Insulin-like growth factor binding protein-3 (IGFBP-3) is a p53 tumor suppressor-regulated protein and a major carrier for IGFs in circulation. Among six high-affinity IGFBPs, which are IGFBP-1 through 6, IGFBP-3 is the most extensively investigated IGFBP species with respect to its IGF/IGF-I receptor (IGF-IR)-independent biological actions beyond its endocrine/paracrine/autocrine role in modulating IGF action in cancer. Disruption of IGFBP-3 at transcriptional and post-translational levels has been implicated in the pathophysiology of many different types of cancer including breast, prostate, and lung cancer. Over the past two decades, a wealth of evidence has revealed both tumor suppressing and tumor promoting effects of IGF/IGF-IR-independent actions of IGFBP-3 depending upon cell types, post-translational modifications, and assay methods. However, IGFBP-3′s anti-tumor function has been well accepted due to identification of functional IGFBP-3-interacting proteins, putative receptors, or crosstalk with other signaling cascades. This review mainly focuses on transmembrane protein 219 (TMEM219), which represents a novel IGFBP-3 receptor mediating antitumor effect of IGFBP-3. Furthermore, this review delineates the potential underlying mechanisms involved and the subsequent biological significance, emphasizing the clinical significance of the IGFBP-3/TMEM219 axis in assessing both the diagnosis and the prognosis of cancer as well as the therapeutic potential of TMEM219 agonists for cancer treatment.

Colitis-associated colon cancer (CAC) accompanies the massive infiltration of neutrophils during tumorigenesis and progression of CAC. Depletion of neutrophils in circulation results in significant inhibition of tumor incidence in CAC. However, the underlying mechanisms are largely unclear. In this study, we provide evidence for the crucial involvement of inflammatory neutrophil-activated serine proteases (NSPs) on the dysregulation of the anti-inflammatory and antitumor IGFBP-3/IGFBP-3R signaling axis in CAC using a chronic AOM/DSS mouse model. We also provide preclinical evidence for α1-antitrypsin (AAT) as a preventive and as a therapeutic for CAC. AAT administration not only prevented colitis-associated tumorigenesis but also inhibited established CAC. AOM/DSS treatment results in the significant activation of NSPs, leading to CAC through increased pro-inflammatory cytokines and decreased anti-inflammatory and antitumor IGFBP-3. Collectively, these data suggest that the NSPs proteolyze IGFBP-3, whereas AAT inhibits chronic colonic inflammation-induced NSP activity and subsequently suppresses IGFBP-3 proteolysis. Therefore, the anti-inflammatory and antitumor functions of the IGFBP-3/IGFBP-3R axis are restored. AAT mimicking small peptides also showed their inhibitory effects on NSP-induced IGFBP-3 proteolysis. These results suggest that targeting the NSP-IGFBP-3/IGFBP-3R axis using NSP inhibitors such as AAT and the AAT mimics and IGFBP-3R agonists could lead to novel approaches for the prevention and treatment of CAC.

Radiation therapy is a fundamental pillar in cancer treatment, yet its clinical efficacy is frequently compromised by the development of intrinsic and acquired tumor radioresistance. This review provides a comprehensive analysis of the molecular mechanisms underlying radioresistance, with a specific focus on the Epithelial–Mesenchymal Transition (EMT) and its regulation by microRNAs (miRNAs). EMT is recognized as a key driver of therapeutic resistance, enabling cancer cells to acquire enhanced migratory capacity, stem-like characteristics, and resistance to apoptosis. Importantly, ionizing radiation can itself function as a cellular stressor that induces EMT through major signaling pathways, including TGF-β, Wnt, and Notch, thereby establishing a self-reinforcing loop that promotes resistance. In addition, this review highlights the pivotal role of miRNAs as post-transcriptional regulators within this network. Dysregulated miRNAs, acting as either tumor suppressors or oncogenes, modulate EMT-transcription factors and DNA damage repair pathways to influence cellular radiosensitivity. The complex interplay between these factors and the tumor microenvironment is also explored. Finally, emerging therapeutic strategies designed to break this resistance loop, such as EMT inhibitors, miRNA mimics, and antagomirs, as well as combination therapies, are evaluated. Collectively, these approaches hold significant promise for restoring radiosensitivity and improving clinical outcomes in precision oncology.