The deubiquitinase OTUB1 fosters papillary thyroid carcinoma growth through EYA1 stabilization

Deubiquitinating enzyme OTU domain-containing ubiquitin aldehyde-binding proteins 1 (OTUB1) has been shown to have an essential role in multiple carcinomas. However, the function of OTUB1 in papillary thyroid cancer (PTC) and the underlying mechanisms regulating PTC cells proliferation remain poorly understood. In this study, OTUB1 was significantly upregulated in papillary thyroid carcinoma tissues and cells. Through in vitro and in vivo experiments, knockdown of OTUB1 suppressed PTC cells growth whereas OTUB1 overexpression enhanced the proliferation ability of PTC cells. Moreover, the eyes absent homologue 1 (EYA1) was recognized as a potential target of OTUB1 through mass spectrometry analysis, and we further verified that EYA1 protein level was positively correlated with OTUB1 expression in PTC cells and clinical samples. Mechanistically, OTUB1 could interact with EYA1 directly and deubiquitinate EYA1 to stabilize it. At last, EYA1 was found to play an essential role in OTUB1-derived PTC cells growth. Overall, our investigation reveals that OTUB1 is a previously unrecognized oncogenic factor in PTC cells proliferation and suggests that OTUB1 might be a novel therapeutic target in PTC.     

Overexpression of lncRNA SLC26A4-AS1 inhibits papillary thyroid carcinoma progression through recruiting ETS1 to promote ITPR1-mediated autophagy

Papillary thyroid carcinoma (PTC), accounting for approximately 85% cases of thyroid cancer, is a common endocrine tumour with a relatively low mortality but an alarmingly high rate of recurrence or persistence. Long non-coding RNAs (lncRNAs) is emerging as a critical player modulating diverse cellular mechanisms correlated with the progression of various cancers, including PTC. Herein, we aimed to investigate the role of lncRNA SLC26A4-AS1 in regulating autophagy and tumour growth during PTC progression. Initially, ITPR1 was identified by bioinformatics analysis as a differentially expressed gene. Then, Western blot and RT-qPCR were conducted to determine the expression of ITPR1 and SLC26A4-AS1 in PTC tissues and cells, both of which were found to be poorly expressed in PTC tissues and cells. Then, we constructed ITPR1-overexpressing cells and revealed that ITPR1 overexpression could trigger the autophagy of PTC cells. Further, we performed a series of gain- and loss-of function experiments. The results suggested that silencing of SLC26A4-AS1 led to declined ITPR1 level, up-regulation of ETS1 promoted ITPR1 expression, and either ETS1 knockdown or autophagy inhibitor Bafilomycin A1 could mitigate the promoting effects of SLC26A4-AS1 overexpression on PTC cell autophagy. In vivo experiments also revealed that SLC26A4-AS1 overexpression suppressed PTC tumour growth. In conclusion, our study elucidated that SLC26A4-AS1 overexpression promoted ITPR1 expression through recruiting ETS1 and thereby promotes autophagy, alleviating PTC progression. These finding provides insight into novel target therapy for the clinical treatment of PTC.     

Expression of TGF-β1, SNAI1 and MMP-9 is associated with lymph node metastasis in papillary thyroid carcinoma

TGF-β1, SNAI1 and MMP-9 are implicated in tumor invasion and metastasis. The purpose of this study was to examine TGF-β1, SNAI1 and MMP-9 expression in papillary thyroid carcinoma (PTC), and to assess association of TGF-β1, SNAI1 and MMP-9 expression with several clinicopathological indicators of PTC. TGF-β1, SNAI1 and MMP-9 protein expression in 83 PTCs and their matched normal thyroid specimens were analyzed using immunohistochemistry. The mRNA expression levels of TGF-β1, SNAI1 and MMP-9 in 12 fresh PTC specimens with lymph node metastasis (LNM), 12 fresh PTC specimens without LNM and their matched normal thyroid specimens were assessed by real-time RT-PCR. The results showed that the mRNA and protein expression levels of TGF-β1, SNAI1 and MMP-9 were significantly higher in PTCs than in their matched normal thyroid tissues. There were not significant differences in TGF-β1, SNAI1 and MMP-9 protein expression relative to age, gender, tumor size and TNM stage, except for MMP-9 whose protein expression correlated with tumor size. However, high mRNA and protein expression levels of TGF-β1, SNAI1 and MMP-9 were significantly correlated with LNM. Furthermore, TGF-β1, SNAI1 and MMP-9 protein expression were significantly correlated with one another. Concomitant expression of any two or all of the three molecules had stronger correlation with LNM than did each alone. Collectively, the present results indicate that immunohistochemical and real-time RT-PCR evaluation of TGF-β1, SNAI1 and MMP-9 expression in PTC may be useful to predict the risk of LNM in PTC patients.     

