Long non‑coding RNA CASC2 inhibits progression and predicts favorable prognosis in epithelial ovarian cancer

  • Authors:
    • Zhuowei Xue
    • Xiaolu Zhu
    • Yincheng Teng
  • View Affiliations

  • Published online on: October 10, 2018     https://doi.org/10.3892/mmr.2018.9550
  • Pages: 5173-5181
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Epithelial ovarian cancer (EOC) is one of the leading causes of cancer‑associated mortality in women. At present, the overall 5‑year survival rate of patients with EOC remains poor despite advancements in diagnosis and treatment. Long non‑coding RNAs (lncRNAs) have attracted increasing attention in recent years for their extensive roles in tumorigenesis and cancer development. The lncRNA cancer susceptibility candidate 2 (CASC2) was originally identified as a downregulated gene in endometrial cancer, and subsequent studies revealed that CASC2 was able to act as a tumor suppressor gene in various types of cancer. The present study is the first, to the best of the authors' knowledge, to identify the clinical significance and potential role of CASC2 in EOC. The results demonstrated that CASC2 was downregulated in EOC cell lines and tissues. Analysis of association between clinicopathological features and CASC2 expression levels suggested that low CASC2 expression is associated with the serous histological subtype (P<0.001), lymph node metastasis (P=0.038), poor histological grade (P<0.001) and large tumor size (P=0.001) in EOC. Furthermore, low CASC2 expression predicted poor overall survival (P<0.001) and progression‑free survival (P<0.001). Functional assays, including Cell Counting kit‑8 assays, colony formation assays, and Transwell and Matrigel assays, confirmed that silencing of CASC2 promoted the proliferation, migration and invasion of EOC cells; whereas, ectopic overexpression of CASC2 suppressed the proliferation, migration and invasion of EOC cells. In addition, in the analysis of the risk factors for poor prognosis, low CASC2 expression was identified as an independent risk factor for reduced overall survival [hazard ratio (HR)=0.417; 95% confidence interval (CI)=0.251‑0.693; P=0.001] and progression‑free survival (HR=0.426; 95% CI=0.260‑0.699; P=0.001) in patients with EOC. In conclusion, CASC2 is downregulated in EOC, and it may suppress EOC progression and is an independent risk factor for poor prognosis. CASC2 may be a promising prognostic marker and therapeutic target in EOC.

Introduction

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer-associated mortality among women worldwide (1). During the past decades, the early detection rate and prognosis of EOC have been substantially improved (2). However, the prognosis for the advanced stages of the disease has not improved significantly in more than two decades (3). Further investigations on the mechanisms of EOC progression are required to aid the development of novel diagnostic markers and therapeutic targets.

Only 2% of the human genome accounts for protein-coding regions, yet >70% of the human genome is transcribed into RNAs that do not encode proteins; these RNAs are called non-coding RNAs (4). Non-coding RNAs are generally divided into two classes according to their size. Long non-coding RNAs (lncRNAs) are defined as a class of non-coding RNAs with a length >200 base pairs. In recent years, numerous lncRNAs have been discovered, and the pivotal roles of lncRNAs in almost every aspect of cell biology have been gradually revealed, such as epigenetic regulation via molecular scaffolding, regulation of mRNA processing, molecular decoying and lncRNA-derived peptides (5).

Cancer susceptibility candidate 2 (CASC2), an lncRNA located at chromosome 10q26, was originally identified as a downregulated gene in endometrial cancer (6). Previous studies suggested that CASC2 may act as a tumor suppressor gene, with epigenetic and genetic alterations contributing to gene inactivation (613). Downregulation of CASC2 may provide a growth advantage in EOC cells (7). Recent studies identified that CASC2 is associated with tumor development and prognosis in various cancer types, including renal cell carcinoma, osteosarcoma, bladder cancer, pancreatic cancer, endometrial cancer, hepatocellular carcinoma, glioma, non-small cell lung cancer and gastric cancer (813). However, little is known regarding the role of CASC2 in EOC.

The present study aimed to investigate the expression, clinical significance and functional role of CASC2 in EOC. The expression levels of CASC2 in EOC cells and tissues were measured, and the association between CASC2 expression and the clincopathological characteristics of patients with EOC were statistically analyzed. Furthermore, CASC2 was overexpressed and silenced in EOC cells, and the functional alterations in the EOC cells were evaluated.

Patients and methods

Patients and tissue samples

A total of 126 female patients (aged 56.9±13.2 years old, ranging between 35–82 years old) with EOC who underwent surgical resection between August 2010 and August 2011 at Shanghai Jiao Tong University Affiliated Sixth People's Hospital (Shanghai, China) were enrolled in the present study, and written informed consent was obtained from each patient. The collected EOC tissues and paired tumor adjacent tissues were frozen in liquid nitrogen immediately following surgical resection and were stored at −80°C until use. The exclusion criteria were patients who had undergone presurgical anticancer therapy and were diagnosed with two or more malignances. The present study was approved by the Ethics Committee of the Shanghai Jiao Tong University Affiliated Sixth People's Hospital.

