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Journal of Molecular Endocrinology (2006) 36, R1-R8    DOI: 10.1677/jme.1.01913
© 2006 Society for Endocrinology
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Rapid Communication

Tensin3 is a novel thyroid-specific gene

Ikuhiro Maeda, Toru Takano1, Hiroshi Yoshida2, Fumio Matsuzuka2, Nobuyuki Amino2 and Akira Miyauchi2

Central Laboratory for Clinical Investigation, Osaka University Hospital, 2–15 Yamadaoka, Suita, Osaka 565-0871, Japan
1 Department of Laboratory Medicine, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
2 Kuma Hospital, Simoyamate-Dori, Chuo-Ku, Kobe, Hyogo 650-0011, Japan

(Requests for offprints should be addressed to I Maeda; Email: maeda{at}hp-lab.med.osaka-u.ac.jp)


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Thyroid-specific genes, such as thyroid peroxidase, thyroglobulin, Na+/I– symporter and thyroid-stimulating hormone receptor, play fundamental roles in thyroid function and relate to many pathological conditions. Using sequence specific-differential display, we detected three genes that showed higher expression levels in normal thyroid tissues than in thyroid tumor tissues. After subcloning and sequencing analysis, one of the genes was revealed to be tensin3. The expression level of tensin3 was examined with real-time quantitative PCR analysis. Its expression levels were more depressed in thyroid tumor tissues than in normal thyroid tissues. The decrease was even more evident in two anaplastic carcinomas. High and moderate levels of tensin3 mRNA expression were observed in the thyroid and placenta respectively. Tensin3 mRNA was expressed only in low levels in other tissues, such as the brain, heart, lung, liver, pancreas, kidney, skeletal muscle, white blood cells and prostate. These results show that tensin3 is a novel thyroid-specific gene and further investigations may reveal its relation to thyroid function or thyroid disease.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Thyroid-specific genes, such as thyroid peroxidase (TPO), thyroglobulin (TG), Na+/I– symporter (NIS) and thyroid-stimulating hormone receptor (TSHR) play fundamental roles in the functions of thyroid follicular cells, especially in the synthesis and secretion of thyroid hormone (Haddad & Sidbury 1959, Baas et al. 1986, Smanik et al. 1996). These genes relate to many thyroid diseases and are used in their clinical diagnoses. The genes are usually underexpressed in thyroid tumor tissue. For example, Lazar et al.(1999) have reported the decreased expression of TPO, TG, NIS and TSHR in thyroid carcinomas.

In a previous study, we developed a modified method of differential display, sequence specific-differential display (SS-DD), which allows the rapid screening of specific changes in mRNAs in tumor tissues (Takano et al. 1997). In SS-DD, a 16- to 18-base degenerate primer instead of a 10-mer primer is used to prevent false positive results by performing the polymerase chain reaction (PCR) with a high annealing temperature. In addition, Ex-Taq polymerase instead of Taq polymerase is used to produce longer PCR products, which helps to avoid amplification of the 3' non-coding region.

Using SS-DD, we have detected three genes in which the expression levels were higher in normal thyroid tissues than in thyroid tumor tissues. One of these genes was identified as acid ceramidase, but the other two genes showed unknown sequences (Maeda et al. 1999). We cloned one of these unknown genes and found that it is identical to the genes named tensin3 (Cui et al. 2004) or TEM6 (Carson-Walter et al. 2001) in other studies. Interestingly, in human tissues, this gene is expressed in the thyroid in a restricted manner, which suggests it is a novel thyroid-specific gene.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Extraction of RNA

Tissue samples were obtained at surgery, and were quickly frozen in liquid nitrogen. Total RNA was extracted according to a method described previously (Chomczynski & Sacchi 1987). All tissues were histologically classified according to WHO guidelines (Hedinger et al. 1989). The study protocol was approved by the institutional ethical committee. Informed consent was obtained from all patients.

