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3980-3986-Long Noncoding RNA PVT1 As a Novel Serum Biomarker

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3980-3986-Long Noncoding RNA PVT1 As a Novel Serum Biomarker Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 3980-3986 Long noncoding RNA PVT1 as a novel serum biomarker for detection of cervical cancer J.-P. YANG, X.-J. YANG, L. XIAO, Y. WANG Department of Laboratory, the Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China Abstract. – OBJECTIVE : To investigate long There were 527,600 estimated new cases of CC noncoding RNA PVT1 expression in the serum and 265,700 estimated deaths of CC in 2012 of cervical cancer patients, and to evaluate worldwide 1. The prognosis of CC patients is serum PVT1 level as a diagnostic biomarker for closely associated with the clinical stage 2. Most cervical cancer. PATIENTS AND METHODS: Eighty-eight cervi - of CC patients with early stage could be suc - cal cancer patients, 64 cervical intraepithelial cessfully cured, but the survival rate of CC pa - neoplasia patients, 25 breast cancer patients, 25 tients diagnosed at the late stages is as low as ovarian cancer patients, and 111 healthy control 15% 3. Therefore, early diagnosis and therapy subjects were enrolled into this study. PVT1 could significantly reduce mortality of CC pa - serum level in these participants and PVT1 ex - tients 4,5 . pression in 20 pairs of cervical cancer tissues and adjacent paired normal tissues was mea - Although cervical smear cytological exami - sured by quantitative reverse transcription-poly - nation is the mainly screening method of early merase chain reaction. The diagnostic values of diagnosis of CC, the inconveniences of exam in - serum PVT1 were evaluated by receiver operat - ing and high false-negative rate limit its applica - ing characteristic curves analysis. tion 6,7 . In addition to cervical smear cytological RESULTS: Serum PVT1 level is significantly in - examination, serum biomarkers, including carbo - creased in cervical cancer patients and correlat - hydrate antigen 125 (CA125) and squamous cell ed with tumor size, clinical stage, and lymph node metastasis of cervical cancer. Serum PVT1 carcinoma antigen (SCC Ag), are commonly 8,9 could accurately discriminate cervical cancer used for the diagnosis of CC . However, the low patients from cervical intraepithelial neoplasia diagnostic sensitivity and specificity limit their patients and healthy control subjects, and also utility 10 . Therefore, novel noninvasive diagnostic discriminate early stage cervical cancer patients biomarkers with high sensitivity and specificity from healthy control subjects. But serum PVT1 are urgently required. level is not changed in breast cancer and ovari - an cancer patients. Furthermore, serum PVT1 Long noncoding RNAs (lncRNAs), which are level is positively correlated with tissue PVT1 ex - longer than 200 nucleotides with limited protein - pression, and could indicate cervical cancer dy - coding potential, have multiple functions in vari - namics. ous pathophysiological processes and are dysreg - CONCLUSIONS: Long noncoding RNA PVT1 ulated in many kinds of diseases, particular in may be a novel noninvasive biomarker for early cancers 11-15 . LncRNA PVT1, CCAT2, HOTAIR, diagnosis of cervical cancer . XLOC_010588, MALAT1, lnc-CC3, and et al. Key Words: have been reported to be upregulated in CC and 16-22 Long noncoding RNA, PVT1, Cervical cancer, promote CC progression . While other lncR - Serum, Biomarker, Diagnosis . NAs, such as GAS5, LET, and MEG3 are down - regulated in CC and inhibit CC progression 23-25 . However, whether these lncRNAs are present in peripheral blood and could be used as diagnostic biomarkers for CC is still unknown. LncRNAs Introduction are really detectable and could be used as diag - nostic biomarkers for many cancers, such as Cervical cancer (CC) is the fourth most com - lncRNA H19, CUDR, LSINCT-5, PTPEN1, and mon cancer and fourth most frequent cause of UCA1 for gastric cancer 26-28 ; HOTTIP-005 and cancer mortality affecting woman in the world 1. HOTTIP-001 for pancreatic cancer 29 ; POU3F3 3980 Corresponding Author: Ying Wang, MD; e-mail: [email protected] Long noncoding RNA PVT1 as a novel serum biomarker for detection of cervical cancer for esophageal squamous cell carcinoma 30 ; XIST RNA Extraction and HIF1A-AS1 for non-small cell lung cancer 31 ; Venus blood was collected from fasting sub - UCA1, WRAP53, uc003wbd, and AF085935 for jects and centrifuged at 3000 rpm for 15 min at 4 hepatocellular carcinoma 32,33 . °C. The supernatant was immediately collected Many reports have shown that lncRNA PVT1 and stored at -80 °C until use . All CC tissues and was increased in CC tissues, associated with paired normal tissues were immediately frozen in poor prognosis, and promoted CC develop - liquid nitrogen and stored at -80 °C until use af - ment 16,17 . In this study, we further measured ter surgery. Total RNAs were extracted from tis - serum PVT1 levels in a large cohort of CC pa - sues and serum using the Trizol reagent (Invitro - tients, cervical intraepithelial neoplasia (CIN) gen, Carlsbad, CA, USA ) according to the manu - patients, and healthy control (HC) subjects, and facturer’s instructions . analyzed the diagnostic sensitivity and specifici - ty of serum PVT1 for CC . Our results showed Quantitative Reverse Transcription- that serum PVT1 is significantly increased in CC Polymerase Chain Reaction (qRT-PCR) patients and could accurately discriminate CC LncRNAs expressions in serum and tissues of patients from CIN patients and HC subjects. CC patients were measured with qRT-PCR as - However, serum PVT1 is not changed in breast says. Complementary DNA was synthesized us - cancer and ovarian cancer patients. Furthermore, ing the PrimeScript™ II 1st Strand cDNA Syn - serum PVT1 level is positively correlated with thesis Kit (Takara, Dalian, China) following the tissue PVT1 expression, and serum PVT1 level manufacturer’s instructions . Quantitative PCR is significantly decreased in post-surgery CC pa - was performed using the SYBR ® Premix Ex tients. Collectively, our data suggested that Taq™ II (Takara) on StepOnePlus™ Real-Time PVT1 may be a novel noninvasive diagnostic PCR Systems (Applied Biosystems, Foster City, biomarker for CC. CA, USA) following the manufacturer’s instruc - tions in triplicate . PVT1 expression in serum and tissues was normalized to GAPDH using the Materials and Methods comparative Ct method. The primer sequences used were as follows: for PVT1 , 5’- ATAGATC - Patients and Samples CTGCCCTGTTTGC-3’ (forward) and 5’- The Ethics Committee of the Affiliated Hospi - CATTTCCTGCTGCCGTTTTC-3’ (reverse); for tal of Jiangxi University of Traditional Chinese GAPDH, 5’- GGAGCGAGATCCCTCCAAAAT- Medicine approved the collection and usage of 3’ (forward) and 5’-GGCTGTTGTCATACTTCT - human specimens . A total of 88 CC patients, 64 CATGG-3’ (reverse) . CIN patients, 25 breast cancer patients, 25 ovari - an cancer patients, and 111 healthy control (HC) Statistical Analysis subjects were enrolled into this study at the Affil - Statistical analyses were performed with the iated Hospital of Jiangxi University of Tradition - GraphPad Prism Software. Mann-Whitney U test al Chinese Medicine . All the patients were diag - or Wilcoxon signed-rank test was used to com - nosed and confirmed by pathological examina - pare serum or tissues PVT1 level between differ - tion in our hospital. CC clinical stages were de - ent groups as indicated. Receiver operating char - termined following the International Federation acteristic (ROC) curves analysis was used to as - of Gynecology and Obstetrics (FIGO). All the sess the sensitivity and specificity of serum HC subjects enrolled in this study were age- PVT1 for CC diagnosis. Pearson correlation matched women with normal cervix examined in analysis was used to evaluate the correlation be - our hospital. Women diagnosed with other tu - tween serum and tissues PVT1 level. p-values < mors, pregnancy, or other chronic diseases are 0.05 was defined as statistically significant . excluded from our study. Twenty fresh CC tis - sues and adjacent paired normal tissues were ob - tained during the surgical resection in our hospi - Results tal. None of the patients received radiation thera - py, chemotherapy, or immunotherapy before the PVT1 is Increased in the Serum of collection of peripheral blood or surgical resec - CC Patients tion . All the patients and HC subjects signed in - To evaluate the clinical significance of serum formed consent . PVT1, we first quantified PVT1 expression by 3981 J.-P. Yang, X.-J. Yang, L. Xiao, Y. Wang qRT-PCR in the serum of 88 CC patients, 64 CIN Table I. Clinical features of the cervical cancer (CC) pa - patients, and 86 age-matched healthy control tients, cervical intraepithelial neoplasia (CIN) patients and (HC) subjects. The clinical features of CC pa - healthy control (HC) subjects. tients, CIN patients, and HC subjects are shown Variable CC CIN HC in Table I. In comparison to HC subjects, PVT1 was significantly increased in CIN patients, and All cases 88 64 86 was further increased in CC patients (Figure 1A). Age Next, we detected the correlation between serum < 50 49 36 45 ≥ 50 39 28 41 PVT1 level and clinical features in the 88 CC pa - Tumor size (cm) tients. As shown in Figure 1B, PVT1 was in - < 4 48 creased in CC patients with larger tumor size. ≥ 4 40 Furthermore, PVT1 was increased in CC patients Histology with advanced FIGO stage (Figure 1C). In com - Squamous 73 Adenocarcinoma 15 parison to CC patients without lymph node FIGO stage metastasis, PVT1 was increased in CC patients I 45 with lymph node metastasis (Figure 1D). II 39 III 4 Circulating PVT1 Could be Used as a Differentiation Well/moderate 58 Novel Noninvasive Biomarker for CC Poor 30 To evaluate whether serum PVT1 could be Lymph node metastasis used as a novel diagnostic biomarker for CC, re - Negative 66 Positive 22 Figure 1. Serum PVT1 levels in CC and CIN patients and its correlation with clinical features. A, Serum PVT1 levels in 88 CC patients, 64 CIN patients, and 86 HC subjects. B, Serum PVT1 levels in CC patients with tumor size < 4 cm or tumor size ≥ 4 cm. C, Serum PVT1 levels in CC patients at different FIGO stages.
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