Cell lines and cell culture

The EOC cell lines (SKOV3, OV90, A2780, ES2 and IGROV-1) and an immortalized ovarian epithelial cell line (Moody) (14) were purchased from the Cell Bank of Type Culture Collection of the Chinese Academy of Science (Beijing, China). Cells were cultured in RPMI-1640 medium (Invitrogen; Thermo Fisher Scientific, Inc., Waltham, MA, USA; SKOV3) or Dulbecco's modified Eagle's medium (Invitrogen; Thermo Fisher Scientific, Inc.; OV90, A2780, ES2 and IGROV-1) supplemented with 10% fetal bovine serum (FBS; Life Technologies; Thermo Fisher Scientific, Inc.), 100 U/ml penicillin and 100 mg/ml streptomycin (Life Technologies; Thermo Fisher Scientific, Inc.) in a humidified atmosphere containing 5% CO2 at 37°C.

Gene ectopic expression, interference and cell transfection

Ectopic expression of CASC2 was achieved by subcloning the CASC2 sequence into the pcDNA3.1 vector (Invitrogen; Thermo Fisher Scientific, Inc.; pcDNA3.1-CASC2; 1.0 µg/µl), with an empty pCDNA3.1 vector serving as an empty control. Small interfering (si)RNAs [siCASC2-1 and siCASC2-2 (sequences unavailable); 5 nM] and non-targeting siRNA [siRNA negative control (siNC)] were all purchased from Genewiz, Inc. (Suzhou, China). When EOC cells were 60–70% confluent, transfection was performed using Lipofectamine® 2000 (Invitrogen; Thermo Fisher Scientific, Inc.) according to the manufacturer's protocol. After 5 h of incubation, the transfection medium was replaced with the appropriate culture medium without antibiotics, followed by incubation for 48 h. The cells were subsequently used in experiments. The expression levels of CASC2 following ectopic expression and interference were confirmed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).

RNA extraction and RT-qPCR

Total RNA was extracted from EOC tissues and cell lines with TRIzol® (Invitrogen; Thermo Fisher Scientific, Inc.) according to the manufacturer's protocol. cDNA was reverse transcribed from total RNA (2.5 µg) using the Superscript III kit (Life Technologies; Thermo Fisher Scientific, Inc.) according to the manufacturer's protocol. Reverse transcription was performed according to the following temperature protocol: Incubation for 5 min at 25°C, followed by 60 min at 42°C and then 70°C for 5 min. The relative expression of selected genes were quantified and analyzed by real-time PCR using the iQ SYBRGreen PCR Supermix kit (Bio-Rad Laboratories, Inc., Hercules, CA, USA). The qPCR thermocycling conditions used were as follows: Initial denaturation at 95°C for 5 min; followed by 40 cycles of denaturation at 95°C for 30 sec, annealing at 50°C for 30 sec and extension at 72°C for 30 sec. The primers were as follows: CASC2 sense, 5′-GCACATTGGACGGTGTTTCC-3′; CASC2 antisense, 5′-CCCAGTCCTTCACAGGTCAC-3′; and GAPDH sense, 5′-AGAAGGCTGGGGCTCATTTG-3′; GAPDH antisense, 5′-AGGGGCCATCCACAGTCTTC-3′. The expression levels of the target genes were calculated using the 2−ΔΔCq method based on the cycle threshold values of the genes compared with those of GAPDH (15). All samples were typically analyzed in triplicate in at least three independent runs.

Transwell assay and Matrigel assay

For the Transwell assay and the Matrigel assay, cells (1×105) were suspended in 200 µl serum-free medium and were seeded into the upper chamber of Matrigel-coated (Matrigel assay) or uncoated (Transwell assay) Boyden chambers (8 µM pore size; BD Biosciences, Franklin Lakes, NJ, USA). Medium containing 20% FBS was added to the lower chamber. After 24 h incubation, cells remaining in the upper chamber were removed with cotton swabs, and cells that had invaded through the membrane were fixed with ethanol for 30 min at room temperature, and subsequently stained with Giemsa for another 30 min at room temperature. The cells that migrated or invaded were counted in five independent fields using an Olympus CKX53 inverted light microscope (magnification, ×10; Olympus Corporation, Tokyo, Japan), and images were obtained (magnification, ×4). The results presented are representative of three independent experiments with technical duplicates.

Cell Counting kit-8 (CCK-8) assay

To analyze the effect of CASC2 on cell proliferation, a CCK-8 assay was performed using a CCK-8 kit (Roche Applied Science, Penzberg, Germany). In total, 5,000 cells were seeded into each well of 96-well plates after 48 h of transfection. CCK-8 was used to quantify the absorbance measurements at 450 nm at the indicated time points (0, 24, 48, 72 and 96 h). The absorbance values were normalized to those of cells transfected with empty vector or siNC. The results represent the average of three replicates under the same conditions.