Sequence specific-differential display

SS-DD was performed essentially as previously described (Takano et al. 1997). In brief, RNAs from nine normal thyroid tissue samples, five papillary carcinomas, two follicular adenomas and two follicular carcinomas were used for the screening using SS-DD. All primers were purchased from Funakoshi (Tokyo, Japan). DNase digestion of 10 µg total RNA was performed with DNase I (Takara, Sigma, Kyoto, Japan), at 37 °C for 30 min. The RNA pellet was phenol/chloroform/isoamyl alcohol-extracted, and was precipitated with ethanol, followed by reconstitution with distilled water. Two micrograms total RNA were converted to cDNA in an reverse transcriptase (RT) mixture containing 8 µl 5xRT buffer, 8 µl 2.5 mM deoxynucleosidetriphosphate (dNTP) (Takara), 0.4 µl 100 mM dithiothreitol, 2 µl 200 U/µl reverse transcriptase (Gibco, Gaithersburg, MD, USA), 0.4 µl 140 µU/µl RNase inhibitor (Takara), and 200 µM oligo dT (Funakoshi) in a total volume of 40 µl (adjusted adding nuclease-free water) at 37 °C for 60 min. Two degenerate primers were used in the following PCR. One, SH2 (2.0 µM): 5'-TTCCTGGTG(A/C)G(A/G)(G/C)A(G/C)(A/T/U) (G/C)-3', was based on the consensus sequence for the Src homology 2 (SH2) domain (Matuoka et al. 1992), and the other, DD3'-2 (2.0 µM): 5'-GTTTTTTTTTTT TTTTTTTT(G/A/C)-3', was designed to anneal to the poly A tail. Each reaction mixture consisted of 1 µl cDNA, 200 µM of each primer, 4 µl 10xEx Taq buffer, 4 µl 2.5 mM dNTP mix, 2 U Ex Taq polymerase, and nuclease-free water to a final volume of 40 µl; 10xEx Taq buffer, 2.5 mM dNTP mix, and Ex Taq polymerase were obtained from Takara. The PCR was performed at 94 °C for 2 min, then 2 cycles of denaturation (94 °C, 1 min), annealing (40 °C, 3 min) and extension (72 °C, 5 min), followed by 40 cycles of denaturation (94 °C, 1 min), annealing (55 °C, 1 min) and extension (72 °C, 2 min with 5 s of auto-segment extension for each cycle). After PCR amplification, 4.0 µl reaction mixture were run on a 3.5% acrylamide gel in a Tris–HCl/boric acid/EDTA (TBE) buffer (pH 8.0) using 360-mm glass sequencing plates (Takara). After electrophoresis, one of the glass plates was removed, and the gel was stained with SYBR Green I (Wako, Osaka, Japan) and analyzed with a Fluor Imager (Molecular Dynamics, Sunnyvale, CA, USA). The bands of interest were cut with a razor, and PCR products were extracted by boiling at 100 °C for 5 min. The PCR products were amplified by PCR with the following two primers: SH2-R (2.0 µM): 5'-ATGCGAATTCTTTCCTGGTG (A/C)G(A/G)(G/C) A-3'and DD3'-R2 (0.5 µM): 5'-ATG CGAATTCGTTTTTTTTTTTTTTTTTTT-3'in a reaction mixture containing 5 µl 10xEx Taq buffer, 4 µl 2.5 mM dNTP mix, 2.5 U Ex Taq polymerase and nuclease-free water to a final volume of 50 µl. The PCR was carried out for 30 cycles at 94 °C, 60 °C and 72 °C for 1 min. Purified PCR products were cloned into a pMOSBlue vector using a pMOSBlue T-vector kit (Amersham, Bucks, UK) according to the manufacturer’s instructions. DNA sequencing was performed using a Taq Dye Primer Cycle Sequencing Kit and a 373 A DNA sequencer (Perkin-Elmer, Foster City, CA, USA).

