Phân Tích Phương Pháp Kết Hợp Kỹ Thuật Lai Tại Chỗ DNA Về Các RNA Không Đọc Dài MALAT1 và HOTAIR Trong Các Khối U Thần Kinh Nội Tiết Tiêu Hóa-Tụy

Ying-Hsia Chu1, Heather Hardin1, Jens Eickhoff2, Ricardo V. Lloyd1
1Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, USA
2Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, USA

Tóm tắt

Các nghiên cứu gần đây gợi ý vai trò điều chỉnh khối u của hai RNA không đọc dài (lncRNAs), MALAT1 và HOTAIR, trong nhiều loại ác tính khác nhau; tuy nhiên, các lncRNAs này chưa được nghiên cứu trước đó trong các khối u thần kinh nội tiết (NENs) có nguồn gốc từ hệ tiêu hóa-tụy (GEP-NENs). Trong nghiên cứu này, chúng tôi đã đánh giá sự biểu hiện và ý nghĩa tiên lượng của MALAT1 và HOTAIR trong 83 trường hợp GEP-NENs (60 khối u loại 1, 17 khối u loại 2 và 6 khối u loại 3) được chẩn đoán trong giai đoạn 2005–2017. Mức độ biểu hiện của MALAT1 và HOTAIR được định lượng kỹ thuật số trong các lát mô vi thể được tổ chức lại bằng kỹ thuật lai tại chỗ hóa học (ISH) sử dụng phần mềm InForm 1.4.0. Chúng tôi phát hiện sự biểu hiện nhân tế bào lan tỏa của cả HOTAIR và MALAT1 trong tất cả các khối u chính của GEP-NENs với cường độ khác nhau. Theo mô hình đa biến điều chỉnh theo tuổi tác và độ phân loại mô học, sự biểu hiện cao của HOTAIR liên quan đến mức độ giai đoạn T và M ban đầu thấp hơn và sự phát triển sau đó của di căn (P < 0.05). Sự biểu hiện của MALAT1 có liên quan đến mức độ giai đoạn T ban đầu và sự phát triển của di căn (P < 0.05). Tóm lại, MALAT1 và HOTAIR thường được biểu hiện trong GEP-NENs. Sự biểu hiện cao của bất kỳ lncRNA nào cho thấy có mối liên hệ độc lập với độ phân loại với bệnh ít hung hãn hơn về lâm sàng.