Colony formation assay

For the colony formation assay, cells were incubated in 6-well plates (1,000 cells/well) in triplicates, and subsequently cultured in a humidified incubator with 5% CO2 for 10–14 days. The medium was changed every 3 days. Subsequent to incubation, the cell colonies were incubated in methanol for 10 min at room temperature, stained with 1% crystal violet for 10 min at room temperature. All colonies in the 6-well plate were manually counted using a light microscope (magnification, ×10). The results presented are representative of three independent experiments.

Statistical analysis

The data were analyzed with SPSS 19.0 (IBM Corp., Armonk, NY, USA) and are presented as the mean ± standard deviation. To statistically evaluate the association between CASC2 expression and the clinical features of patients with EOC, the patients with EOC (n=126) were dichotomized with the mean level of CASC2 expression serving as the cutoff value. Associations between clinicopathological features and CASC2 expression levels were assessed using the χ2 test. Student's t-test was used to analyze the difference between two groups. One-way analysis of variance and Dunnett's t-test was used for multiple comparisons. Survival analysis was conducted using the Kaplan-Meier method. The log-rank test was applied to compare the survival characteristics between groups. Univariate and multivariate Cox's proportional hazards regression models were applied to analyze the survival data. P<0.05 was considered to indicate a statistically significant difference.

Results

CASC2 is downregulated and correlates with tumor progression in EOC

The expression of CASC2 was evaluated in five EOC cell lines and one immortalized ovarian epithelial cell line (Moody) with an RT-qPCR assay. CASC2 exhibited a significantly higher expression level in Moody cells compared with the five EOC cell lines (Fig. 1A; P<0.05). Further detection of CASC2 expression levels in the 126 EOC tissues and paired tumor adjacent tissues revealed that CASC2 was downregulated in the EOC tissues compared with the tumor adjacent tissues [1 vs. (−0.5±3.92); (Fig. 1B)]. The results demonstrated that CASC2 downregulation was associated with histological subtype (P<0.001), lymph node metastasis (P=0.038), histological grade (P<0.001) and tumor size (P=0.001; Table I). Therefore, it may be postulated that CASC2 may be a tumor suppressor in EOC and is able to repress tumor progression.

Table I.

Correlation between long non-coding RNA CASC2 expression and epithelial ovarian cancer clinicopathological characteristics.

Table I.

Correlation between long non-coding RNA CASC2 expression and epithelial ovarian cancer clinicopathological characteristics.

ParametersNumber of patients, n=126CASC2 high/low, 50/76P-value
Age 0.945
  <60 years6024/36
  ≥60 years6626/40
Histology subtype <0.001
  Serous5246/6
  Others7430/44
CA125 0.768
  <35 U/ml3113/18
  ≥35 U/ml9537/58
Lymph node metastasis 0.038
  Yes7725/52
  No4925/24
Residual tumor size 0.218
  <1 cm8035/45
  ≥1 cm4615/31
Histological grade <0.001
  G1+G26837/31
  G35813/45
Tumor size 0.001
  <2 cm6234/28
  ≥2 cm6416/48
FIGO stage 0.519
  I+II5925/34
  III+IV6725/43

[i] CASC2, CASC2, cancer susceptibility candidate 2; FIGO, Fédération Internationale de Gynécologie et d'Obstétrique.

CASC2 inhibits the migration, invasion and proliferation of EOC cells

Cancer metastasis and proliferation are two primary factors leading to tumor progression. Therefore, the functional role of CASC2 in EOC metastasis and cell proliferation was investigated in in vitro studies. To better elucidate the function of CASC2 in EOC cells, siRNAs were used to interfere with the expression of CASC2 in OV90 cells due to their relatively high CASC2 expression level among the six EOC cell lines (Fig. 1A and 1C), and ectopic overexpression was conducted in SKOV3 cells due to their relatively low CASC2 expression level among the six EOC cell lines (Fig. 1A and 1D). CASC2 expression was significantly downregulated and upregulated in OV90 and SKOV3 cells, respectively following transfection (Fig. 1C and D; P<0.01).

The effects of CASC2 interference and overexpression on the motility of EOC cells were determined with the Transwell assay and the Matrigel assay. The results of the migration assay demonstrated that OV90 cells with silenced CASC2 exhibited significantly increased migration ability in the Transwell assay (Fig. 2A; P<0.01); whereas, CASC2 upregulation significantly suppressed the migration of SKOV3 cells (Fig. 2B; P<0.01). Accordingly, CASC2 deficiency significantly promoted invasion in OV90 cells (Fig. 2C; P<0.01), and ectopic overexpression of CASC2 significantly decreased invasion in SKOV3 cells (Fig. 2D; P<0.01). Therefore, CASC2 is able to inhibit the metastasis of EOC cells.

