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Patterns of TPD52 Overexpression in Multiple Human Solid Tumor Types Analyzed by Quantitative PCR

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Patterns of TPD52 Overexpression in Multiple Human Solid Tumor Types Analyzed by Quantitative PCR INTERNATIONAL JOURNAL OF ONCOLOGY 44: 609-615, 2014 Patterns of TPD52 overexpression in multiple human solid tumor types analyzed by quantitative PCR �IERRE TENNSTE�T1*, CHARLOTTE BÖLCH2*, GUN�ULA STROBEL2, SARAH MINNER2, LIA BURKHAR�T2, TOBIAS GROB2, SAWINEE MASSER2, GUI�O SAUTER2, THORSTEN SCHLOMM1,3 ��� RONAL� SIMON2 1M������-C�����, 2I�������� �f �������gy, 3���������� �f U����gy, S������ f�� T������������ �������� C����� R�������, U��v�����y M������ C����� H��b��g-E�������f, H��b��g, G�����y Received Septemb�� 24, 2013; Accepted Octob�� 29, 2013 �OI: 10.3892/�j�.2013.2200 Abstract. Tumor���� protein������� �52��� �TPD��52��� is�� located������� at�� chromo������- for �xample tumors �f the breast, �vary, endometrium, lung, some 8q21, a region that is frequently gained or amplified colon, head and neck, urinary bladder, kidney and prostate in multiple human cancer �ypes. TPD52 has been suggested �1,2�. Whereas gains �ften �ffect larg� portions �f 8q or as � potential target for new anticancer therapies. I� order even the entire q-arm, high-level amplifications are typically to analyz� TPD52 �xpression in the most prevalent human focused on the chromosomal bands 8q21 �3-5� and 8q24 �6,7�, cancer �ypes, w� employed quantitativ� �CR to measure thus highlighting the loci �f putativ� oncogenes, including TPD52 mRNA levels in formalin-fixed tissue samples from MYC at 8q24. S�veral candidate oncogenes hav� been more than 900 cancer tissues �btained from 29 different suggested to reside inside the 8q21 region, including tumor human cancer �ypes. TPD52 was �xpressed at varying levels protein �52 �TPD52� �3,8-13�. TPD52 has been suggested to in all tested normal tissues, including �kin, �ymph node, lung, play a role for vesicle trafficking and Ca2+ dependent �xocy- oral mucosa, breast, endometrium, �vary, vulv�, �yometrium, totic secretion, and has been show� to facilitate �ytokinesis in liver, pancreas, stomach, kidney, prostate, testis, urinary rapidly proliferating cells �14,15�. bladder, thyroid gland, brain, muscle and fat tissue. TPD52 I� line with an oncogenic role, TPD52 �verexpression has was upregulated in 18/29 �62%� tested cancer �ypes. Strongest been described from � multitude �f cancer �ypes, including �xpression was found in non-seminoma �56-fold �verexpres- breast �9�, lung prostate �2�, �varian �8�, pancreatic cancer �16�, sion compared to corresponding normal tissue), seminoma multiple �yeloma �17,18�, Burkitt'� �ymphoma �19�, melanoma �42-fold), ductal �28-fold) and lobular breast cancer �14-fold). �20� and testicular germ cell tumors �21�, and has been linked I� these tumor �ypes, TPD52 upregulation was found in the to poor prognosis in breast, medulloblastoma, lung and prostate vast majority �>80%� �f tested samples. Downregulation was cancer patients �22�. Moreov��, cell line �xperiments and in vivo found in 11 �38%� tumor �ypes, most strong�y in papillary analysis in mice support the implication �f TPD52 in tumori- renal cell cancer �-8-fold), leiomyosarcoma �-6-fold), clear genesis and progression to metastasis �23,24�. According�y, cell renal cell cancer �-5-fold), liposarcoma �-5-fold) and lung TPD52 has been suggested as � promising target for antitumor cancer �-4-fold). These results demonstrate that TPD52 is therapies in breast �25� and prostate cancer �24�, and it seems frequently and strong�y upregulated in many human cancer likely that also other tumor �ypes showing TPD52 �verexpres- �ypes, which may represent candidate tumor �ypes for poten- sion could profit from a TPD52 specific therapy. tial anti-TPD52 therapies. A �ystematic analysis �f TPD52 �xpression in human cancers in order to identify tumor types that might benefit Introduction from potential anti-TPD52 therapies is lacking. I� this study, w� hav� employed quantitativ� real-time �CR in more than Copy numb�� increase involving chromosome 8q belong to the 900 tumor samples to compare the prevalence and �xpression most frequent �berrations in human solid cancers, including levels �f TPD52 across 29 important human cancer �ypes and corresponding normal tissues. Materials and methods Correspondence to: Dr Ronald Simon, Institute �f Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Tissue specimens. Formalin-fixed, paraffin embedded tissues �-20246 Hamburg, Germany were selected from the archiv� �f the Institute �f Pathology, E-mail: �.simon@�k�.uni-hamburg.de University Medical Center Hamburg-Eppendorf �Hamburg, * Germany�. A total �f 999 cancer samples and 40 normal Contributed �qually tissue samples were included into the study. A detailed list �f all samples is g�ven in T�ble I. One pathologist