Cross-talk among MEN1, p53 and Notch regulates the proliferation of pancreatic neuroendocrine tumor cells by modulating INSM1 expression and subcellular localization

Abstract

Genomic analysis of Pancreatic Neuroendocrine Tumors (PanNETs) has revealed that these tumors often lack mutations in typical cancer-related genes such as the tumor suppressor gene p53 . Instead, PanNET tumorigenesis usually involves mutations in specific PanNET-related genes, such as tumor suppressor gene MEN1 . Using a PanNET mouse model, human tissues and human cell lines, we studied the cross-talk among MEN1, p53 and Notch signaling pathways and their role in PanNETs. Here, we show that reactivation of the early developmental program of islet cells underlies PanNET tumorigenesis by restoring the proliferative capacity of PanNET cells. We investigated the role of INSM1, a transcriptional regulator of islet cells’ development, and revealed that its expression and subcellular localization is regulated by MEN1 and p53 . Both human and mouse data show that loss of MEN1 in a p53 wild-type genetic background results in increased nuclear INSM1 expression and cell proliferation. Additionally, inhibition of Notch signaling in a p53 wild-type background reduces the proliferation of PanNET cells, due to repression of INSM1 transcription and nuclear localization. Our study elucidates the molecular mechanisms governing the interactions of INSM1 with MEN1, p53 and Notch and their roles in PanNET tumorigenesis, suggesting INSM1 as a key transcriptional regulator of PanNET cell proliferation.

The Clinical Application of Immunohistochemical Expression of Notch4 Protein in Patients with Colon Adenocarcinoma

“…The potential mechanisms of carcinogenesis associated with the oncogenic activity of Notch involve such biological events as the control of the phenotype of cancer-initiating cells, upregulation of tumour-associated signalling factors such as P53, facilitation of tumour angiogenesis and invasion, and cell cycle regulation [ 8 , 9 , 10 ]. It should also be noted that Notch may function as a tumour suppressor in other cancers, like squamous cell carcinoma (SCC) and neuroendocrine tumours [ 40 ]. The anti-tumour activity is related to the regulation of the malignant transcription factors, downstream suppressor gene activation and suppression of the cell cycle [ 8 , 9 , 10 ].…”

A Novel Signature Based on m6A RNA Methylation Regulators Reveals Distinct Prognostic Subgroups and Associates with Tumor Immunity of Patients with Pancreatic Neuroendocrine Neoplasms

“…High HNRNPC expression was correlated with recurrence and PD-L1 expression, which may allow the development of a combinatorial therapeutic regimen using HNRNPC inhibitor and PD-L1 monoclonal antibody. Recent studies have shown that genomic mutations in PanNENs can be relevant to classify patients beyond their tumor grade and identify novel prognostic markers and therapeutic targets that could be relevant in the future for adjuvant therapy [ 56 ]. It will be interesting to investigate whether such a clinical approach is feasible in PanNENs with high HNRNPC expression in prospective clinical trials.…”

The link between menin and pleiotrophin in the tumor biology of pancreatic neuroendocrine neoplasms

“…This was confirmed by our in vitro studies that showed no differences in the proliferation assay. Most previous studies on tumor biology of pNEN have focused on the role of menin in pNEN cell growth, [43][44][45] but its effect on metastasis of pNEN is mainly unknown. 46 This study demonstrated that the absence of menin activated the migration and invasion abilities modifications in different environments.…”

“…Most previous studies on tumor biology of pNEN have focused on the role of menin in pNEN cell growth, 43 , 44 , 45 but its effect on metastasis of pNEN is mainly unknown. 46 This study demonstrated that the absence of menin activated the migration and invasion abilities of BON1 cells by increasing PTN expression.…”