The CCK-8 assay and the colony formation assay were used to investigate the role of CASC2 in EOC cell proliferation. The results identified that CASC2 silencing increased the colony numbers and the optical density values of OV90 cells in the colony formation assay and CCK-8 assay, respectively (Fig. 3A and B). However, CASC2 upregulation reduced the proliferative ability of SKOV3 cells (Fig. 3C and 3D). Overall, CASC2 suppressed the proliferation of EOC cells.

Low CASC2 expression is an independent risk factor for poor prognosis

To verify the prognostic role of CASC2 in EOC, statistical analysis was performed to evaluate the association between CASC2 expression level and EOC prognosis. Notably, patients with EOC with low CASC2 expression demonstrated a markedly poorer overall survival rate (Fig. 4A) and progression-free survival rate (Fig. 4B) compared with patients with high CASC2 expression. In addition, the subtype analysis identified that low CASC2 expression predicted shorter overall survival time in patients with EOC with Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) (16) I/II (Fig. 4C) and FIGO III/IV (Fig. 4D).

Furthermore, the risk factors for overall survival in EOC were analyzed by univariate analysis and multivariate analysis. Lymph node metastasis (HR=1.754; 95% CI=1.075–2.860; P=0.024), advanced FIGO stage (HR=1.977; 95% CI=1.234–3.169; P=0.005) and low CASC2 expression (HR=0.403; 95% CI=0.245–0.663; P<0.001) were revealed to be risk factors for poor overall survival (Table II). The subsequent multivariate analysis identified advanced FIGO stage (HR=1.989; 95% CI=1.237–3.197; P=0.005) and low CASC2 expression (HR=0.417; 95% CI=0.251–0.693; P=0.001) as independent risk factors of EOC overall survival (Table II). In addition, the risk factors for progression-free survival were analyzed. As expected, lymph node metastasis (HR=2.021; 95% CI=1.238–3.300; P=0.005), advanced FIGO stage (HR=1.799; 95% CI=1.139–2.842; P=0.012) and low CASC2 expression (HR=0.405; 95% CI=0.249–0.659; P<0.001) were identified as risk factors for poor progression-free survival (Table III). The subsequent multivariate analysis identified the following three factors as independent risk factors for progression-free survival in EOC, lymph node metastasis (HR=1.680; 95% CI=1.019–2.768; P=0.042), advanced FIGO stage (HR=1.810; 95% CI=1.142–2.870; P=0.012), low CASC2 expression (HR=0.426; 95% CI=0.260–0.699; P=0.001; Table III). Taken together, these results suggest that CASC2 may be a promising biomarker for the prediction of prognosis in patients with EOC.

Table II.

Univariate and multivariate analysis of clinicopathological features for overall survival of patients with epithelial ovarian cancer.

Table II.

Univariate and multivariate analysis of clinicopathological features for overall survival of patients with epithelial ovarian cancer.

Univariate analysisMultivariate analysis


ParametersHR95% CIP-valueHR95% CIP-value
Age ≥60 years vs. <60 years1.0560.944–2.4030.086
Histology subtype serous vs. others1.4140.893–2.2390.139
CA125 <35 U/ml vs. ≥35 U/ml1.7680.987–3.1680.055
Lymph node metastasis yes vs. no1.7541.075–2.8600.0241.4310.866–2.3580.160
Residual tumor size <1 cm vs. ≥1 cm1.1130.698–1.7750.653
Histological grade G1+G2 vs. G31.0520.665–1.6640.827
Tumor size ≥2 cm vs. <2 cm1.0610.672–1.6740.799
FIGO stage (III+IV) vs. (I +II)1.9771.234–3.1690.0051.9891.237–3.1970.005
CSCA2 low vs. high0.4030.245–0.663<0.0010.4170.251–0.6930.001

[i] HR, hazard ratio; CI, confidence interval; CA125, cancer antigen 125; FIGO, Fédération Internationale de Gynécologie et d'Obstétrique; CASC2, CASC2, cancer susceptibility candidate 2.

Table III.

Univariate and multivariate analysis of clinicopathological features for progression-free survival of patients with epithelial ovarian cancer.

Table III.

Univariate and multivariate analysis of clinicopathological features for progression-free survival of patients with epithelial ovarian cancer.

Univariate analysisMultivariate analysis


ParametersHR95% CIP-valueHR95% CIP-value
Age ≥60 years vs. <60 years1.4600.925–2.3030.104
Histology subtype serous vs. others1.4850.947–2.3280.085
CA125 <35 U/ml vs. ≥35 U/ml1.5830.911–2.7490.103
Lymph node metastasis yes vs. no2.0211.238–3.3000.0051.6801.019–2.7680.042
Residual tumor size <1 cm vs. ≥1 cm1.1730.744–1.8500.492
Histological grade, G1+G2 vs. G31.1550.734–1.8180.533
Tumor size ≥2 cm vs. <2 cm1.1270.720–1.7640.600
FIGO stage (III+IV) vs. (I +II)1.7991.139–2.8420.0121.8101.142–2.8700.012
CASC2 low vs. high0.4050.249–0.659<0.0010.4260.260–0.6990.001

[i] HR, hazard ratio; CI, confidence interval; CA125, cancer antigen 125; FIGO, Fédération Internationale de Gynécologie et d'Obstétrique; CASC2, cancer susceptibility candidate 2.