Cloning of an unknown gene

Cloning of an unknown gene was carried out using a human thyroid cDNA library (Takara) with hybridization analysis. A cDNA fragment for hybridization was amplified from a human thyroid cDNA with RT-PCR using the following two primers: 5SN1SC (0.5 µM): 5'-TTCCTGTCCCACAACTTTCTCACG-3' (base 3202–3225 of tensin3 cDNA), and 3SN1SC (0.5 µM): 5'-ATATCCGCCTTGTACCAGAACTTG-3' (base 3516–3539 of tensin3 cDNA). The amplified probe was labeled with an AlkPhos labeling kit and the CDP-Star detection reagent (Amersham Pharmacia Biotech, UK) was used for signal detection. Hybridization and detection were performed according to the manufacturer’s protocol.

Reverse transcription-PCR

Reverse transcription-PCR (RT-PCR) was performed as previously described (Takano et al. 1997). cDNAs from four thyroid tissue samples and human cDNAs (Clontech, Palo Alto, CA, USA) from brain, heart, lung, liver, pancreas, kidney, placenta, skeletal muscle, white blood cells (WBC) and prostate were analyzed. The following primers were used for the PCR: one was 5SN1SC (0.5 µM): 5'-TTCCTGTCCCACAACTTTC TCACG-3' (base 3202–3225 of tensin3 cDNA (GenBank AF417489 [GenBank] )), and the other was 3SN1SC (0.5 µM): 5'-ATATCCGCCTTGTACCAGAACTTG-3' (base 3516–3539 of tensin3 cDNA). The PCR was performed at 95 °C for 10 min, and 35 cycles of 95 °C, 60 °C and 72 °C for 30 s. Four microliters of each PCR product were electrophoresed on a 1.5% SeaKem GTG agarose gel (Takara) in a Tris–HCl/acetate/EDTA (pH 8.0) buffer. The gel was stained with ethidium bromide, then analyzed with a Fluor Imager.

Real-time quantitative RT-PCR of tensin3 mRNA

Real-time quantitative RT-PCR (TaqMan RT-PCR) using the ABI PRISM 7700 Sequence Detection System (Perkin-Elmer) was performed according to the manufacturer’s protocol. The amplified sequence was different from that amplified in the RT-PCR analysis. The two primers and one TaqMan probe used for the quantification of tensin3 mRNA were: 5 TMSN1 (0.5 µM): 5'-CATATTTCGGGAGCCTGACG-3' (base 3773–3792), 3 TMSN1 (0.5 µM): 5'-TCAAGTACCAC ACATTGCAG-3' (base 3940–3958), and SN1-TM (10 pmol): 5'-FAM-CAGAGAGAGATCCATTGGAG GAA-TAMRA-3' (base 3851–3873). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA (GenBank BC013310 [GenBank] ) was used as an internal control since the expression levels of GAPDH mRNA in normal thyroid tissues, follicular adenomas, papillary carcinomas and follicular carcinomas were almost equal (Takano et al. 2000). The two primers and one TaqMan probe used for the quantification of GAPDH were: TMGPD5 (0.5 µM): 5'-TCCATGACAACTTTGGTATC-3' (base 551–570), TMGPD3 (0.5 µM): 5'-AAGGTCATCCCT GAGCTAGA-3' (base 715–734), and GPD-TM (10 pmol): 5'-FAM-AGAACATCATCCCTGCCTCTA CT-TAMRA-3' (base 671–693). The analyzed cDNAs were reverse-transcribed from RNAs extracted from 28 normal thyroid tissues, 13 follicular adenomas, 10 adenomatous goiters, 15 papillary carcinomas, 5 follicular carcinomas and 2 anaplastic carcinomas, as described above. Human cDNAs (Clontech) from brain, heart, lung, liver, pancreas, kidney, placenta, skeletal muscle, WBC and prostate were also analyzed. The conditions for the TaqMan RT-PCR were as follows: 95 °C for 10 min and 40 cycles of 95 °C for 15 s, and 60 °C for 1 min. Recombinant pGEM T-vectors (Promega, Tokyo, Japan) containing either tensin3 or GAPDH cDNA were constructed by PCR-cloning with the same sets of primers used in the TaqMan RT-PCR, and were used as standard samples.

