The role of HMGA1 protein in gastroenteropancreatic neuroendocrine tumors

ABSTRACT Neuroendocrine tumors (NETs) are neoplasms derived from neuroendocrine cells. One of their main features is to often remain asymptomatic and clinically undetectable. High Mobility Group A (HMGA) proteins belong to a family of non-histone chromatinic proteins able to modulate gene expression through the interaction with DNA and transcription factors. They are overexpressed in most of the human malignancies, playing a critical role in carcinogenesis. However, their expression levels and their role in neuroendocrine carcinogenesis has not been exhaustively evaluated until now. Therefore, in this study, we have addressed the validity of using the expression of HMGA1 as a diagnostic marker and have investigated its role in NET carcinogenesis. The expression of HMGA1 has been evaluated by qRT-PCR and immunohistochemistry, using NET tissue microarrays, in a cohort of gastroenteropancreatic (GEP)-NET samples. The expression levels of HMGA1 have been then correlated with the main clinical features of NET samples. Finally, the contribution of HMGA1 overexpression to NET development has been addressed as far as the modulation of proliferation and migration abilities of NET cells is concerned. Here, we report that HMGA1 is overexpressed in GEP-NET samples, at both mRNA and protein levels, and that the silencing of HMGA1 protein expression interferes with the ability of NET cells to proliferate and migrate through the downregulation of Cyclin E, Cyclin B1 and EZH2. These results propose the HMGA proteins as new diagnostic and prognostic markers.

[1]  A. Fusco,et al.  Critical role of the high mobility group A proteins in hematological malignancies , 2021, Hematological oncology.

[2]  G. Botti,et al.  HMGA1-Regulating microRNAs Let-7a and miR-26a are Downregulated in Human Seminomas , 2020, International journal of molecular sciences.

[3]  Zhaojian Liu,et al.  MYC-regulated pseudogene HMGA1P6 promotes ovarian cancer malignancy via augmenting the oncogenic HMGA1/2 , 2020, Cell Death and Disease.

[4]  A. Fusco,et al.  Overexpression of HMGA1 Figures as a Potential Prognostic Factor in Endometrioid Endometrial Carcinoma (EEC) , 2019, Genes.

[5]  A. Fusco,et al.  HMGA2, but not HMGA1, is overexpressed in human larynx carcinomas , 2018, Histopathology.

[6]  A. Fusco,et al.  HMGA2 overexpression plays a critical role in the progression of esophageal squamous carcinoma. , 2016, Oncotarget.

[7]  S. Piazza,et al.  A novel HMGA1-CCNE2-YAP axis regulates breast cancer aggressiveness , 2015, Oncotarget.

[8]  A. Fusco,et al.  High Mobility Group A Proteins as Tumor Markers , 2015, Front. Med..

[9]  A. Fusco,et al.  HMGA1-pseudogene overexpression contributes to cancer progression , 2014, Cell cycle.

[10]  A. Fusco,et al.  The impairment of the High Mobility Group A (HMGA) protein function contributes to the anticancer activity of trabectedin. , 2013, European journal of cancer.

[11]  A. Fusco,et al.  HMGA1 and HMGA2 protein expression correlates with advanced tumour grade and lymph node metastasis in pancreatic adenocarcinoma , 2012, Histopathology.

[12]  C. Iacobuzio-Donahue,et al.  HMGA1 Induces Intestinal Polyposis in Transgenic Mice and Drives Tumor Progression and Stem Cell Properties in Colon Cancer Cells , 2012, PloS one.

[13]  J. Kowalski,et al.  HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis , 2011, BMC Genomics.

[14]  Michael A. Choti,et al.  DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors , 2011, Science.

[15]  Cher Heng Tan,et al.  Imaging of gastroenteropancreatic neuroendocrine tumors. , 2011, World journal of clinical oncology.

[16]  Domenico Coppola,et al.  The Pathologic Classification of Neuroendocrine Tumors: A Review of Nomenclature, Grading, and Staging Systems , 2010, Pancreas.

[17]  T. Berge,et al.  Carcinoid tumours. Frequency in a defined population during a 12-year period. , 2009, Acta pathologica et microbiologica Scandinavica. Section A, Pathology.

[18]  G. Botti,et al.  Detection of high‐mobility group proteins A1 and A2 represents a valid diagnostic marker in post‐pubertal testicular germ cell tumours , 2008, The Journal of pathology.

[19]  A. Fusco,et al.  Roles of HMGA proteins in cancer , 2007, Nature Reviews Cancer.

[20]  F. Gleeson,et al.  Anatomic and functional imaging of metastatic carcinoid tumors. , 2007, Radiographics : a review publication of the Radiological Society of North America, Inc.

[21]  B. Eriksson,et al.  Endocrine tumours of the pancreas. , 2005, Best practice & research. Clinical gastroenterology.

[22]  D. Breen,et al.  Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs) , 2005, Gut.

[23]  R. Sutton,et al.  Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours , 2005, Gut.

[24]  I. Modlin,et al.  A 5‐decade analysis of 13,715 carcinoid tumors , 2003, Cancer.

[25]  C. Croce,et al.  Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas , 2002, Oncogene.

[26]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[27]  H. Moch,et al.  Tissue microarrays for rapid linking of molecular changes to clinical endpoints. , 2001, The American journal of pathology.

[28]  Santa Jeremy Ono,et al.  Transgenic Mice Expressing a Truncated Form of the High Mobility Group I-C Protein Develop Adiposity and an Abnormally High Prevalence of Lipomas* , 2000, The Journal of Biological Chemistry.

[29]  C. Croce,et al.  The expression of a truncated HMGI-C gene induces gigantism associated with lipomatosis. , 1999, Cancer research.

[30]  P. Chieffi,et al.  HMGA1 induces EZH2 overexpression in human B-cell lymphomas. , 2021, American journal of cancer research.

[31]  G. Sauter,et al.  Prognostic value of cell cycle and apoptosis regulatory proteins in mismatch repair-proficient colorectal cancer: a tissue microarray-based approach. , 2007, American journal of clinical pathology.

[32]  L. Sobin,et al.  From the archives of the AFIP: Gastrointestinal carcinoids: imaging features with clinicopathologic comparison. , 2007, Radiographics : a review publication of the Radiological Society of North America, Inc.