Discussion

Due to the various functional roles of lncRNAs in cancer biology, an increasing number of studies have focused on the role of lncRNAs in different types of cancer. Through analysis of the differential expression of lncRNAs in normal tissues and cancer tissues, lncRNAs have been observed to be involved in the initial of carcinogenesis (17,18). A larger number of lncRNAs have been discovered as a result of the extensive use of next-generation sequencing technologies, and additional functional roles of lncRNAs have been detected in carcinogenesis and cancer progression (17,18). Through analysis of the expression profiles of lncRNAs in EOC, specific differentially expressed lncRNAs have been identified (19). Further comprehensive analysis of the expression profiles of lncRNAs in EOC revealed that an eight-lncRNA signature may be a measure for predicting the chemotherapeutic response and identifying patients with platinum resistance, who may benefit from other more effective therapies (20). At present, a number of lncRNAs have been suggested to be associated with EOC progression, chemoresistance and prognosis, including deleted in lymphocytic leukemia 1 (21), H19, imprinted maternally expressed transcript (22), HOX transcript antisense RNA (2326), nuclear paraspeckle assembly transcript 1 (27,28) and metastasis associated lung adenocarcinoma transcript 1 (29). Mechanistically, lncRNAs have been identified to regulate EOC progression by mediating cancer cell proliferation, metastasis, inflammasome formation, and the epithelial to mesenchymal transition (23,30,31). Numerous lncRNAs are involved in regulating EOC biology through various ways. In addition, certain lncRNAs, including AB073614 (32), colon cancer associated transcript 2 (33) and neuroblastoma associated transcript 1 (34), have been demonstrated to be potential prognostic markers in patients with EOC. However, the significance of CASC2 in EOC has not been elucidated yet.

The lncRNA CASC2 was discovered in 2004 in patients with endometrial carcinoma as a potential tumor suppressor (6). CASC2 transcripts may be classified into three subgroups; CASC2a, CASC2b and CASC2c (5). Evidence suggested that the expression levels of CASC2b and CASC2c mRNA were similar in normal and neoplastic endometrial tissues; whereas, CASC2a was identified to be downregulated in neoplastic samples compared with the normal counterparts (5). Since then, further studies in other types of neoplasia have been conducted, and the mechanisms and the interactions of CASC2 in cancer have been better elucidated (35); in addition, CASC2 has become synonymous with CASC2a. Aberrant expression of CASC2 was detected in renal cell carcinoma (12), osteosarcoma (36), pancreatic cancer (13), endometrial cancer (6), hepatocellular carcinoma (37), glioma (10,38,39), non-small cell lung cancer (8) and gastric cancer (11). Functionally, different previous studies have verified that CASC2 may be involved in cancer tumorigenesis, autophagy, proliferation, invasion, metastasis and apoptosis (35). Mechanistically, CASC2 has been demonstrated to function by interacting with microRNAs (38,4043), the phosphatase and tensin homology pathway (13,44) and the Wnt/β-catenin signaling pathway (45). Furthermore, survival analyses identified that low CASC2 expression predicts poor prognosis in thyroid cancer (46), glioma (10), astrocytoma (40) and non-small cell lung cancer (8). Taken together, these results suggest that CASC2 may act as a tumor suppressor in a wide range of cancer types through different signaling pathways.

The present study investigated the significance of CASC2 in EOC by determining its baseline expression level. In accordance with the results of previous studies (35), CASC2 demonstrated significantly decreased expression levels in EOC cells and tissues. In addition, the clinical significance analysis of the association CASC2 expression and the clinicopathological features of patients with EOC identified that low CASC2 expression was associated with the serous histological subtype, lymph node metastasis, poor histological grade and large tumor size, all of which contribute to EOC progression. Indeed, the prognostic evaluation revealed that patients with low CASC2 expression exhibited a markedly poorer overall survival rate and progression-free survival rate. In addition, further analysis revealed that patients with FIGO stage I/II or III/IV demonstrated a poorer overall survival rate if they additionally had low CASC2 expression. Furthermore, low CASC2 expression was confirmed to be an independent risk factor for poor prognosis in EOC. These results suggested that CASC2 has a primary role in inhibiting EOC progression in patients. To verify the function of CASC2 in EOC cells, CASC2 was overexpressed or silenced, and the results of the functional studies confirmed that CASC2 may inhibit the proliferation and metastasis of EOC cells. However, the clinical specimens used in the present study were collected in one medical center. Future studies investigating CASC2 should be performed in numerous different centers using a larger sample size. The underlying mechanism by which CASC2 exerts its function should be further explored.