Statistical analysis

The Mann-Whitney test was used to determine differences between the tensin3 mRNA/GAPDH mRNA of normal thyroid tissues and that of thyroid tumors. P values of less than 0.05 were considered to be significant.

Analysis of the SAGE database

A tag counting analysis based on the SAGE libraries was performed with the public database (http://www.ncbi.nlm.nih.gov/projects/SAGE/index.cgi?cmd=tagsearch).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Screening of the specific changes in mRNAs in thyroid tumors with SS-DD

In the results of electrophoresis, three bands, SN1, SN2 and SN3, which decrease in tumor tissues, were observed (Fig. 1Go). A band of SN1 was cut out from the gel, and the extracted PCR products were then reamplified with PCR with the primers, SH2R and DD3'-R2. The reamplified PCR products were cloned into a pMOSBlue vector, and sequencing analysis was carried out. The sequence of SN2 corresponded to the 1482–2330 bp position of acid ceramidase mRNA (Maeda et al. 1999). The other two clones showed no homology to known sequences.


Figure 1
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  		Figure 1 Representative image of SS-DD using RNA from normal thyroid tissues and from thyroid papillary carcinomas. PCR products derived from normal thyroid tissues (N), papillary carcinomas (P), follicular adenomas (FA) and follicular carcinomas (FC) were separated on an acrylamide gel. The gel was stained with SYBR Green I, and the fluorescent image was detected with a Fluor Imager. A band, SN1 (indicated by a box) was cut out from the gel for extraction.

 
Sequence of an unknown gene

Using a human thyroid cDNA library, we screened about 10 000 clones, and found 3 positive clones. The detected clones were 5076 bp and had a huge 3' non-coding region. The predicted amino acid sequence showed the existence of an SH2 domain and a phosphotyrosine binding (PTB) domain. Thus, we named this gene the thyroid-specific PTB domain protein (TPP) (GenBank AB062750 [GenBank] ). This gene has also been cloned by two other groups. Carson-Walter et al.(2001) named it TEM6 (GenBank AF3787560) and Cui et al.(2004) named it tensin3 (GenBank AF417489 [GenBank] ). The comparison of these three reported sequences is summarized in Fig. 2Go. The coding region of tensin3 mRNA is the longest, 1445 amino acid residues, among the three genes.


Figure 2
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  		Figure 2 Comparison of the sequences of tensin3 mRNA, TEM6 mRNA and TPP mRNA. The sequence of the region base 2254–4388 of tensin3 mRNA (indicated by stippled bars) was common with TPP mRNA and TEM6 mRNA. The actin-binding domain (ABD) I is coded in the NH2 terminus regions of tensin3 mRNA, and the Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains are coded in the COOH terminus regions of tensin3 mRNA, TEM6 mRNA and TPP mRNA respectively. The open reading frame of tensin3 mRNA is base 10–4347. A bold line with an asterisk shows the position of the probe used for the library screening.

 
Using cDNAs from human thyroid tissues, the expression of the 5' sequence of tensin3 mRNA, which is lacking in TPP mRNA, was confirmed with RT-PCR analyses using a couple of pairs of specific sense- and antisense-primers for 5' region tensin3 mRNA (data not shown).

Quantitative analysis of tensin3 mRNA

To confirm the decreased expression of tensin3 mRNA in thyroid tumors, TaqMan RT-PCR was carried out. The expression levels of tensin3 mRNA were decreased in papillary carcinomas, follicular carcinomas and follicular adenomas. It expression was decreased markedly in the 2 anaplastic carcinomas (Fig. 3Go).