DNMT3B-mediated FAM111B methylation promotes papillary thyroid tumor glycolysis,growth and metastasis

Over the past decades, the incidence of thyroid cancer (TC) rapidly increased all over the world, with the papillary thyroid cancer (PTC) accounting for the vast majority of TC cases. It is crucial to investigate novel diagnostic and therapeutic targets for PTC and explore more detailed molecular mechanisms in the carcinogenesis and progression of PTC. Based on the TCGA and GEO databases, FAM111B is downregulated in PTC tissues and predicts better prognosis in PTC patients. FAM111B suppresses the growth, migration, invasion and glycolysis of PTC both in vitro and in vivo. Furthermore, estrogen inhibits FAM111B expression by DNMT3B methylation via enhancing the recruitment of DNMT3B to FAM111B promoter. DNMT3B-mediated FAM111B methylation accelerates the growth, migration, invasion and glycolysis of PTC cells. In clinical TC patient specimens, the expression of FAM111B is inversely correlated with the expressions of DNMT3B and the glycolytic gene PGK1. Besides, the expression of FAM111B is inversely correlated while DNMT3B is positively correlated with glucose uptake in PTC patients. Our work established E2/DNMT3B/FAM111B as a crucial axis in regulating the growth and progression of PTC. Suppression of DNMT3B or promotion of FAM111B will be potential promising strategies in the estrogen induced PTC.     

Downregulation of miR-33b promotes non-small cell lung cancer cell growth through reprogramming glucose metabolism miR-33b regulates non-small cell lung cancer cell growth

Glucose metabolism is a common target for cancer regulation and microRNAs (miRNAs) are important regulators of this process. Here we aim to investigate a tumor-suppressing miRNA, miR-33b, in regulating the glucose metabolism of non-small cell lung cancer (NSCLC). In our study, quantitative real-time polymerase chain reaction (qRT-PCR) showed that miR-33b was downregulated in NSCLC tissues and cell lines, which was correlated with increased cell proliferation and colony formation. Overexpression of miR-33b through miR-33b mimics transfection suppressed NSCLC proliferation, colony formation, and induced cell-cycle arrest and apoptosis. Meanwhile, miR-33b overexpression inhibited glucose metabolism in NSCLC cells. Luciferase reporter assay confirmed that miR-33b directly binds to the 3′-untranslated region of lactate dehydrogenase A (LDHA). qRT-PCR and Western blot analysis showed that miR-33b downregulated the expression of LDHA. Moreover, introducing LDHA mRNA into cells over-expressing miR-33b attenuated the inhibitory effect of miR-33b on the growth and glucose metabolism in NSCLC cells. Taken together, these results confirm that miR-33b is an anti-oncogenic miRNA, which inhibits NSCLC cell growth by targeting LDHA through reprogramming glucose metabolism.     

mRNA Expression in Papillary and Anaplastic Thyroid Carcinoma: Molecular Anatomy of a Killing Switch

Anaplastic thyroid carcinoma (ATC) is the most lethal form of thyroid neoplasia and represents the end stage of thyroid tumor progression. No effective treatment exists so far. ATC frequently derive from papillary thyroid carcinomas (PTC), which have a good prognosis. In this study, we analyzed the mRNA expression profiles of 59 thyroid tumors (11 ATC and 48 PTC) by microarrays. ATC and PTC showed largely overlapping mRNA expression profiles with most genes regulated in all ATC being also regulated in several PTC. 43% of the probes regulated in all the PTC are similarly regulated in all ATC. Many genes modulations observed in PTC are amplified in ATC. This illustrates the fact that ATC mostly derived from PTC. A molecular signature of aggressiveness composed of 9 genes clearly separates the two tumors. Moreover, this study demonstrates gene regulations corresponding to the ATC or PTC phenotypes like inflammatory reaction, epithelial to mesenchymal transition (EMT) and invasion, high proliferation rate, dedifferentiation, calcification and fibrosis processes, high glucose metabolism and glycolysis, lactate generation and chemoresistance. The main qualitative differences between the two tumor types bear on the much stronger EMT, dedifferentiation and glycolytic phenotypes showed by the ATC.     

