Meng Ye

The metastasis of hepatocellular carcinoma (HCC) cells remains a major obstacle to achieving favorable clinical outcomes, yet the underlying molecular mechanisms are still not fully understood. The dysregulation of ion channels is related to epithelial-mesenchymal transition (EMT) phenotype-related pathways, especially the aberrant function of K+ ion channels in HCC. In this study, we observed that the potassium-calcium-activated channel subfamily N member 3 (KCNN3/SK3/ KCa2.3) ion channels were significantly upregulated in HCC cells, promoting the migration and invasion of HCC in vitro and in vivo. Mechanistically, activation of the KCNN3 ion channel was found to enhance phosphorylation of the CCCTC-binding factor (CTCF), which in turn stimulates transcription of the EMT-related factor special AT-rich sequence-binding protein 1 (SATB1) via binding the “CCCTC” region within its promoter, thereby driving HCC cell migration and invasion. Furthermore, we identified that speckle-type POZ protein (SPOP), an E3 ligase adaptor, recognizes the SPOP-binding consensus (SBC) motif “ASSTT” (aa 250-254) in KCNN3 and mediates its ubiquitination via K27-linked ubiquitin chain. Notably, this type of ubiquitination does not induce KCNN3 turnover, but induced KCNN3 translocation from the cell membrane into the cytosol, thus suppressing KCNN3-mediated ion channel activity. Importantly, HCC-associated SPOP mutations or KCNN3-ΔSBC dramatically disrupt the SPOP–KCNN3 regulatory axis, accelerating HCC progression. These effects can be effectively counteracted by treatment with the KCNN3 channel inhibitor edelfosine and the calcium chelators BAPTA-AM, suggesting a promising therapeutic strategy for HCC patients.

Paclitaxel combination therapy is the main chemotherapy regimen for endometrial cancer (EC); however, subsequent drug resistance is a bottleneck limiting its widespread clinical application. We found that human insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) was abnormally elevated in paclitaxel-resistant EC cells and confirmed that the reduction of IGF2BP3 can effectively improve the sensitivity of EC cells to paclitaxel in vitro and in vivo. Mechanistically, elevated IGF2BP3 promotes the half-life of c-Myc by competitively inhibiting Speckle-type POZ protein (SPOP)-mediated ubiquitination and degradation of c-Myc. As a transcription factor, c-Myc can bind to the promoter of IGF2BP3, thus contributing to the increased transcription of IGF2BP3 via positive feedback and forming a signaling loop that ultimately causes the accumulation of c-Myc-induced paclitaxel resistance. Based on these findings, the application of c-Myc inhibitors (10058-F4) combined with paclitaxel helped paclitaxel-resistant EC cells regain paclitaxel sensitivity in vitro and in vivo. Together, we reveal the underlying mechanism of paclitaxel resistance in endometrial cancer cells and provide insights into treatment strategies for paclitaxel-resistant EC patients.

Cytoplasmic DNA-RNA hybrids are emerging as important immunogenic nucleic acids, that were previously underappreciated. DNA-RNA hybrids, formed during cellular processes like transcription and replication, or by exogenous pathogens, are recognized by pattern recognition receptors (PRRs), including cGAS, DDX41, and TLR9, which trigger immune responses. Post-translational modifications (PTMs) including ubiquitination, phosphorylation, acetylation, and palmitoylation regulate the activity of PRRs and downstream signaling molecules, fine-tuning the immune response. Targeting enzymes involved in DNA-RNA hybrid metabolism and PTMs regulation offers therapeutic potential for inflammatory diseases. Herein, we discuss the sources, immune response, and therapeutic implications of DNA-RNA hybrids in inflammation, highlighting the significance of DNA-RNA hybrids as potential targets for the treatment of inflammation.