Từ khóa

#MALAT1 #HOTAIR #RNA không đọc dài #khối u thần kinh nội tiết #di căn #GEP-NENs

Tài liệu tham khảo

Ohike N, Adsay NV, La Rosa S, Volante M, Zamboni G. 2017. WHO Classification of Tumours of Endocrine Organs, 10 ed. WHO Press, World Health Organization, Geneva. Coriat R, Walter T, Terris B, Couvelard A, Ruszniewski P. 2016. Gastroenteropancreatic Well-Differentiated Grade 3 Neuroendocrine Tumors: Review and Position Statement. Oncologist 21:1191–1199. Oberg K. 2009. Genetics and molecular pathology of neuroendocrine gastrointestinal and pancreatic tumors (gastroenteropancreatic neuroendocrine tumors). Curr Opin Endocrinol Diabetes Obes 16:72–78. Lewis MA, Yao JC. 2014. Molecular pathology and genetics of gastrointestinal neuroendocrine tumours. Current Opinion in Endocrinology, Diabetes and Obesity 21:22–27. Amair-Pinedo F, Matos I, Sauri T, Hernando J, Capdevila J. 2017. The Treatment Landscape and New Opportunities of Molecular Targeted Therapies in Gastroenteropancreatic Neuroendocrine Tumors. Target Oncol 12:757–774. Thorns C, Schurmann C, Gebauer N, et al. 2014. Global microRNA profiling of pancreatic neuroendocrine neoplasias. Anticancer Res 34:2249–2254. Malczewska A, Kidd M, Matar S, Kos-Kudla B, Modlin IM. 2018. A Comprehensive Assessment of the Role of miRNAs as Biomarkers in Gastroenteropancreatic Neuroendocrine Tumors. Neuroendocrinology 107:73–90. Yoon JH, Abdelmohsen K, Gorospe M. 2013. Posttranscriptional gene regulation by long noncoding RNA. J Mol Biol 425:3723–3730. Rinn JL, Chang HY. 2012. Genome regulation by long noncoding RNAs. Annu Rev Biochem 81:145–166. Yang Y, Junjie P, Sanjun C, Ma Y. 2017. Long non-coding RNAs in Colorectal Cancer: Progression and Future Directions. J Cancer 8:3212–3225. Modali SD, Parekh VI, Kebebew E, Agarwal SK. 2015. Epigenetic regulation of the lncRNA MEG3 and its target c-MET in pancreatic neuroendocrine tumors. Mol Endocrinol 29:224–237. Parekh VI, Modali SD, Desai SS, Agarwal SK. 2015. Consequence of Menin Deficiency in Mouse Adipocytes Derived by In Vitro Differentiation. Int J Endocrinol 2015:149826. Wei YL, Hua J, Liu XY, Hua XM, Sun C, Bai JA, Tang QY 2018. LncNEN885 inhibits epithelial-mesenchymal transition by partially regulation of Wnt/beta-catenin signalling in gastroenteropancreatic neuroendocrine neoplasms. Cancer Sci 109:3139–3148. Pang EJ, Yang R, Fu XB, Liu YF. 2015. Overexpression of long non-coding RNA MALAT1 is correlated with clinical progression and unfavorable prognosis in pancreatic cancer. Tumour Biol 36:2403–2407. Zheng HT, Shi DB, Wang YW, Li XX, Xu Y, Tripathi P, Gu WL, Cai GX, Cai SJ 2014. High expression of lncRNA MALAT1 suggests a biomarker of poor prognosis in colorectal cancer. Int J Clin Exp Pathol 7:3174–3181. Wu ZH, Wang XL, Tang HM, et al. 2014. Long non-coding RNA HOTAIR is a powerful predictor of metastasis and poor prognosis and is associated with epithelial-mesenchymal transition in colon cancer. Oncol Rep 32:395–402. Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, Kim S, Safe S 2013. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene 32:1616–1625. Emadi-Andani E, Nikpour P, Emadi-Baygi M, Bidmeshkipour A. 2014. Association of HOTAIR expression in gastric carcinoma with invasion and distant metastasis. Adv Biomed Res 3:135. Ge XS, Ma HJ, Zheng XH, Ruan HL, Liao XY, Xue WQ, Chen YB, Zhang Y, Jia WH 2013. HOTAIR, a prognostic factor in esophageal squamous cell carcinoma, inhibits WIF-1 expression and activates Wnt pathway. Cancer Sci 104:1675–1682. Kwok ZH, Roche V, Chew XH, Fadieieva A, Tay Y. 2018. A non-canonical tumor suppressive role for the long non-coding RNA MALAT1 in colon and breast cancers. Int J Cancer https://doi.org/10.1002/ijc.31386, 143, 668, 678. Han Y, Wu Z, Wu T, Huang Y., Cheng Z., Li X., Sun T., Xie X., Zhou Y., du Z. 2016. Tumor-suppressive function of long noncoding RNA MALAT1 in glioma cells by downregulation of MMP2 and inactivation of ERK/MAPK signaling. Cell Death Dis 7:e2123. Cao S, Wang Y, Li J, Lv M, Niu H, Tian Y. 2016. Tumor-suppressive function of long noncoding RNA MALAT1 in glioma cells by suppressing miR-155 expression and activating FBXW7 function. Am J Cancer Res 6:2561–2574. Kim J, Piao HL, Kim BJ, Yao F, Han Z, Wang Y, Xiao Z, Siverly AN, Lawhon SE, Ton BN, Lee H, Zhou Z, Gan B, Nakagawa S, Ellis MJ, Liang H, Hung MC, You MJ, Sun Y, Ma L 2018. Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nat Genet 50:1705–1715. Zhao M, Wang S, Li Q, Ji Q, Guo P, Liu X. 2018. MALAT1: A long non-coding RNA highly associated with human cancers. Oncol Lett 16:19–26. Hajjari M, Salavaty A. 2015. HOTAIR: an oncogenic long non-coding RNA in different cancers. Cancer Biol Med 12:1–9. Hirata H, Hinoda Y, Shahryari V, Deng G., Nakajima K., Tabatabai Z.L., Ishii N., Dahiya R. 2015. Long Noncoding RNA MALAT1 Promotes Aggressive Renal Cell Carcinoma through Ezh2 and Interacts with miR-205. Cancer Res 75:1322–1331. Zhang R, Hardin H, Huang W, Chen J, Asioli S, Righi A, Maletta F, Sapino A, Lloyd RV 2017. MALAT1 Long Non-coding RNA Expression in Thyroid Tissues: Analysis by In Situ Hybridization and Real-Time PCR. Endocr Pathol 28:7–12. Amodio N, Raimondi L, Juli G, Stamato MA, Caracciolo D, Tagliaferri P, Tassone P 2018. MALAT1: a druggable long non-coding RNA for targeted anti-cancer approaches. J Hematol Oncol 11:63. Tang Q, Hann SS. 2018. HOTAIR: An Oncogenic Long Non-Coding RNA in Human Cancer. Cell Physiol Biochem 47:893–913. Ji S, Qin Y, Shi S, Liu X., Hu H., Zhou H., Gao J., Zhang B., Xu W., Liu J., Liang D., Liu L., Liu C., Long J., Zhou H., Chiao P.J., Xu J., Ni Q., Gao D., Yu X. 2015. ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer. Cell Res 25:561–573. Chang YT, Lin TP, Tang JT, Campbell M, Luo YL, Lu SY, Yang CP, Cheng TY, Chang CH, Liu TT, Lin CH, Kung HJ, Pan CC, Chang PC 2018. HOTAIR is a REST-regulated lncRNA that promotes neuroendocrine differentiation in castration resistant prostate cancer. Cancer Lett 433:43–52. Chakravadhanula M, Ozols VV, Hampton CN, Zhou L, Catchpoole D, Bhardwaj RD. 2014. Expression of the HOX genes and HOTAIR in atypical teratoid rhabdoid tumors and other pediatric brain tumors. Cancer Genet 207:425–428. Zhang R, Hardin H, Huang W, Buehler D, Lloyd RV. 2018. Long Non-coding RNA Linc-ROR Is Upregulated in Papillary Thyroid Carcinoma. Endocr Pathol 29:1–8. Hardin H, Helein H, Meyer K, Robertson S, Zhang R, Zhong W, Lloyd RV 2018. Thyroid cancer stem-like cell exosomes: regulation of EMT via transfer of lncRNAs. Lab Invest 98:1133–1142. Vijayvergia N, Boland PM, Handorf E, Gustafson KS, Gong Y, Cooper HS, Sheriff F, Astsaturov I, Cohen SJ, Engstrom PF 2016. Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study. Br J Cancer 115:564–570. Kim ST, Lee SJ, Park SH, Park JO, Lim HY, Kang WK, Lee J, Park YS 2016. Genomic Profiling of Metastatic Gastroenteropancreatic Neuroendocrine Tumor (GEP-NET) Patients in the Personalized-Medicine Era. J Cancer 7:1044–1048. Kyriakopoulos G, Mavroeidi V, Chatzellis E, Kaltsas GA, Alexandraki KI. 2018. Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms. Ann Transl Med 6:252. Yadav R, Kakkar A, Sharma A, Malik PS, Sharma MC. 2016. Study of clinicopathological features, hormone immunoexpression, and loss of ATRX and DAXX expression in pancreatic neuroendocrine tumors. Scand J Gastroenterol 51:994–999. Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF. 2018. Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol https://doi.org/10.1038/s41379-018-0122-7. Lilo MT, Chen Y, LeBlanc RE. 2018. INSM1 is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell Carcinoma. Am J Surg Pathol https://doi.org/10.1097/pas.0000000000001136, 42, 1541, 1548. Rosenbaum JN, Guo Z, Baus RM, Werner H, Rehrauer WM, Lloyd RV. 2015. INSM1: A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and Neuroepithelial Neoplasms. Am J Clin Pathol 144:579–591. Tanigawa M, Nakayama M, Taira T, Hattori S, Mihara Y, Kondo R, Kusano H, Nakamura K, Abe Y, Ishida Y, Okabe Y, Hisaka T, Okuda K, Fujino K, Ito T, Kawahara A, Naito Y, Yamaguchi R, Akiba J, Akagi Y, Yano H 2018. Insulinoma-associated protein 1 (INSM1) is a useful marker for pancreatic neuroendocrine tumor. Med Mol Morphol 51:32–40. Rooper LM, Bishop JA, Westra WH. 2018. INSM1 is a Sensitive and Specific Marker of Neuroendocrine Differentiation in Head and Neck Tumors. Am J Surg Pathol 42:665–671. Xin Z, Zhang Y, Jiang Z, Zhao L, Fan L, Wang Y, Xie S, Shangguan X, Zhu Y, Pan J, Liu Q, Huang Y, Dong B, Xue W 2018. Insulinoma-associated protein 1 is a novel sensitive and specific marker for small cell carcinoma of the prostate. Hum Pathol 79:151–159. Uri I, Grozinsky-Glasberg S. 2018. Current treatment strategies for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Clin Diabetes Endocrinol 4:16. Oberg KE, Reubi JC, Kwekkeboom DJ, Krenning EP. 2010. Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology 139:742–753, 753.e741