Silencing of long noncoding RNA RP11-476D10.1 enhances apoptosis and autophagy while inhibiting proliferation of papillary thyroid carcinoma cells via microRNA-138-5p-dependent inhibition of LRRK2

The distant metastasis in papillary thyroid carcinoma (PTC) is a major threat for PTC patients. Moreover, the involvement of long noncoding RNAs (lncRNAs) in the regulation of PTC progression has been extensively investigated. The aim of this study was to underscore whether lncRNA RP11-476D10.1 affects the proliferation, apoptosis and autophagy of PTC cells. Initially, we determined that lncRNA RP11-476D10.1 and LRRK2 were highly expressed in PTC cells. Meanwhile, through experimentation, miR-138-5p was confirmed to bind with lncRNA RP11-476D10.1 and LRRK2. It was also revealed that lncRNA RP11-476D10.1 downregulated the miR-138-5p expression, thereby upregulating the LRRK2 expression. After that, PTC cells were transfected with siRNA against RP11-476D10.1, or inhibitor or mimic of miR-138-5p to evaluate the influence of lncRNA RP11-476D10.1 on the PTC cell proliferation, apoptosis, and autophagy in vitro and on the tumor formation ability in vivo. The results showed that silenced lncRNA RP11-476D10.1 or overexpressed miR-138-5p enhanced the apoptosis and autophagy of PTC cells while reducing cell proliferation, with increased levels of Bax, LC3B, and Beclin1 and decreased Bcl-2 level were observed. The inhibitory role of silenced lncRNA RP11-476D10.1 role in the PTC development was further verified by the reduced tumor formation ability in nude mice. Our results demonstrated that lncRNA RP11-476D10.1 could bind to miR-138-5p and promote LRRK2 expression. Moreover, the silencing of lncRNA RP11-476D10.1 may inhibit the development of PTC, highlighting a novel insight for the development of superior therapeutic targets for PTC treatment.     

Influence of RET/PTC1 and RET/PTC3 oncoproteins in radiation-induced papillary thyroid carcinomas on amounts of cytoskeletal protein species

Radiation-induced human papillary thyroid carcinomas (PTCs) show a high prevalence of fusions of the RET proto-oncogene to heterologous genes H4 (RET/PTC1) and ELE1 (RET/PTC3), respectively. In contrast to the normal membrane-bound RET protein, aberrant RET fusion proteins are constitutively active oncogenic cytosolic proteins that can lead to malignant transformation of thyroid epithelia. To detect specific tumor-associated protein changes that reflect the effect of RET/PTC fusion proteins, we analyzed normal thyroid tissues, thyroid tumors of the RET/PTC1 and RET/PTC3 type and their respective lymph node metastases by a combination of high-resolution two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-mass spectrometry. PTCs without RET rearrangements served as controls. Several cytoskeletal protein species showed quantitative changes in tumors and lymph node metastases harboring RET/PTC1 or RET/PTC3. We observed prominent C-terminal actin fragments assumedly generated by protease cleavages induced due to enhanced amounts of the active actin-binding protein cofilin-1. In addition, three truncated vimentin species, one of which was proven to be headless, were shown to be highly abundant in tumors and metastases of both RET/PTC types. The observed protein changes are closely connected with the constitutive activation of RET-rearranged oncoproteins and reflect the importance to elucidate disease-related typical signatures on the protein species level.     

