells, cells viability, including proliferation, apoptosis, cell-cycle distribution, migration, and invasion were examined by colony formation assay, flow cytometry, wound-healing assay, and transwell assay, respectively. The expression levels of proteins associated with the cell cycle and AKT/mTOR pathway were measured by the western blot. Stably transfected HepG2 cells were used to construct nude mice models, and tumorigenesis was evaluated to investigate the in vivo functions of CASC2 in HCC progression. RESULTS: In tissues and cells of HCC, decreased CASC2 expressions were confirmed. Overexpression of CASC2 made cell cycle stagnated at G0/G1 phase and induced apoptosis. Meanwhile, the overexpression of CASC2 played significant roles in inhibiting the proliferation, migration, and invasion of HCC cells. Furthermore, In vivo experiment indicated that CASC2 restrained the growth of tumors. CONCLUSION: Our study suggested that CASC2 promoted cell apoptosis and suppressed cell growth and metastasis in HCC, indicating that CASC2 might be a useful biomarker of HCC.

Long noncoding RNA cancer susceptibility candidate 2 suppresses papillary thyroid carcinoma growth by inactivating the AKT/ERK1/2 signaling pathway.

OBJECTIVES: Cancer susceptibility candidate 2 (CASC2) and long noncoding RNA (lncRNA) have been identified as a tumor suppressor in colorectal, lung, renal, and stomach cancer as well as in patient gliomas, but the function of CASC2 in papillary thyroid carcinoma (PTC) is not yet clear. The present study aimed to explore the effects of CASC2 in PTC. METHODS: The CASC2 expression was measured in PTC samples and normal tissues by using quantitative real-time polymerase chain reaction. The lentiviral vectors were used to establish CASC2 overexpression models in PTC cell lines to determine the effects of CASC2 on cell proliferation, apoptosis, migration, and invasion. A tumor xenograft animal model was used to examine the functions of overexpression CASC2. RESULTS: CASC2 expression was significantly decreased in PTC tumor tissues than adjacent normal tissues. CASC2 downregulation in PTC tissues significantly correlated with the tumor size, the presence of multifocal lesions, and the advanced pathological stage. CASC2 overexpression suppressed the cell proliferation and promoted apoptosis in PTC cell lines and CASC2 overexpression resulted in the inactivation of protein kinase B (PKB/AKT) and extracellular signal-regulated kinases (ERK1/2). The regulatory effects of CASC2 on PTC cell biological behavior were further enhanced by mitogen-activated protein kinase kinase (MEK) inhibitor U0126 or AKT1/2/3 inhibitor MK-2206 2HCl. CASC2 overexpression suppressed tumor growth in PTC cells in xenograft mouse models. CONCLUSION: Our results indicated that CASC2 significantly suppressed tumorigenesis in PTC and CASC2 may serve as a novel prognostic marker or therapeutic target.

HNF1A/CASC2 regulates pancreatic cancer cell proliferation through PTEN/Akt signaling.

Pancreatic cancer (PC) has a high mortality rate in all cancers worldwide. According to recent studies, long noncoding RNA-CASC2 is involved in the development and progression of many malignant tumors; in the present study, we demonstrated that lncRNA-CASC2 was specifically downregulated in PC tissues and cell lines, and a lower CASC2 expression in PC was related with a poorer prognosis. CASC2 suppressed PC cell proliferation. Hepatocyte nuclear factor 1 alpha (HNF1A) is a transcription factor known to regulate pancreatic differentiation and maintain the homeostasis of the endocrine pancreas. Recently, HNF1A is considered to be a possible tumor suppressor in PC. In the present study, we observed that HNF1A positively regulated CASC2 expression. Through luciferase assays, we demonstrated that CASC2 gene possessed an HNF1A-responsive element (CASC2-HNF1A RE); HNF1A could promote CASC2 expression through direct binding to CASC2-HNF1A RE. Further, PTEN/Akt signaling was involved in HNF1A regulation of CASC2. Finally, we evaluated the expression level of HNF1A in PC tissues; lower HNF1A expression was correlated with shorter overall survival in patients with PC. Taken together, these findings will shed light on the role and mechanism of HNF1A/CASC2 in regulating PC cells proliferation through PTEN/Akt signaling. CASC2 may serve as a potential therapeutic target in PC in the future.

Long noncoding RNA CASC2 promotes paclitaxel resistance in breast cancer through regulation of miR-18a-5p/CDK19.

Breast cancer is one of the most prevalent cancers in women. Chemoresistance is a major obstacle for the treatment of breast cancer. We investigated the role of long noncoding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2) in paclitaxel (PTX) resistance in breast cancer. CASC2 expression was increased in PTX-resistant clinical samples and cell lines. PTX induced CASC2 expression in a concentration-dependent manner. Downregulation of CASC2 increased PTX toxicity and decreased IC50 value, while upregulation of CASC2 decreased PTX toxicity and increased IC50 value in MCF-7/PTX and MDA-MB-231/PTX cells. Moreover, downregulation of CASC2 decreased tumor growth in xenograft mice implanted with MCF-7/PTX cells. miR-18a-5p possessed a putative binding site in 3'-UTR of CASC2 and cyclin-dependent kinase 19 (CDK19). In PTX-resistant breast cancer cells, miR-18a-5p expression was decreased. CASC2 and miR-18a-5p could negatively regulate the expression of each other. CDK19 expression could be negatively regulated by miR-18a-5p, but positively regulated by CASC2. miR-18a-5p mimics or downregulation of CDK19 decreased tumor growth in xenograft mice implanted with MCF-7/PTX cells. In summary, we identified that CASC2 activated PTX resistance in breast cancer through regulation of miR-18a-5p/CDK19. We highlight the importance of CASC2/miR-18a-5p/CDK19 axis in the chemoresistance of breast cancer and provide potential targets for the improving chemotherapy of breast cancer.