J Gastrointestin Liver Dis, December 2020 Vol. 29 No 4: 647-658 1) Endocrinology Department, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj- Napoca; 2) 11 th Department of Medical Oncology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca; 3) Department of Medical Oncology, Ion Chiricuță Institute of Oncology, Cluj- Napoca; 4) Department of Genetics, Genomics and Experimental Pathology, Ion Chiricuță Institute of Oncology, Cluj- Napoca, Romania Address for correspondence: Ioana Rada Popa Ilie Endocrinology Department, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj- Napoca, Romania ioanamanaila@yahoo.com Received: 28.07.2020 Accepted: 01.11.2020 MicroRNAs and Treatment with Somatostatin Analogs in Gastro- Entero-Pancreatic Neuroendocrine Neoplasms: Challenges in Personalized Medicine Ana Maria Curt 1 , Ioana Rada Popa Ilie 1 , Călin Căinap 2,3 , Ovidiu Bălăcescu 2,4 , Cristina Ghervan 1 INTRODUCTION Nearly 50 years have passed since President Nixon declared war on cancer [1]. Although momentous achievements have DOI: http://dx.doi.org/10.15403/jgld-2866 ABSTRACT Molecular predictive biomarkers represent an essential tool for the future of personalized oncotherapy. Gastro- entero-pancreatic neuroendocrine neoplasms are a heterogeneous group of epithelial tumors with a steady increase in incidence and prevalence. Teir efective management depends on early diagnosis, personalized risk stratifcation, and monitoring response to therapy. A crucial element is identifying accurate biomarkers to predict/monitor therapeutic responses, assess drug resistance, and quantify residual disease in a reproducible and less invasive way. Taking into consideration their role in cell diferentiation, cell proliferation, apoptosis and tumor development, microRNAs have gained interest as potential prognostic markers and treatment response predictors in neuroendocrine neoplasms. Tis review is the frst to summarize the available data on the possible role of microRNAs in evaluating the efcacy of somatostatin analogs treatment in gastro- entero-pancreatic neuroendocrine neoplasms. Although the literature is scarce, the let-7 family targeting phosphoinositide 3 kinase – protein kinase B 1 – mammalian target of rapamycin signaling pathway might represent a promising biomarker with potential clinical beneft, but further research is required before their eventual clinical application. Furthermore, the ambiguous molecular mechanisms of neuroendocrine proliferation and the undefned signaling pathway of somatostatin analogs should encourage future research in this feld that may lead to a diferent clinical approach to neuroendocrine disease. Key words: neuroendocrine neoplasms − somatostatin analogs – microRNAs – predictive biomarker – let-7 family. Abbreviations: AKT: protein kinase B; BACH1: transcription factor BTB and CNC homology 1; cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EMT: epithelial-mesenchymal transition; GEP-NENs: gastro-entero-pancreatic neuroendocrine neoplasms; GH: growth hormone; HMGA2: high mobility group A2; HOXA9: homeobox protein A9; HOXB7: homeobox protein B7; IGF1: insulin-like growth factor; IGF1R = insulin-like growth factor receptor; IGFBP-7: insulin-like growth factor binding protein 7; IRS1: insulin receptor substrate 1; IRS2: insulin receptor substrate 2; LRP4: low-density lipoprotein receptor-related protein 4; MAPK: mitogen- activated protein kinase; miRNAs: microRNAs; miRs: microRNAs; MMP1: matrix metalloproteinse-1; mTOR = mammalian target of rapamycin; mTORC1: mammalian target of rapamycin complex 1; mTORC2: mammalian target of rapamycin complex 2; NEN: neuroendocrine neoplasm; NF-kB: nuclear factor kappa-light-chain- enhancer of activated B cells; PDK1: phosphoinositide-dependent kinase 1; PI3K: phosphoinositide 3 kinase; PI3KCD: phosphatidylinositol -4,5-biphosphate 3 kinase catalytic subunit delta; PIP 3 -phosphatidylinositol (3,4,5)–triphosphate; PTP: protein tyrosine phosphatases; pNEN: pancreatic NEN; RSPO2: roof-plate specifc spondin-2; SI-NEN: small intestinal NEN; SSAs: somatostatin analogs; SST: somatostatin; SSTR: somatostatin receptor; TSC1: tuberous sclerosis complex 1; TSC2: tuberous sclerosis complex 2; WNT: wingless-type MMTV integration site family; WNT2B: wingless-type MMTV integration site family, member 2B; ZEB1: zinc fnger E-box binding homeobox 1; ZEB2: zinc fnger E-box binding homeobox 2. been made in understanding carcinogenesis, struggles still exist when transposing this new, valuable information into clinical practice. Genetic and epigenetic alterations that lead to carcinogenesis occur at various levels, from depletion or gain of an entire chromosome to dysregulating a single microRNA that controls hundreds of genes. REVIEW