Insulin receptor alternative splicing in breast and prostate cancer

Abstract

Cancer etiology represents an intricate, multifactorial orchestration where metabolically associated insulin-like growth factors (IGFs) and insulin foster cellular proliferation and growth throughout tumorigenesis. The insulin receptor (IR) exhibits two splice variants arising from alternative mRNA processing, namely IR-A, and IR-B, with remarkable distribution and biological effects disparities. This insightful review elucidates the structural intricacies, widespread distribution, and functional significance of IR-A and IR-B. Additionally, it explores the regulatory mechanisms governing alternative splicing processes, intricate signal transduction pathways, and the intricate association linking IR-A and IR-B splicing variants to breast and prostate cancer tumorigenesis. Breast cancer and prostate cancer are the most common malignant tumors with the highest incidence rates among women and men, respectively. These findings provide a promising theoretical framework for advancing preventive strategies, diagnostic modalities, and therapeutic interventions targeting breast and prostate cancer.

Keywords: Alternative splicing; Cancer; Insulin receptor isoforms.

Fig. 1

Expression of IR-A and IR-B in different cancer types. A IR isoforms in GEPIA (Gene Expression Profiling Interactive Analysis). INSR-001: IR-B, INSR-002: IR-A. Furin-like: The furin-like structure domain is capable of cleaving specific peptide chains, thus participating in the processing and activation of certain proteins during the alternative splicing process. Pkinase_Tyr: The Pkinase_Tyr domain is capable of regulating the activation status of relevant signaling pathways during alternative splicing. Recep_L_domain: The Recep_L domain structure can mediate RNA-RNA or RNA–protein interactions during the process of alternative splicing, thereby influencing splice site selection and efficiency. B.C Violin plot (B) and box plot (C) showing the expression level of IR-A and IR-B in different cancer types by isoform usage profiling in GEPIA. INSR-001 IR-B, INSR-002 IR-A. ACC Adrenocortical carcinoma, BLCA Bladder Urothelial Carcinoma, BRCA Breast invasive carcinoma, CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma, CHOL Cholangiocarcinoma, COAD Colon adenocarcinoma, DLBC Lymphoid Neoplasm Diffuse Large B-cell Lymphoma, ESCA Esophageal carcinoma, GBM Glioblastoma multiforme, HNSC Head and Neck squamous cell carcinoma, KICH Kidney Chromophobe, KIRC Kidney renal clear cell carcinoma, KIRP Kidney renal papillary cell carcinoma, LAML Acute Myeloid Leukemia, LGG Brain Lower Grade Glioma, LIHC Liver hepatocellular carcinoma, LUAD Lung adenocarcinoma, LUSC Lung squamous cell carcinoma, MESO Mesothelioma, OV Ovarian serous cystadenocarcinoma, PAAD Pancreatic adenocarcinoma, PCPG Pheochromocytoma and Paraganglioma, PRAD Prostate adenocarcinoma, READ Rectum adenocarcinoma, SARC Sarcoma, SKCM Skin Cutaneous Melanoma, STAD Stomach adenocarcinoma, TGCT Testicular Germ Cell Tumors, THCA Thyroid carcinoma, THYM Thymoma, UCEC Uterine Corpus Endometrial Carcinoma, UCS Uterine Carcinosarcoma, UVM Uveal Melanoma

Fig. 2

Proposed model for the regulation of IR pre-mRNA alternative splicing by splicing factors in cancers. The diagram provides an overview of the primary regulators that influence insulin IR activity at both the promoter and mRNA levels. Splicing factors play a crucial role in controlling IR gene transcription by either promoting or inhibiting it. Multiple splicing factors are involved in regulating IR expression after transcription. Once the IR mRNA is formed, splicing factors remove introns and facilitate the joining of exons. They also regulate the alternative splicing of exon 11, resulting in the production of either IR-A (exon11-) or IR-B (exon11 +) isoforms. In cancer cells, there is an elevated expression of the IR-A isoform, which can have oncogenic effects. ISS Intronic Splicing Silence, ESS Exonic Splicing Silence

Fig. 3

Proposed model for the IR signal diversification and partitioning in cancers. Activation of IR isoforms leads to the activation of specific signaling pathways, such as the PI3K-Akt pathway and the MAPK pathway, which regulate various cellular processes.In cells where IR-A is primarily expressed and IGF-2 is produced, such as fetal or cancer cells, activation of IR-A by IGF-2 promotes non-metabolic responses, including cell proliferation and movement. On the other hand, in cells and tissues with a higher expression of IR-B, insulin activation of IR-B supports metabolic and physiological functions through downstream signaling