reviewed Key words: TPD52, cancer, real-time �CR, �RNA analysis, normal tissue all hematoxylin and eosin stained sections �f all tissues and selected one block per tumor for RNA isolation. For tumor 610 TENNSTE�T et al: TPD52 U�REGULATION IN �IFFERENT TUMOR TY�ES T�b�� I. T����� ������� f�� TPD52 �x�������� ����y���. T����� �y�� O�g�� � O�g�� � N����� Sk�� 2 Pancreas 1 Ly��� ���� 2 S������ 2 L��g 2 K����y 2 O��� ��v���y 2 Prostate 2 B����� 1 T����� 3 E���������� 2 B������ 2 Ov�� 2 T�y���� g���� 2 V��v� 2 B���� 2 My�������� 2 Sk������ ������ 2 L�v�� 3 A������ ������ 2 C����� M���g���� �������� 11 L�v�� ������ 50 L��y�x ��������� 39 Pancreatic ������ 38 L��g ������, ���g� ���� �24�, ����� �68�, ����� ���� �17� ��� �q������ ���� �25� 134 S������ ������ 50 O��� ��v��y ������ 56 R���� ���� ������ 59 B����� ������, ������ �26� ��� ��b���� �27� 53 Prostate ������ 48 E���������� ��������� 31 T����� ������, �������� �30� ��� ���-�������� �29� 59 Ov����� ������ 33 U�����y b������ ������, ���-��v���v� ��T� 27� and invasive (≥pT2 28) 55 U����� ���v�x ��������� 28 T�y���� g���� ������ 40 V��v� ������ 39 L����y�������� 42 C���� ������ 50 L���������� 36 E�����g��� ������, �q������ ���� �23� ��� �������������� �25� 48 samples areas with high tumor cell content (≥60% tumor amplification of TPD52 and the housekeeping gene TB� the cells) were marked on the slide. A hollow needle was used QuantiTect Primer Assay �Qiagen) was used. The following to tak� �w� tissue �ylinders (diameter from 0.5 mm) from conditions were used for �CR: i) initial denaturation step at each tissue block for nucleic acid isolation. The local ethics 95˚C for 10 min; and ii) 40 cycles at 95˚C for 20 sec and committee approved usag� �f the human tissue samples for 55˚C for 40 sec. Relative quantity of TPD52 �xpression in research purposes. tumor samples was calculated by the 2-∆∆C� method standard- �zed to TPD52 �xpression in corresponding normal tissue. RNA extraction and cDNA synthesis. Punched tissue mate- A fold chang� �f 2 was used to determine the frequency �f rial was deparaffinized with xylene and 80% ethanol. After significant TPD52 regulated cancers. digestion with proteinases K at 56˚C overnight, total RNA was isolated using the RNeasy FF�E kit �Qiagen) in � full- Results automated nucleic acid isolation device �QIAcub�, Qiagen). cDNA was �ynthesized in � 96-well plate format using the Technical issue. A total �f 894 cancer samples from 29 different high‑capacity cDNA reverse transcription kit �Applied tumor �ypes and 40 normal tissue samples from 20 different Biosystems) following the manufacturer'� instructions. Total normal tissue �ypes were included in the analysis �T�ble I�. A RNA �1 µg� was used for reverse transcription �f all samples. total �f 105 �10.5%� tumor samples and 3 �7.5%� normal tissue samples were �xcluded from analysis because either the ref��- Quantitative PCR analysis. Real-time �CR was performed ence gene TBP or the target gene TPD52 showed � C� value using the L�ghtCycler LC480 �Roche) detection �ystem, and �xceeding 35, indicating that too little cDNA was generated the QuantiTect SYBR-Green PCR Kit (Qiagen). For specific for reliable TPD52 �xpression analysis. INTERNATIONAL JOURNAL OF ONCOLOGY 44: 609-615, 2014 611 F�gure 1. TPD52 �xpression ��vels in different normal tissue. Relativ� TPD52 �xpression ��vel (log2� was standardized to TPD52 �xpression in testis. TPD52 expression in normal tissues. TPD52 transcript was Prevalence of TPD52 expression in cancer. I� order to estimate found in all analyzed normal tissues. Averag� ∆C� was 2.4±0.4. the variability �f TPD52 �xpression in the analyzed tumor �ypes, For � direct comparison �f the TPD52 �xpression levels �f the w� determined the fraction �f samples showing at least 2-fold different normal tissues, the �xpression levels were normalized up- or downregulation. This analysis revealed that TPD52 �ver- to the TPD52 �xpression level in testis, which had the lowest �xpression was particular frequent �80% �f samples showing �xpression level �f all analyzed normal tissues. According�y, ≥2-fold overexpression) in germ cell tumors (non-seminoma highest TPD52 expression levels [≥32 (25� -fold �verexpression and seminoma), bladder cancer, esophageal carcinoma and as compared to normal testis] were found in normal oral cavity mamma carcinoma, whereas cancer �ypes �ypically showing mucosa �104-fold �verexpression), pancreas �91-fold), thyroid TPD52 downregulation included renal cell carcinoma �90% gland �79-fold), kidney �76-fold), prostate �69-fold), stomach papillary and 68% clear cell), leiomyosarcoma (69%� and lipo- �56-fold), vulv� �45-fold), liv�� �39-fold), �ymph node �38-fold), sarcoma �52%�. All data are show� in F�g. 3. and breast �32-fold). All data are summarized in F�g. 1. Discussion TPD52 expression in cancer. T� compare TPD52 �xpression across the different tumor �ypes, �verag�
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