In conclusion, CASC2 expression levels were decreased in EOC cells and tissues, and a low CASC2 expression level was associated with clinical progression in patients with EOC. The results of the functional studies identified that CASC2 may inhibit the proliferation and metastasis of EOC cells. Furthermore, patients with low CASC2 expression exhibited a poorer overall survival rate and a shorter progression-free survival period. Notably, low CASC2 expression was identified as an independent risk factor for overall survival and progression-free survival in patients with EOC. However, the detailed mechanisms of the influence of CASC2 on EOC progression were not further verified in the present study. The functional role of CASC2 as a tumor suppressor was demonstrated in EOC, and CASC2 may be considered a promising prognostic marker and therapeutic target in EOC.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

ZX performed the statistical analysis of clinical data, performed in vitro assays and wrote the manuscript. XZ determined the expression levels of CASC2 in EOC cells and tissues, and performed statistical analysis. YT designed the study, performed the statistical analysis and wrote the manuscript. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

The present study was approved by the Ethics Committee of the Shanghai Jiao Tong University Affiliated Sixth People's Hospital. Written informed consent was obtained from each patient.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Goff BA, Mandel L, Muntz HG and Melancon CH: Ovarian carcinoma diagnosis. Cancer. 89:2068–2075. 2000. View Article : Google Scholar : PubMed/NCBI

3 

Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, Friedlander M, Colombo N, Fowler JM, Argenta PA, De Geest K, et al: Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: A Phase III Trial of the Gynecologic Cancer Intergroup. J Clin Oncol. 27:1419–1425. 2009. View Article : Google Scholar : PubMed/NCBI

4 

Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Morales Rivea D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A, et al: Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci USA. 106:11667–11672. 2009. View Article : Google Scholar : PubMed/NCBI

5 

Ulitsky I and Bartel DP: lincRNAs: Genomics, evolution, and mechanisms. Cell. 154:26–46. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Baldinu P, Cossu A, Manca A, Satta MP, Sini MC, Rozzo C, Dessole S, Cherchi P, Gianfrancesco F, Pintus A, et al: Identification of a novel candidate gene, CASC2, in a region of common allelic loss at chromosome 10q26 in human endometrial cancer. Hum Mutat. 23:318–326. 2004. View Article : Google Scholar : PubMed/NCBI

7 

Baldinu P, Cossu A, Manca A, Satta MP, Sini MC, Palomba G, Dessole S, Cherchi P, Mara L, Tanda F and Palmieri G: CASC2a gene is down-regulated in endometrial cancer. Anticancer Res. 27:235–243. 2007.PubMed/NCBI

8 

He X, Liu Z, Su J, Yang J, Yin D, Han L, De W and Guo R: Low expression of long noncoding RNA CASC2 indicates a poor prognosis and regulates cell proliferation in non-small cell lung cancer. Tumour Biol. 37:9503–9510. 2016. View Article : Google Scholar : PubMed/NCBI

9 

Gan Y, Han N, He X, Yu J, Zhang M, Zhou Y, Liang H, Deng J, Zheng Y, Ge W, et al: Long non-coding RNA CASC2 regulates cell biological behaviour through the MAPK signalling pathway in hepatocellular carcinoma. Tumor Biol. 39:10104283177062292017. View Article : Google Scholar

10 

Wang R, Li Y, Zhu G, Tian B, Zeng W, Yang Y and Li Z: Long noncoding RNA CASC2 predicts the prognosis of glioma patients and functions as a suppressor for gliomas by suppressing Wnt/β-catenin signaling pathway. Neuropsychiatr Dis Treat. 13:1805–1813. 2017. View Article : Google Scholar : PubMed/NCBI

11 

Zhou J, Huang H, Tong S and Huo R: Overexpression of long non-coding RNA cancer susceptibility 2 inhibits cell invasion and angiogenesis in gastric cancer. Mol Med Rep. 16:5235–5240. 2017. View Article : Google Scholar : PubMed/NCBI

12 

Cao Y, Xu R, Xu X, Zhou Y, Cui L and He X: Downregulation of lncRNA CASC2 by microRNA-21 increases the proliferation and migration of renal cell carcinoma cells. Mol Med Rep. 14:1019–1025. 2016. View Article : Google Scholar : PubMed/NCBI

13 

Yu Y, Liang S, Zhou Y, Li S, Li Y and Liao W: HNF1A/CASC2 regulates pancreatic cancer cell proliferation through PTEN/Akt signaling. J Cell Biochem. 2017.(Epub ahead of print). View Article : Google Scholar

14 

Yang X, Wang J, Li WP, Jin ZJ and Liu XJ: Desmocollin 3 mediates follicle stimulating hormone-induced ovarian epithelial cancer cell proliferation by activating the EGFR/Akt signaling pathway. Int J Clin Exp Patho. 8:6716–6723. 2015.

