Advances in The Study of The Tumor Suppressor PTEN and Thyroid Tumor_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 YANChen , PENGDong-mei , WUWen-shuang , WEITao ,  ZHUJing-qiang

Center for Diagnosis and Ttreatment of Thyroid and Parathyroid Diseases, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China;

Corresponding author：

ZHUJing-qiang, Email: zjq-wkys@163.com

Keywords：

PTEN; Tumor suppressor gene; Anti-tumor mechanism; PTEN-hamartoma syndrome; Thyroid tumor

DOI：

10.7507/1007-9424.20160133

Video：

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Objective To summarize and analyze the relevant studies about the tumor suppressor phosphatase and tensin homolog deleted on chromosome ten (PTEN) and thyroid tumor then further elucidate?the possible mechanism of thyroid tumor formation and progression. Mothods Domestic and international literatures investigating the correlation between PTEN and thyroid tumor were retrieved and reviewed. Results The abnormal expression of PTEN protein resulted by the mutation or methylation of PTEN gene may up-regulate the expression of its downstream effectors such as PI3K, mTOR, FAK, etc. This probably correlate with thyroid neoplasia and progression. Conciusions Abnormalites of PTEN and its downstream signal ways may correlate with the initiation and development of thyroid tumors. However, the specific mechanism still remains unclear and need more further researches

Citation： YANChen, PENGDong-mei, WUWen-shuang, WEITao, ZHUJing-qiang. Advances in The Study of The Tumor Suppressor PTEN and Thyroid Tumor. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2016, 23(4): 503-506. doi: 10.7507/1007-9424.20160133 Copy

