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Circulating CYTOR as a Potential Biomarker in Breast Cancer

Long non-coding RNAs (lncRNAs) are newly introduced as tumor-related molecules. They are being considered as potential diagnostic and therapeutic targets in cancer studies. Here, we have assessed the importance of CYTOR (linc00152) as a biomarker for the detection of breast cancer in both tumoral tissue and plasma. The relative expression of breast cancer-associated CYTOR was measured in 20 tumoral and paired margin tissues, and moreover, in 80 plasma samples by real-time-polymerase chain reaction. In addition, plasma levels of CA 15-3 were measured using the ELISA test. The receiver operating characteristic curve (ROC) was applied for assessing the sensitivity and specificity of tested biomarkers. The results of the present study disclosed significantly increases in the CYTOR expression levels in tumor tissue with relative quantitation (RQ) equals to 5.15 (P<0.001) and in plasma (RQ =3.03, P<0.01) of breast cancer patients. The area under the ROC curve (AUC) of circulating CYTOR was 0.907 (95% CI: 0.842-0.972, P<0.001), while it was 0.868 (95% CI: 0.783–0.952, P<0.001) for CA 15-3. Based on these findings, we suggest lncRNA CYTOR as a new potential biomarker for breast cancer detection in both solid tumor tissue and plasma.

Early detection is critical for reducing the mortality and improving prognosis of this malignancy. Blood-based testing is recom-mended for detecting cancer biomarkers due to its easiness and lower invasiveness (4).
However, measuring conventional serum biomarkers for BC detection, such as carbohydrate antigens (CA125 and CA15- 3) and carcinoembryonic antigen (CEA) are not convincing in early detection (5). By definition, long non-coding RNAs (lncRNAs) are biomolecules which their length is longer than 200 nucleotides. They can act as oncogenes or tumor suppressor genes, and their aberrant expression is probably involved in the progression of tumors (6). Linc00152, known as a cytoskeleton regulator long non-coding RNA (CYTOR), is an 828 bp gene located on the human chromosome 2p11.2 (7). CYTOR is up-regulated in various cancer types, including all subtypes of BC (8). Furthermore, recently it has been indicated that CYTOR could act as a circulating biomarker for the esophageal squamous-cell carcinoma, gastric cancer, and non-small-cell lung cancer (9)(10)(11). However, the potential clinic value of circulating CYTOR (c.CYTOR) in BC has not been investigated. Therefore, the aim of the present investigation was to study the levels of c.CYTOR in plasma of BC patientsto show its role as a novel BC biomarker.

Participants and sample collection
The BC cases were recruited at the time of

Statistical analysis
Comparisons between groups were analyzed with Student's t-test and X 2 tests.
Statistical analyses were performed using SPSS tumor stages.

The plasma levels of c.CYTOR was significantly higher in BC patients
The relative level of circulating CYTOR expression was determined in each plasma sample. We found that the expression level of CYTOR in plasma samples collected from BC patients was significantly higher than the cancer-free donors (RQ= 3.03, P<0.01, Figure   1B). This excess lncRNA CYTOR in the patient's plasma is probably released from the tumor. Also, the analysis showed the absence of a significant correlation between the c.CYTOR levels and the status of hormone-responsiveness markers (ER, PR, or HER2) or tumor stages.

Analysis of c.CYTOR stability in plasma
To analyze the lncRNA stability in plasma, three plasma samples were divided into 4 equal parts, and incubated at room temperature for 0, 6, 12, and 24 h. Through defined time, no  Since it can be speculated that lncRNAs in circulation are unstable, thus, we then attempted to assess the stability of CYTOR in circulation. The results disclosed that CYTOR levels remained stable in plasma, which was consistent with previous studies (9,11). Afterwards, we further found that  (32).
CYTOR through the epidermal growth factor receptor (EGFR)-dependent pathway could promote cell viability (33) and through binding to the enhancer of zeste homolog 2 (EZH2) and consequently repressing p15 and p21 triggers cell cycle progression in gastric tumor (34).
Furthermore, CYTOR through EGFR/PI3K/ATK pathway was shown to support cell viability and invasion in lung cancer (35). Some studies indicated that CYTOR can promote EMT in gastric cancer cells, liver cancer cells, and BC cells (28,30,36). EMT is a cellular process that is involved in tumor metastasis. In liver cancer cells, CYTOR could promote EMT by interacting with EZH2 and suppression of E-cadherin (28).
Totally, it seems that CYTOR through activation of EGFR signaling and suppression of PTEN and E-cadherin promotes EMT, which plays an important role in BC progression.
In conclusion, the findings of the present study suggest a role for plasma levels of lncRNA CYTOR as a candidate biomarker for BC that its level significantly increases in plasma of patients affected with BC. However, the biomarker role of this lncRNA needs to be investigated in other populations.