Testicular germ cell tumors (TGCTs) are the most common tumors in men aged 20‑40 years and are primarily treated with cisplatin‑based drugs. Although TGCTs are highly sensitive to DNA damage induced by cisplatin and show a hypersensitive apoptotic response, cisplatin resistance still exists. Emerging evidence shows that cisplatin resistance in TGCTs is mainly related to the inhibition of apoptotic pathways such as MDM2/p53, OCT4/NOXA, PDGFR/PI3K/AKT, inhibition of cell cycle checkpoints, increased methylation or neddylation and DNA repair balance. In this review, recent advances regarding the mechanisms of TGCTs' sensitivity and resistance to cisplatin were summarized and potential therapeutic agents for cisplatin‑resistant TGCTs were presented, providing a new therapeutic strategy for drug‑resistant TGCTs.

Angiomotin (Amot) family members, including Amot, Amot‑like protein 1 (Amotl1) and Amot‑like protein 2 (Amotl2), have been found to interact with angiostatins. In addition, Amot family members are involved in various physiological and pathological functions such as embryonic development, angiogenesis and tumorigenesis. Some studies have also demonstrated its regulation in signaling pathways such as the Hippo signaling pathway, AMPK signaling pathway and mTOR signaling pathways. Amot family members play an important role in neural stem cell differentiation, dendritic formation and synaptic maturation. In addition, an increasing number of studies have focused on their function in promoting and/or suppressing cancer, but the underlying mechanisms remain to be elucidated. The present review integrated relevant studies on upstream regulation and downstream signals of Amot family members, as well as the latest progress in physiological and pathological functions and clinical applications, hoping to offer important ideas for further research.

Lenvatinib (LEN) is a multi-target TKI, which plays a pivotal role in the treatment of advanced hepatocellular carcinoma (HCC). The inevitable occurrence of drug resistance still prevents curative potential and is deleterious for the prognosis, and a growing body of studies is accumulating, which have devoted themselves to unveiling its underlying resistance mechanism and made some progress. The dysregulation of crucial signaling pathways, non-coding RNA and RNA modifications were proven to be associated with LEN resistance. A range of drugs were found to influence LEN therapeutic efficacy. In addition, the superiority of LEN combination therapy has been shown to potentially overcome the limitations of LEN monotherapy in a series of research, and a range of promising indicators for predicting treatment response and prognosis have been discovered in recent years. In this review, we summarize the latest developments in LEN resistance, the efficacy and safety of LEN combination therapy as well as associated indicators, which may provide new insight into its resistance as well as ideas in the treatment of advanced HCC.

Thyroid cancer (THCA) is the most common endocrine malignancy, mainly affecting women’s unilateral glandular lobes. However, for relapsed and distant metastasis of THCA patients, the existing early diagnosis and treatment methods were still insufficient, and a new method was urgently needed to diagnose and treat them. Nucleolar and coiled-body phosphoprotein 1 (NOLC1) was one of the most phosphorylated proteins in the cell, which was located mainly in the nucleolus. In addition, more and more studies have confirmed that NOLC1 plays a crucial role in various pathological processes, such as the occurrence and progression of cancer and viral infection. A previous study showed that NOLC1, as a member of RNA-binding protein, was significantly correlated with the prognosis of THCA patients. However, further exploration of NOLC1 in THCA is limited. To further explore the role of NOLC1 in THCA, we conducted expression and survival prognosis analysis of NOLC1 using multiple databases. We also evaluated the correlation between NOLC1 gene expression and clinical characteristics of THCA patients. Furthermore, we analyzed the relationship between NOLC1 and other genes, followed by enrichment analysis to investigate its metabolic pathways and molecular metabolism processes. Additionally, we examined the association between immune cell infiltration in tumor microenvironment and NOLC1. Notably, through vitro experiments, we confirmed the tumor suppressive effect of NOLC1 on the proliferation and migration of human THCA cells, providing evidence for clinical diagnosis of THCA. Furthermore, we confirmed the tumor suppressive effect of NOLC1 in vivo xenograft assay. To sum up, our results suggest that NOLC1 is a tumor suppressor gene for THCA.