Investigation of ANKHD1-related signaling pathways and biological processes in Stomach Cancer

• Grant number: 22/11038-8
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: July 01, 2023
• End date: July 31, 2027
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: João Agostinho Machado Neto
• Grantee: Bruna Oliveira de Almeida
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Stomach cancer is the fifth most diagnosed type of cancer and the fourth leading cause of cancer death in the world. Patients with advanced clinical stage (IV) gastric adenocarcinoma have an average survival between 9 and 10 months. Thus, despite advances in the understanding of its biology, it is evident the relevance of identifying new molecular markers that may be useful for the clinical management and treatment of patients with stomach cancer. In this sense, by establishing several protein interactions, the protein Ankyrin repeat and KH domain-containing 1, ANKHD1, has been demonstrated as a regulator of signaling pathways and cellular processes relevant to cancer biology. Among the known interactors of ANKHD1, its interaction with the Yes-associated protein 1, YAP1, an effector of the Hippo signaling pathway, stands out. Recently, according to the expression of YAP1 and its activity as an oncogene or tumor suppressor, a pan-cancer study proposed a new binary classification of the different tumor types into YAPon and YAPoff. In this context, it is noteworthy that 71% of the patients in the TCGA cohort of gastric adenocarcinoma, a YAPon tumor type, present alterations in genes involved in the Hippo signaling pathway. Thus, in view of the proposed new pan-cancer division, based on the expression and function of a well-characterized ANKHD1 interactor, the absence of studies aimed at understanding its role in a wide range of tumor types and adding to our preliminary results that indicated higher expression of ANKHD1 gene in the tumor tissue of gastric adenocarcinoma, when compared to the normal one, the present project seeks to investigate the biological role of ANKHD1 and the signaling pathways associated with it in stomach cancer cell lines, a YAPon tumor model. For this, the cell lines HGC-27 and AGS, WT and KO for the ANKHD1 gene will be used. KO cell lines for ANKHD1 gene will be established using CRISPR/Cas9 technology. Initially, functional assays will be conducted in order to identify whether the ANKHD1 protein contributes to the manifestation of malignant characteristics, in this experimental model. Then, if the involvement of ANKHD1 in the neoplastic phenotype of stomach cancer cells is demonstrated, it will be conducted proteomic analysis of the ANKHD1 interactome in WT cells, transcriptomic analysis of WT and KO cells for the ANKHD1 gene, followed by bioinformatics analyses, and molecular assays, in order to elucidate the mechanisms associated with the observed phenotypes. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PARDUCCI, NATALIA SUDAN; GARNIQUE, ANALI DEL MILAGRO BERNABE; DE ALMEIDA, BRUNA OLIVEIRA; MACHADO-NETO, JOA AGOSTINHO. Exploring the dual role of SIVA1 in cancer biology. Gene, v. 950, p. 9-pg., 2025-03-03. (23/11752-5, 22/11038-8)

CARVALHO, MARIA FERNANDA LOPES; DE ALMEIDA, BRUNA OLIVEIRA; BUENO, MAURA LIMA PEREIRA; VICARI, HUGO PASSOS; LIMA, KELI; ROVERSI, FERNANDA MARCONI; MACHADO-NETO, JOAO AGOSTINHO. Comprehensive analysis of the HCK gene in myeloid neoplasms: Insights into biological functions, prognosis, and response to antineoplastic agents. Hematology, Transfusion and Cell Therapy, v. 46, n. 3, p. 10-pg., 2024-06-08. (20/12842-0, 19/23864-7, 22/11038-8, 22/14505-6, 21/11606-3, 21/01460-1)

ALCANTARA, GUILHERME AUGUSTO SOUSA; DO NASCIMENTO, MARIANE CRISTINA; DE MIRANDA, LIVIA BASSANI LINS; DE ALMEIDA, BRUNA OLIVEIRA; LIMA, KELI; REGO, EDUARDO MAGALHAES; COSTA-LOTUFO, LETICIA VERAS; MACHADO-NETO, JOAO AGOSTINHO. Eribulin exerts multitarget antineoplastic activity in glioma cells. PHARMACOLOGICAL REPORTS, v. N/A, p. 12-pg., 2025-03-08. (21/11606-3, 23/12246-6, 20/12842-0, 22/11038-8, 22/03316-8)

CARVALHO, MARIA FERNANDA LOPES; CALICCHIO, CAROLINA SANTANA; DE ALMEIDA, BRUNA OLIVEIRA; DE MIRANDA, LIVIA BASSANI LINS; DA SILVA, JEAN CARLOS LIPRERI; LIMA, KELI; MACHADO-NETO, JOAO AGOSTINHO. Transcriptomics analysis identified ezrin as a potential druggable target in cervical and gastric cancer cells. Clinics, v. 79, p. 10-pg., 2024-07-06. (20/12842-0, 19/23864-7, 23/12246-6, 22/11038-8, 20/12909-7, 22/14505-6, 21/11606-3, 22/03316-8)