Wen Li

Renal cell carcinoma (RCC) is a prevalent, highly aggressive malignant tumor that affects the urinary system. RCC has a pronounced propensity for metastasis. Despite the widespread use of sunitinib as first-line therapy for advanced RCC, the occurrence of primary and acquired resistance is frequent and presents significant challenges for effective clinical management. Epithelial–mesenchymal transition (EMT) induction is mediated by hypoxia-HIF signaling, chronic inflammatory stimulation, stromal-tumor cell interactions, and metabolic reprogramming, which confers increased cellular plasticity, migratory potential, and survival benefits. EMT activation is closely associated with reorganization of cellular signaling networks under tumor microenvironment stress, the initiation of alternative angiogenic pathways, and the enhanced anti-apoptotic capacity, all of which contribute to the development of sunitinib resistance. This review systematically summarizes current evidence involving the molecular basis of EMT-driven sunitinib resistance in RCC and investigates potential therapeutic targets, establishing a conceptual foundation for the development of novel strategies to counteract resistance and enhance clinical efficacy.

Chromosomal translocation (CT) is characterized by incorrect ligation between chromosome fragments when multiple DNA double-strand breaks (DSBs) exist simultaneously. DNA repair, the three-dimensional structure of the nucleoskeleton, and the spatial and temporal movement of DSB ends contribute to CTs. Our earlier research showed that Intermediate Filament Family Orphan 1 (IFFO1) links the nucleoskeleton and non-homologous end joining (NHEJ) to prevent CTs. In this study, we identified the paralog IFFO2, which, together with IFFO1, forms a complex interaction network. We demonstrate that the C-terminus of these IFFOs binds to XRCC4 to facilitate its participation in the NHEJ process. In contrast, their N-termini oversee the building of the nucleoskeleton by connecting with each other and Lamin A/C. Interestingly, IFFO1 and IFFO2 show epistatic effects in suppressing CT by anchoring broken DNA ends and have non-epistatic roles in NHEJ-mediated DSB repair. Our results define an integrated nucleoskeleton composed of IFFO1–IFFO2–Lamin A/C, and reveal its dual functions in genome stability maintenance, the promotion of end-joining, and the suppression of CT.

The metastasis of lung cancer represents a significant factor contributing to the failure of clinical treatment, and the mechanisms involved are intricate and not yet completely elucidated. Intermediate filaments, which constitute a key element of the cytoskeleton, function not only as diagnostic markers but also play a role in malignant processes, including tumor proliferation, apoptosis, and migration. The intermediate filament IFFO1 is essential for genomic stability, and its expression level serves as a prognostic indicator in various tumors. However, the functional contributions of IFFO1 in tumor progression remain inadequately understood. Our study revealed that IFFO1 is downregulated in lung cancer patients and is correlated with a poorer prognosis. The depletion of IFFO1 led to enhanced tumor proliferation both in vitro and in vivo, as well as increased cellular migration, alterations in the cytoskeleton and modifications in GTPase-mediated signal transduction. Mechanically, IFFO1 was found to interact directly with the GTPase-related scaffold IQGAP3 through the 2 A coiled-coil domain, which was critical for the inhibition of cellular mobility. Moreover, the increased cell migration observed in IFFO1-deficient cells was substantiated as being facilitated by IQGAP3. Finally, IFFO1 was shown to inhibit the association of IQGAP3 with its effector Cdc42 in a dose-dependent manner. Our study demonstrates the multifaceted roles of IFFO1 in lung cancer by modulating the IQGAP3-Cdc42 axis and suggests the potential for identifying tumor targets through the examination of intermediate filament networks and their associated co-factors.