RBM47/SNHG5/FOXO3 axis activates autophagy and inhibits cell proliferation in papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) is the main type of thyroid carcinoma. Despite the good prognosis, some PTC patients may deteriorate into more aggressive diseases, leading to poor survival. Molecular technology has been increasingly used in the diagnosis and treatment of thyroid carcinoma. In this study, we identified that RNA Binding Motif Protein 47 (RBM47) was downregulated in PTC tissues and cells, and overexpression of RBM47 could activate autophagy and inhibit proliferation in PTC cells. RBM47 promotes but can not bind directly to Forkhead Box O3 (FOXO3). FOXO3 activates Autophagy Related Gene 3 (ATG3), ATG5, and RBM47 to form a loop and promote autophagy. RBM47 can bind directly to and stabilized lncRNA Small Nucleolar RNA Host Gene 5 (SNHG5) to inhibit PTC cells proliferation and activate autophagy in vitro and in vivo. SNHG5 inhibits ubiquitination and degradation of FOXO3 by recruiting Ubiquitin Specific Peptidase 21 (USP21), then promotes the translocation of FOXO3 from cytoplasm to nucleus. Our study revealed the regulatory mechanism of RBM47/SNHG5/FOXO3 axis on cell proliferation and autophagy in PTC, which may provide valuable insight for the treatment of PTC.Subject terms: Oncogenes, Head and neck cancer     

Overexpression of miR-329-3p sensitizes osteosarcoma cells to cisplatin through suppression of glucose metabolism by targeting LDHA

Osteosarcoma (OS) is one of the most frequent malignant bone tumor types. Traditional treatments of OS involve standard chemotherapy or combination with radiation before and after surgery. Cisplatin is one of the most effective chemotherapeutic drugs used for treating osteosarcoma. However, patients with advanced tumor stages develop cisplatin resistance, leading to a major clinical challenge. In this study, we investigated the roles of miR-329-3p in cisplatin sensitivity of osteosarcoma cells. We found miR-329-3p was significantly downregulated in osteosarcoma tissues compared with normal bone tissues. Overexpression of miR-329-3p suppressed osteosarcoma cell proliferation. Moreover, we observed low-toxic cisplatin treatments suppressed miR-329-3p but higher concentrations of cisplatin-induced miR-329-3p expression. In addition, miR-329-3p was significantly downregulated in cisplatin-resistant Saos-2 cells which displayed elevated glucose metabolism. Overexpression of miR-329-3p significantly impaired glucose metabolism of Saos-2 cells. Bioinformatics analysis and luciferase assay consistently demonstrated the glycolysis enzyme, lactate dehydrogenase-A (LDHA) was a direct target of miR-329-3p in osteosarcoma cells. Rescue experiments revealed restoration of LDHA in miR-329-3p-overexpressed cisplatin-resistant cells effectively recovered glucose metabolism, resulting in increased cisplatin resistance. This study demonstrates a miR-329-3p-LDHA-glucose metabolism-cisplatin resistance axis in osteosarcoma cells, providing a miRNA-based therapeutic strategy against chemoresistant osteosarcoma.     

ANXA2P2/miR-9/LDHA axis regulates Warburg effect and affects glioblastoma proliferation and apoptosis

BackgroundAerobic glycolysis is a unique tumor cell phenotype considered as one of the hallmarks of cancer. Aerobic glycolysis can accelerate tumor development by increasing glucose uptake and lactate production. In the present study, lactate dehydrogenase A (LDHA) is significantly increased within glioma tissue samples and cells, further confirming the oncogenic role of LDHA within glioma.MethodsHematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were applied for histopathological examination. The protein levels of LDHA, transporter isoform 1 (GLUT1), hexokinase 2 (HK2), phosphofructokinase (PFK) in target cells were detected by Immunoblotting. The predicted miR-9 binding to lncRNA Annexin A2 Pseudogene 2 (ANXA2P2) or the 3′ untranslated region (UTR) of LDHA was verified using Luciferase reporter assay. Cell viability or apoptosis were examined by MTT assay or Flow cytometry. Intracellular glucose and Lactate levels were measured using glucose assay kit and lactate colorimetric assay kit.ResultsThe expression of ANXA2P2 showed to be dramatically upregulated within glioma tissue samples and cells. Knocking down ANXA2P2 within glioma cells significantly inhibited cell proliferation and aerobic glycolysis, as manifested as decreased lactate and increased glucose in culture medium, and downregulated protein levels of glycolysis markers, GLUT1, HK2, PFK, as well as LDHA. miR-9 was predicted to target both lncRNA ANXA2P2 and LDHA. The overexpression of miR-9 suppressed the cell proliferation and aerobic glycolysis of glioma cells. Notably, miR-9 could directly bind to LDHA 3′UTR to inhibit LDHA expression and decrease the protein levels of LDHA. ANXA2P2 competitively targeted miR-9, therefore counteracting miR-9-mediated repression on LDHA. Within tissues, miR-9 exhibited a negative correlation with ANXA2P2 and LDHA, respectively, whereas ANXA2P2 and LDHA exhibited a positive correlation with each other.ConclusionsIn conclusion, ANXA2P2/miR-9/LDHA axis modulates the aerobic glycolysis progression in glioma cells, therefore affecting glioma cell proliferation.     