Figure 3
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  		Figure 3 Tensin3 mRNA/GAPDH mRNA in quantitative RT-PCR analysis. Each closed circle shows the mean of a duplicate assay. *P<0.005, **P<0.01.

 
RT-PCR and quantitative RT-PCR analyses of tensin3 mRNA in human tissues

To confirm the specific restricted expression of tensin3 mRNA in the thyroid, semi-quantitative RT-PCR was carried out using cDNAs from the brain, heart, lung, liver, pancreas, kidney, placenta, skeletal muscle, WBC and prostate. As shown in Fig. 4Go, tensin3 mRNA was expressed at high levels in thyroid tissues. Moderate expression of tensin3 was observed in the placenta and it was only weakly expressed in other tissues.


Figure 4
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  		Figure 4 RT-PCR and quantitative RT-PCR analyses of tensin3 mRNA in human tissues. cDNAs from brain, heart, lung, liver, pancreas, kidney, placenta, skeletal muscle, white blood cells (hWBC), prostate and four thyroid tissues were analyzed. The upper panel shows the image of electrophoresis after RT-PCR, and the lower panel shows the results of quantitative measurement of tensin3 mRNA. GAPDH mRNA was used as an internal control.

 
Analysis of the SAGE database

Based on the sequence of TPP mRNA, the following ten bases after the last CATG in the 3'-noncoding region are TTAAAAGTCA. There were only six libraries from normal human tissues with this tag (Table 1Go). The tag count was high in the thyroid and placenta, which is identical to the result obtained with RT-PCR.


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  		Table 1 SAGE library data for tag TTAAAAGTCA
 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Cui et al.(2004) cloned tensin3 as a member of the tensin family, to which Cten (Lo & Lo 2002), tensin1 and tensin2 belong, and tensin3 localizes in focal adhesions of the plasma membrane (Chen et al. 2002). According to a recent study (Cui et al. 2004), the NH2 terminus of tensin3 contains an actin-binding domain (ABD) I, and the COOH terminus contains an SH2 domain and a PTB domain. Tyrosine phosphorylation of tensin3 is induced by epidermal growth factor (EGF) in MDA-MB-468 cells in a time- and dose-dependent manner, and tensin3 may be related to the cell migration promoted by EGF. Cui et al.(2004) reported that tensin3 was expressed as a 180 kDa protein in various cell types, although they did not examine the expression in the thyroid.

TEM6 was first reported by St Croix et al. in 2000. They identified 46 transcripts named TEMs (tumor endothelial markers), which were significantly up-regulated in tumors compared with normal endothelium. However, they did not undertake further study on the TEM6 gene.

In the present study, we confirmed the overexpression of tensin3 mRNA in the human thyroid. Tensin3 mRNA was also expressed in thyroid tumors, although its expression levels were much lower in tumor tissues and even lower in anaplastic carcinomas. The restricted expression of tensin3 in the thyroid was confirmed by both quantitative RT-PCR and the SAGE database analysis. In the SAGE database analysis, the SAGE tag was also detected in the prostate, placenta, lung, kidney, liver and heart. However, in three of these six libraries, the corresponding tag sequence appeared only once, which suggests the possibility that the expression levels of tensin3 in these tissues are much lower than those expected from the data of ‘tags per million’.

The role of tensin3 in the thyroid cell is not clear. Chiang et al.(2005) generated mutant mice with a disrupted tensin3 gene and suggested that the tensin3 gene might be related to a sub-population of Silver-Russell syndrome patients. Interestingly, although Chiang et al. did not examine the thyroids or thyroid function in these mice, the mice were distinct dwarves, which suggest the existence of inherited hypothyroidism.

Finally, the results of our presented study show that tensin3 mRNA is expressed in a restricted manner in the human thyroid. This fact suggests that tensin3 may play some fundamental role in thyroid function and may relate to some thyroid diseases, as do the other thyroid-specific genes such as TPO, TG, NIS and TSHR.