15 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

16 

Prat J: Staging classification for cancer of the ovary, fallopian tube, and peritoneum. International journal of gynaecology and obstetrics: The official organ of the International Federation of Gynaecology and Obstetrics. 124:1–5. 2014. View Article : Google Scholar : PubMed/NCBI

17 

Bhan A, Soleimani M and Mandal SS: Long Noncoding RNA and Cancer: A New Paradigm. Cancer Res. 77:3965–3981. 2017. View Article : Google Scholar : PubMed/NCBI

18 

Jarroux J, Morillon A and Pinskaya M: History, discovery, and classification of lncRNAs. Adv Exp Med Biol. 1008:1–46. 2017. View Article : Google Scholar : PubMed/NCBI

19 

Shen L, Liu W, Cui J, Li J and Li C: Analysis of long non-coding RNA expression profiles in ovarian cancer. Oncol Lett. 14:1526–1530. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Zhou M, Sun Y, Sun Y, Xu W, Zhang Z, Zhao H, Zhong Z and Sun J: Comprehensive analysis of lncRNA expression profiles reveals a novel lncRNA signature to discriminate nonequivalent outcomes in patients with ovarian cancer. Oncotarget. 7:32433–32448. 2016.PubMed/NCBI

21 

Wang LL, Sun KX, Wu DD, Xiu YL, Chen X, Chen S, Zong ZH, Sang XB, Liu Y and Zhao Y: DLEU1 contributes to ovarian carcinoma tumourigenesis and development by interacting with miR-490-3p and altering CDK1 expression. J Cell Mol Med. 21:3055–3065. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Medrzycki M, Zhang Y, Zhang W, Cao K, Pan C, Lailler N, McDonald JF, Bouhassira EE and Fan Y: Histone h1.3 suppresses h19 noncoding RNA expression and cell growth of ovarian cancer cells. Cancer Res. 74:6463–6473. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Dong L and Hui L: HOTAIR promotes proliferation, migration, and invasion of ovarian cancer SKOV3 cells through regulating PIK3R3. Med Sci Monit. 22:325–331. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Teschendorff AE, Lee SH, Jones A, Fiegl H, Kalwa M, Wagner W, Chindera K, Evans I, Dubeau L, Orjalo A, et al: HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer. Genome Med. 7:1082015. View Article : Google Scholar : PubMed/NCBI

25 

Zhang Z, Cheng J, Wu Y, Qiu J, Sun Y and Tong X: LncRNA HOTAIR controls the expression of Rab22a by sponging miR-373 in ovarian cancer. Mol Med Rep. 14:2465–2472. 2016. View Article : Google Scholar : PubMed/NCBI

26 

Ozes AR, Miller DF, Ozes ON, Fang F, Liu Y, Matei D, Huang T and Nephew KP: NF-κB-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer. Oncogene. 35:5350–5361. 2016. View Article : Google Scholar : PubMed/NCBI

27 

Chai Y, Liu J, Zhang Z and Liu L: HuR-regulated lncRNA NEAT1 stability in tumorigenesis and progression of ovarian cancer. Cancer Med. 5:1588–1598. 2016. View Article : Google Scholar : PubMed/NCBI

28 

An J, Lv W and Zhang Y: LncRNA NEAT1 contributes to paclitaxel resistance of ovarian cancer cells by regulating ZEB1 expression via miR-194. Onco Targets Ther. 10:5377–5390. 2017. View Article : Google Scholar : PubMed/NCBI

29 

Zhou Y, Xu X, Lv H, Wen Q, Li J, Tan L, Li J and Sheng X: The long noncoding RNA MALAT-1 is highly expressed in ovarian cancer and induces cell growth and migration. PLoS One. 11:e01552502016. View Article : Google Scholar : PubMed/NCBI

30 

Mitra R, Chen X, Greenawalt EJ, Maulik U, Jiang W, Zhao Z and Eischen CM: Decoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition. Nat Commun. 8:16042017. View Article : Google Scholar : PubMed/NCBI

31 

Ren C, Li X, Wang T, Wang G, Zhao C, Liang T, Zhu Y, Li M, Yang C, Zhao Y and Zhang GM: Functions and mechanisms of long noncoding RNAs in ovarian cancer. Int J Gynecol Cancer. 25:566–569. 2015. View Article : Google Scholar : PubMed/NCBI

32 

Cheng Z, Guo J, Chen L, Luo N, Yang W and Qu X: A long noncoding RNA AB073614 promotes tumorigenesis and predicts poor prognosis in ovarian cancer. Oncotarget. 6:25381–25389. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Huang S, Qing C, Huang Z and Zhu Y: The long non-coding RNA CCAT2 is up-regulated in ovarian cancer and associated with poor prognosis. Diagn Pathol. 11:492016. View Article : Google Scholar : PubMed/NCBI

34 

Yan C, Jiang Y, Wan Y, Zhang L, Liu J, Zhou S and Cheng W: Long noncoding RNA NBAT-1 suppresses tumorigenesis and predicts favorable prognosis in ovarian cancer. Onco Targets Ther. 10:1993–2002. 2017. View Article : Google Scholar : PubMed/NCBI