BRAF mutation and RASSF1A expression in thyroid carcinoma of southern Italy

Aim of this work is to provide a detailed comparison of clinical‐pathologic features between well‐differentiated and poorly differentiated tumors according to their BRAF and RASSF1A status. We analyzed RASSF1A methylation by MSP and BRAF mutation by LCRT‐PCR with LightMix® kit BRAF V600E in neoplastic thyroid tissues. Immunohistochemical evaluation of RASSF1A expression was also performed by standard automated LSAB‐HRP technique. An overall higher degree of RASSF1A over‐expression than normal thyroid parenchyma surrounding tumors (P < 0.05) has been found in all malignant well‐differentiated lesions. Moreover, statistically significant higher levels of RASSF1A expression were observed in differentiated cancers associated to an inflammatory autoimmune background (P = 0.01). Amplifiable DNA for LC PCR with LightMix® kit BRAF V600E was obtained in nine PTCs, four FVPTCs, five ATCs, and one control. The V600E mutation was found in 13 of 18 (72%) tumors. BRAF was mutated in 6 of 9 (66%) classical PTC, in 2 of 4 (50%) follicular variant PTC and in all ACs (100%). The overall frequency of RASSF1A promoter methylation observed was 20.5% (9 cases out 44). Hypermethylation of RASSF1A in primary tumors was variable according to histotypes ranging from100% (5/5) in ACs to only 12.5% (4/32) in PTCs. We show a correlation between RASSF1A methylation status and RASSF1A protein expression. Finally, we conclude that BRAF V600E mutation and RASSF1A methylation were pathogenetic event restricted to a subgroup of PTC/FVPTCs in early stage and to clinically aggressive ATCs. J. Cell. Biochem. 114: 1174–1182, 2013. © 2012 Wiley Periodicals, Inc.     

1-Methylnicotinamide ameliorates lipotoxicity-induced oxidative stress and cell death in kidney proximal tubular cells

Free fatty acid-bound albumin (FFA-albumin)-related oxidative stress is involved in the pathogenesis of proximal tubular cell (PTC) damage and subsequent renal dysfunction in patients with refractory proteinuria. Nicotinamide adenine dinucleotide (NAD) metabolism has recently been focused on as a novel therapeutic target for several modern diseases, including diabetes. This study was designed to identify a novel molecule in NAD metabolism to protect PTCs from lipotoxicity-related oxidative stress. Among 19 candidate enzymes involved in mammalian NAD metabolism, the mRNA expression level of nicotinamide n-methyltransferase (NNMT) was significantly increased in both the kidneys of FFA-albumin-overloaded mice and cultured PTCs stimulated with palmitate-albumin. Knockdown of NNMT exacerbated palmitate-albumin-induced cell death in cultured PTCs, whereas overexpression of NNMT inhibited it. Intracellular concentration of 1-Methylnicotinamide (1-MNA), a metabolite of NNMT, increased and decreased in cultured NNMT-overexpressing and -knockdown PTCs, respectively. Treatment with 1-MNA inhibited palmitate-albumin-induced mitochondrial reactive oxygen species generation and cell death in cultured PTCs. Furthermore, oral administration of 1-MNA ameliorated oxidative stress, apoptosis, necrosis, inflammation, and fibrosis in the kidneys of FFA-albumin-overloaded mice. In conclusion, NNMT-derived 1-MNA can reduce lipotoxicity-mediated oxidative stress and cell damage in PTCs. Supplementation of 1-MNA may have potential as a new therapy in patients with refractory proteinuria.     