   Acknowledgements
 
This research was partially supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grants-in-Aid for Scientific Research C 2004–5, no. 16590456. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Baas F, van Ommen GJB, Bikker H, Arnberg AC & de Vijlder JJM 1986 The human thyroglobulin gene is over 300 kb long and contains introns of up to 64 kb. Nucleic Acids Research 14 5171–5186.[Abstract/Free Full Text]

Carson-Walter EB, Vogelstein B, Kinzler KW & St Croix B 2001 Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Research 61 6649–6655.[Abstract/Free Full Text]

Chen H, Duncan IC, Bozorgchami H & Lo SH 2002 Tensin1 and a previously undocumented family member, tensin2, positively regulate cell migration. PNAS 99 733–738.[Abstract/Free Full Text]

Chiang MK, Liao YC, Kuwabara Y & Lo SH 2005 Inactivation of tensin3 in mice results in growth retardation and postnatal lethality. Developmental Biology 279 368–377.[CrossRef][ISI][Medline]

Chomczynski P & Sacchi N 1987 Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Analytical Biochemistry 162 156–159.[ISI][Medline]

Cui Y, Liao Y & Lo SH 2004 Epidermal growth factor modulates tyrosine phosphorylation of novel tensin family member, tensin3. Molecular Cancer Research 2 225–232.[Abstract/Free Full Text]

Haddad HM & Sidbury JB Jr 1959 Defect of the iodinating system in congenital goitrous cretinism: report of a case with biochemical studies. Journal of Clinical Endocrinology 19 1446–1457.

Hedinger C, Williams ED & Sobin LH 1989 The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer 63 908–911.[CrossRef][ISI][Medline]

Lazar V, Bidart JM, Caillou B, Mahe C, Lacroix L, Filetti S & Schlumberger M 1999 Expression of the Na(+)/I(–) symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. Journal of Clinical Endocrinology and Metabolism 84 3228–3234.[Abstract/Free Full Text]

Lo SH & Lo TB 2002 Cten, a COOH-terminal tensin-like protein with prostate restricted expression, is down-regulated in prostate cancer. Cancer Research 62 4217–4221.[Abstract/Free Full Text]

Maeda I, Takano T, Matsuzuka F, Maruyama T, Higashiyama T, Liu G, Kuma K & Amino N 1999 Rapid screening of specific changes in mRNA in thyroid carcinomas by sequence specific-differential display: decreased expression of acid ceramidase mRNA in malignant and benign thyroid tumors. International Journal of Cancer 81 700–704.[CrossRef]

Matuoka K, Shibata M, Yamakawa A & Takenawa T 1992 Cloning of ASH, a ubiquitous protein composed of one src homology region (SH) 2 and two SH3 domains, from human and rat cDNA libraries. PNAS 89 9015–9019.[Abstract/Free Full Text]

Smanik PA, Liu Q, Furminger TL, Ryu K, Xing S, Mazzaferri EL & Jhiang SM 1996 Cloning of the human sodium iodide symporter. Biochemical and Biophysical Research Communications 226 339–345.[CrossRef][ISI][Medline]

St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E, Lal A, Riggins GJ, Lengauer C, Vogelstein B & Kinzler KW 2000 Genes expressed in human tumor endothelium. Science 289 1197–1202.[Abstract/Free Full Text]

Takano T, Matsuzuka F, Sumizaki H, Kuma K & Amino N 1997 Rapid detection of specific messenger RNAs in thyroid carcinomas by reverse transcription-PCR with degenerate primers: specific expression of oncofetal fibronectin messenger RNA in papillary carcinoma. Cancer Research 57 3792–3797.[Abstract/Free Full Text]

Takano T, Hasegawa Y, Matsuzuka F, Miyauchi A, Yoshida H, Higashiyama T, Kuma K & Amino N 2000 Gene expression profiles in thyroid carcinomas. British Journal of Cancer 83 1495–1502.[CrossRef][ISI][Medline]

Received in final form 7 November 2005
Accepted 2 December 2005




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