1.	Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res, 1997, 57(11): 2124-2129.
2.	Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet, 1997, 15(4): 356-362.
3.	Li J, Yen C, Liaw D, et al.PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 1997, 275(5308): 1943-1947.
4.	Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol, 2004, 22(14): 2954-2963.
5.	Davies L, Welch HG.Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg, 2014, 140(4): 317-322.
6.	Worby CA, Dixon JE. PTEN.Annu Rev Biochem, 2014, 83: 641-669.
7.	Baquero P, Jiménez-Mora E, Santos A, et al. TGFbeta induces epithelial-mesenchymal transition of thyroid cancer cells by both the BRAF/MEK/ERK and Src/FAK pathways. Mol Carcinog, 2015 Sep 21. [Epub ahead of print].
8.	Tai YL, Chen LC, Shen TL.Emerging roles of focal adhesion kinase in cancer. Biomed Res Int, 2015, 2015: 690690.
9.	Chetram MA, Don-Salu-Hewage AS, Hinton CV. ROS enhances CXCR4-mediated functions through inactivation of PTEN in prostate cancer cells. Biochem Biophys Res Commun, 2011, 410(2): 195-200.
10.	Tamura M, Gu J, Danen EH, et al. PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem, 1999, 274(29): 20693-20703.
11.	Zhang LL, Liu J, Lei S, et al. PTEN inhibits the invasion and metastasis of gastric cancer via downregulation of FAK expression. Cell Signal, 2014, 26(5): 1011-1020.
12.	Thomas SL, Alam R, Lemke N, et al. PTEN augments SPARC suppression of proliferation and inhibits SPARC-induced migration by suppressing SHC-RAF-ERK and AKT signaling. Neuro Oncol, 2010, 12(9): 941-955.
13.	13Nogueira C, Kim KH, Sung H, et al. C ooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis. Oncogene, 2010, 29(47): 6222-6232.
14.	Deb TB, Barndt RJ, Zuo AH, et al. PTEN-mediated ERK1/2 inhibition and paradoxical cellular proliferation following Pnck overexpression. Cell Cycle, 2014, 13(6): 961-973.
15.	Freeman DJ, Li AG, Wei G, et al. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and-independent mechanisms. Cancer Cell, 2003, 3(2): 117-130.
16.	Abraham AG, O'Neill E. PI3K/Akt-mediated regulation of p53 in cancer. Biochem Soc Trans, 2014, 42(4): 798-803.
17.	Nakanishi A, Kitagishi Y, Ogura Y, et al. The tumor suppressor PTEN interacts with p53 in hereditary cancer (Review). Int J Oncol, 2014, 44(6): 1813-1819.
18.	Pilarski R, Burt R, Kohlman W, et al. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst, 2013, 105(21): 1607-1616.
19.	Pellegriti G, Frasca F, Regalbuto C, et al.Worldwide Increasing Incidence of Thyroid Cancer: Update on Epidemiology and Risk Factors. J Cancer Epidemiol, 2013, 2013: 965212.
20.	Gimm O, Perren A, Weng LP, et al. Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors. Am J Pathol, 2000, 156(5): 1693-1700.
21.	Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site, April 2015. Section 26, thyroid.
22.	Nieuwenhuis MH, Kets CM, Murphy-Ryan M, et al. Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome. Fam Cancer, 2014, 13(1): 57-63.
23.	Ngeow J, Eng C. PTEN hamartoma tumor syndrome: clinical risk assessment and management protocol. Methods, 2015, 77-78: 11-19.
24.	Bubien V, Bonnet F, Brouste V, et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet, 2013, 50(4): 255-263.