Notch Pathway Is Activated by MAPK Signaling and Influences Papillary Thyroid Cancer Proliferation

Mutually exclusive genetic alterations in the RET, RAS, or BRAF genes, which result in constitutively active mitogen-activated protein kinase (MAPK) signaling, are present in about 70% of papillary thyroid carcinomas (PTCs). However, the effect of MAPK activation on other signaling pathways involved in oncogenic transformation, such as Notch, remains unclear. In this study, we tested the hypothesis that the MAPK pathway regulates Notch signaling and that Notch signaling plays a role in PTC cell proliferation. Conditional induction of MAPK signaling oncogenes RET/PTC3 or BRAF^T1799A in normal rat thyroid cell line mediated activation of Notch signaling, upregulating Notch1 receptor and Hes1, the downstream effector of Notch pathway. Conversely, pharmacological inhibition of MAPK reduced Notch signaling in PTC cell. Thyroid tumor samples from transgenic mice expressing BRAF^T1799A and primary human PTC samples showed high levels of Notch1 expression. Down-regulation of Notch signaling by γ-secretase inhibitor (GSI) or NOTCH1 RNA interference reduces PTC cell proliferation. Moreover, the combination of GSI with a MAPK inhibitor enhanced the growth suppression in PTC cells. This study revealed that RET/PTC and BRAF^T1799A activate Notch signaling and promote tumor growth in thyroid follicular cell. Taken together, these data suggest that Notch signaling may be explored as an adjuvant therapy for thyroid papillary cancer.     

miR-26a and its Target CKS2 Modulate Cell Growth and Tumorigenesis of Papillary Thyroid Carcinoma

Background

While many studies have shown that levels of miR-26a are lower in papillary thyroid carcinoma (PTC), the role and mechanism of miR-26a in PTC are unclear.

Method

We used database searches to select potential mRNA targets of miR-26a. Anti-miR-26a, miR-26a mimic, siRNA for CKS2 and their effects on cell growth, cell-cycle distribution and colony formation were evaluated. We also evaluate the over-expressed miR-26a in TPC-1 cells in severe combined immune-deficient mice. We used luciferase reporter assays, real-time PCR and western blot analysis to measure the expression and activity of miR-26a, CKS2, and related factors such as cyclin B1, cyclin A, cdk1, bcl-xl and Akt. Finally, we measured the relationship between the levels of miR-26a and CKS2 in PTC and normal thyroid tissues.

Results

Relative to normal thyroid tissues, miR-26a is consistently down-regulated in TPC specimens, and CKS2 was identified as a potential target. Up-regulated miR-26a expression or down-regulated CKS2 expression in TPC-1 and CGTH W3 cells lines caused G2 phase-arrest. Decreased miR-26a expression or increased CKS2 expression could have inverse function on PTC cell lines. CyclinB1, cyclinA, bcl-xl and AKt are indirectly regulated by miR-26a in a CKS2-dependent manner. Finally, CKS2 is overexpressed in PTC specimens relative to normal thyroid tissue, and a significant inverse correlation exists between miR-26a and CKS2 expression in clinical PTC specimens.

Conclusion

Our data indicate that miR-26a functions as a growth-suppressive miRNA in PTC, and that its suppressive effects are mediated mainly by repressing CKS2 expression.     

IGFBP7在甲状腺乳头状癌中的表达及意义

目的观察胰岛素样生长结合蛋白-7(IGFBP7)在甲状腺乳头状癌中的表达及意义。方法对87例甲状腺乳头癌(PTC)组织及癌旁组织(PeT)进行IGFBP7、Ki67、p53免疫组织化学分析,其中10例提取蛋白用半定量western blot方法进行IGFBP7表达水平分析。结果 (1)IGFBP7免疫组化显示,PTC癌组织IGFBP7阳性率达78.16%(68/87),明显高于癌旁组织的31.03%(27/87)(P0.05);(2)Western blot灰度值比较,癌组织IGFBP7表达水平显著高于癌旁组织(t=2.875,P0.05);(3)Ki67、p53与IGFBP7相关性分析显示,p53表达水平与IGFBP7表达水平呈显著正相关性(r=0.261,P0.05),而Ki67表达水平与IGFBP7表达水平无相关性(r=0.148,P=0.170);(4)高水平表达的IGFBP7与PTC淋巴结转移高度相关(r=0.238,P0.05)。结论 IGFBP7表达异常增高可能与甲状腺乳头状癌发生及发展有关,有望成为诊断PTC的一项新型的生物标记物。