35 

Palmieri G, Paliogiannis P, Sini MC, Manca A, Palomba G, Doneddu V, Tanda F, Pascale MR and Cossu A: Long non-coding RNA CASC2 in human cancer. Crit Rev Oncol Hematol. 111:31–38. 2017. View Article : Google Scholar : PubMed/NCBI

36 

Ba Z, Gu L, Hao S, Wang X, Cheng Z and Nie G: Downregulation of lncRNA CASC2 facilitates osteosarcoma growth and invasion through miR-181a. Cell Prolif. 51:2018. View Article : Google Scholar : PubMed/NCBI

37 

Zeng F, Le YG, Fan JC and Xin L: LncRNA CASC2 inhibited the viability and induced the apoptosis of hepatocellular carcinoma cells through regulating miR-24-3p. J Cell Biochem. 119:6391–6397. 2018. View Article : Google Scholar : PubMed/NCBI

38 

Liao Y, Shen L, Zhao H, Liu Q, Fu J, Guo Y, Peng R and Cheng L: LncRNA CASC2 interacts with miR-181a to modulate glioma growth and resistance to TMZ through PTEN pathway. J Cell Biochem. 118:1889–1899. 2017. View Article : Google Scholar : PubMed/NCBI

39 

Jiang C, Shen F, Du J, Fang X, Li X, Su J, Wang X, Huang X and Liu Z: Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR-193a-5p and regulating mTOR expression. Biomed Pharmacother. 97:844–850. 2018. View Article : Google Scholar : PubMed/NCBI

40 

Liu C, Sun Y, She X, Tu C, Cheng X, Wang L, Yu Z, Li P, Liu Q, Yang H, et al: CASC2c as an unfavorable prognosis factor interacts with miR-101 to mediate astrocytoma tumorigenesis. Cell Death Dis. 8:e26392017. View Article : Google Scholar : PubMed/NCBI

41 

Zhang W, He W, Gao J, Wang Y, Zang W, Dong Z and Zhao G: Retraction notice to the long noncoding RNA CASC2 inhibits tumorigenesis through modulating the expression of PTEN by targeting miR-18a-5p in esophageal carcinoma. Exp Cell Res. 361:30–38. 2017. View Article : Google Scholar : PubMed/NCBI

42 

Wang Y, Liu Z, Yao B, Li Q, Wang L, Wang C, Dou C, Xu M, Liu Q and Tu K: Long non-coding RNA CASC2 suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells through CASC2/miR-367/FBXW7 axis. Mol Cancer. 16:1232017. View Article : Google Scholar : PubMed/NCBI

43 

Wang P, Liu YH, Yao YL, Li Z, Li ZQ, Ma J and Xue YX: Long non-coding RNA CASC2 suppresses malignancy in human gliomas by miR-21. Cell Signal. 27:275–282. 2015. View Article : Google Scholar : PubMed/NCBI

44 

Feng Y, Zou W, Hu C, Li G, Zhou S, He Y, Ma F, Deng C and Sun L: Modulation of CASC2/miR-21/PTEN pathway sensitizes cervical cancer to cisplatin. Arch Biochem Biophys. 623–624:20–30. 2017. View Article : Google Scholar

45 

Pei Z, Du X, Song Y, Fan L, Li F, Gao Y, Wu R, Chen Y, Li W, Zhou H, et al: Down-regulation of lncRNA CASC2 promotes cell proliferation and metastasis of bladder cancer by activation of the Wnt/beta-catenin signaling pathway. Oncotarget. 8:18145–18153. 2017. View Article : Google Scholar : PubMed/NCBI

46 

Xiong X, Zhu H and Chen X: Low expression of long noncoding RNA CASC2 indicates a poor prognosis and promotes tumorigenesis in thyroid carcinoma. Biomed Pharmacother. 93:391–397. 2017. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

December-2018
Volume 18 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Xue Z, Zhu X and Teng Y: Long non‑coding RNA CASC2 inhibits progression and predicts favorable prognosis in epithelial ovarian cancer. Mol Med Rep 18: 5173-5181, 2018.
APA
Xue, Z., Zhu, X., & Teng, Y. (2018). Long non‑coding RNA CASC2 inhibits progression and predicts favorable prognosis in epithelial ovarian cancer. Molecular Medicine Reports, 18, 5173-5181. https://doi.org/10.3892/mmr.2018.9550
MLA
Xue, Z., Zhu, X., Teng, Y."Long non‑coding RNA CASC2 inhibits progression and predicts favorable prognosis in epithelial ovarian cancer". Molecular Medicine Reports 18.6 (2018): 5173-5181.
Chicago
Xue, Z., Zhu, X., Teng, Y."Long non‑coding RNA CASC2 inhibits progression and predicts favorable prognosis in epithelial ovarian cancer". Molecular Medicine Reports 18, no. 6 (2018): 5173-5181. https://doi.org/10.3892/mmr.2018.9550