25.	Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res, 2012, 18(2): 400-407.
26.	Laury AR, Bongiovanni M, Tille JC, et al. Thyroid pathology in PTEN-hamartoma tumor syndrome: characteristic findings of a distinct entity. Thyroid, 2011, 21(2): 135-144.
27.	Yeager N, Klein-Szanto A, Kimura S, et al. PTEN loss in the mouse thyroid causes goiter and follicular adenomas: insights into thyroid function and Cowden disease pathogenesis. Cancer Res, 2007, 67(3): 959-966.
28.	Antico-Arciuch VG, Dima M, Liao XH, et al. Cross-talk between PI3K and estrogen in the mouse thyroid predisposes to the development of follicular carcinomas with a higher incidence in females. Oncogene, 2010, 29(42): 5678-5686.
29.	Hou P, Ji M, Xing M. Association of PTEN gene methylation with genetic alterations in the phosphatidylinositol 3-kinase/AKT signaling pathway in thyroid tumors. Cancer, 2008, 113(9): 2440-2047.
30.	Antico Arciuch VG, Russo MA, Dima M, et al. Thyrocyte-specific inactivation of p53 and PTEN results in anaplastic thyroid carcinomas faithfully recapitulating human tumors. Oncotarget, 2011, 2(12): 1109-1126.
31.	Guigon CJ, Zhao L, Willingham MC, et al. PTEN deficiency accelerates tumour progression in a mouse model of thyroid cancer. Oncogene, 2009, 28(4): 509-517.
32.	Pringle DR, Yin Z, Lee AA, et al. Thyroid-specific ablation of the Carney complex gene, PRKAR1A, results in hyperthyroidism and follicular thyroid cancer. Endocr Relat Cancer, 2012, 19(3): 435-446.
33.	Pringle DR, Vasko VV, Yu L, et al.Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and PTEN in mice. J Clin Endocrinol Metab, 2014, 99(5): E804-E812.
34.	Dahia PL, Marsh DJ, Zheng Z, et al. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res, 1997, 57(21): 4710-4713.
35.	Nagy R, Ganapathi S, Comeras I, et al. Frequency of germline PTEN mutations in differentiated thyroid cancer. Thyroid, 2011, 21(5): 505-510.
36.	Alvarez-Nuñez F, Bussaglia E, Mauricio D, et al. PTEN promoter methylation in sporadic thyroid carcinomas. Thyroid, 2006, 16(1): 17-23.
37.	Beg S, Siraj AK, Jehan Z, et al. PTEN loss is associated with follicular variant of Middle Eastern papillary thyroid carcinoma. Br J Cancer, 2015, 112(12): 1938-1943.
38.	Frisk T, Foukakis T, Dwight T, et al. Silencing of the PTEN tumor-suppressor gene in anaplastic thyroid cancer. Genes Chromosomes Cancer, 2002, 35(1): 74-80.
39.	Lim HJ, Crowe P, Yang JL. Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer. J Cancer Res Clin Oncol, 2015, 141(4): 671-689.
40.	Milosevic Z, Pesic M, Stankovic T, et al. Targeting RAS-MAPK-ERK and PI3K-AKT-mTOR signal transduction pathways to chemosensitize anaplastic thyroid carcinoma. Transl Res, 2014, 164(5): 411-423.
41.	Golubovskaya VM. Targeting FAK in human cancer: from finding to first clinical trials. Front Biosci (Landmark Ed), 2014, 19: 687-706.
42.	Ahmed M, Hussain AR, Bavi P, et al. High prevalence of mTOR complex activity can be targeted using Torin2 in papillary thyroid carcinoma. Carcinogenesis, 2014, 35(7): 1564-1572.
43.	Biswas R, Mondal A, Ahn JC. Deregulation of EGFR/PI3K and activation of PTEN by photodynamic therapy combined with carboplatin in human anaplastic thyroid cancer cells and xenograft tumors in nude mice. J Photochem Photobiol B, 2015, 148: 118-127.

1. Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res, 1997, 57(11): 2124-2129.
2. Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet, 1997, 15(4): 356-362.
3. Li J, Yen C, Liaw D, et al.PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 1997, 275(5308): 1943-1947.
4. Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol, 2004, 22(14): 2954-2963.
5. Davies L, Welch HG.Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg, 2014, 140(4): 317-322.
6. Worby CA, Dixon JE. PTEN.Annu Rev Biochem, 2014, 83: 641-669.
7. Baquero P, Jiménez-Mora E, Santos A, et al. TGFbeta induces epithelial-mesenchymal transition of thyroid cancer cells by both the BRAF/MEK/ERK and Src/FAK pathways. Mol Carcinog, 2015 Sep 21. [Epub ahead of print].
8. Tai YL, Chen LC, Shen TL.Emerging roles of focal adhesion kinase in cancer. Biomed Res Int, 2015, 2015: 690690.
9. Chetram MA, Don-Salu-Hewage AS, Hinton CV. ROS enhances CXCR4-mediated functions through inactivation of PTEN in prostate cancer cells. Biochem Biophys Res Commun, 2011, 410(2): 195-200.
10. Tamura M, Gu J, Danen EH, et al. PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem, 1999, 274(29): 20693-20703.
11. Zhang LL, Liu J, Lei S, et al. PTEN inhibits the invasion and metastasis of gastric cancer via downregulation of FAK expression. Cell Signal, 2014, 26(5): 1011-1020.
12. Thomas SL, Alam R, Lemke N, et al. PTEN augments SPARC suppression of proliferation and inhibits SPARC-induced migration by suppressing SHC-RAF-ERK and AKT signaling. Neuro Oncol, 2010, 12(9): 941-955.
13. 13Nogueira C, Kim KH, Sung H, et al. C ooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis. Oncogene, 2010, 29(47): 6222-6232.
14. Deb TB, Barndt RJ, Zuo AH, et al. PTEN-mediated ERK1/2 inhibition and paradoxical cellular proliferation following Pnck overexpression. Cell Cycle, 2014, 13(6): 961-973.
15. Freeman DJ, Li AG, Wei G, et al. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and-independent mechanisms. Cancer Cell, 2003, 3(2): 117-130.
16. Abraham AG, O'Neill E. PI3K/Akt-mediated regulation of p53 in cancer. Biochem Soc Trans, 2014, 42(4): 798-803.
17. Nakanishi A, Kitagishi Y, Ogura Y, et al. The tumor suppressor PTEN interacts with p53 in hereditary cancer (Review). Int J Oncol, 2014, 44(6): 1813-1819.
18. Pilarski R, Burt R, Kohlman W, et al. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst, 2013, 105(21): 1607-1616.
19. Pellegriti G, Frasca F, Regalbuto C, et al.Worldwide Increasing Incidence of Thyroid Cancer: Update on Epidemiology and Risk Factors. J Cancer Epidemiol, 2013, 2013: 965212.
20. Gimm O, Perren A, Weng LP, et al. Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors. Am J Pathol, 2000, 156(5): 1693-1700.
21. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site, April 2015. Section 26, thyroid.
22. Nieuwenhuis MH, Kets CM, Murphy-Ryan M, et al. Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome. Fam Cancer, 2014, 13(1): 57-63.
23. Ngeow J, Eng C. PTEN hamartoma tumor syndrome: clinical risk assessment and management protocol. Methods, 2015, 77-78: 11-19.
24. Bubien V, Bonnet F, Brouste V, et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet, 2013, 50(4): 255-263.
25. Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res, 2012, 18(2): 400-407.
26. Laury AR, Bongiovanni M, Tille JC, et al. Thyroid pathology in PTEN-hamartoma tumor syndrome: characteristic findings of a distinct entity. Thyroid, 2011, 21(2): 135-144.
27. Yeager N, Klein-Szanto A, Kimura S, et al. PTEN loss in the mouse thyroid causes goiter and follicular adenomas: insights into thyroid function and Cowden disease pathogenesis. Cancer Res, 2007, 67(3): 959-966.
28. Antico-Arciuch VG, Dima M, Liao XH, et al. Cross-talk between PI3K and estrogen in the mouse thyroid predisposes to the development of follicular carcinomas with a higher incidence in females. Oncogene, 2010, 29(42): 5678-5686.
29. Hou P, Ji M, Xing M. Association of PTEN gene methylation with genetic alterations in the phosphatidylinositol 3-kinase/AKT signaling pathway in thyroid tumors. Cancer, 2008, 113(9): 2440-2047.
30. Antico Arciuch VG, Russo MA, Dima M, et al. Thyrocyte-specific inactivation of p53 and PTEN results in anaplastic thyroid carcinomas faithfully recapitulating human tumors. Oncotarget, 2011, 2(12): 1109-1126.
31. Guigon CJ, Zhao L, Willingham MC, et al. PTEN deficiency accelerates tumour progression in a mouse model of thyroid cancer. Oncogene, 2009, 28(4): 509-517.
32. Pringle DR, Yin Z, Lee AA, et al. Thyroid-specific ablation of the Carney complex gene, PRKAR1A, results in hyperthyroidism and follicular thyroid cancer. Endocr Relat Cancer, 2012, 19(3): 435-446.
33. Pringle DR, Vasko VV, Yu L, et al.Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and PTEN in mice. J Clin Endocrinol Metab, 2014, 99(5): E804-E812.
34. Dahia PL, Marsh DJ, Zheng Z, et al. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res, 1997, 57(21): 4710-4713.
35. Nagy R, Ganapathi S, Comeras I, et al. Frequency of germline PTEN mutations in differentiated thyroid cancer. Thyroid, 2011, 21(5): 505-510.
36. Alvarez-Nuñez F, Bussaglia E, Mauricio D, et al. PTEN promoter methylation in sporadic thyroid carcinomas. Thyroid, 2006, 16(1): 17-23.
37. Beg S, Siraj AK, Jehan Z, et al. PTEN loss is associated with follicular variant of Middle Eastern papillary thyroid carcinoma. Br J Cancer, 2015, 112(12): 1938-1943.
38. Frisk T, Foukakis T, Dwight T, et al. Silencing of the PTEN tumor-suppressor gene in anaplastic thyroid cancer. Genes Chromosomes Cancer, 2002, 35(1): 74-80.
39. Lim HJ, Crowe P, Yang JL. Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer. J Cancer Res Clin Oncol, 2015, 141(4): 671-689.
40. Milosevic Z, Pesic M, Stankovic T, et al. Targeting RAS-MAPK-ERK and PI3K-AKT-mTOR signal transduction pathways to chemosensitize anaplastic thyroid carcinoma. Transl Res, 2014, 164(5): 411-423.
41. Golubovskaya VM. Targeting FAK in human cancer: from finding to first clinical trials. Front Biosci (Landmark Ed), 2014, 19: 687-706.
42. Ahmed M, Hussain AR, Bavi P, et al. High prevalence of mTOR complex activity can be targeted using Torin2 in papillary thyroid carcinoma. Carcinogenesis, 2014, 35(7): 1564-1572.
43. Biswas R, Mondal A, Ahn JC. Deregulation of EGFR/PI3K and activation of PTEN by photodynamic therapy combined with carboplatin in human anaplastic thyroid cancer cells and xenograft tumors in nude mice. J Photochem Photobiol B, 2015, 148: 118-127.

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Advances in The Study of The Tumor Suppressor PTEN and Thyroid Tumor

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