Hypoopharyngeal squamous cell carcinoma (HPSCC) is one of the most aggressive cancers and is characterized by an extremely poor prognosis. We screened TROP2 to be highly expressed in HPSCC, but its effect on HPSCC remains unclear. This study is intended to determine the underlying mechanism by which TROP2 regulates HPSCC. Detecting TROP2 expression in HPSCC and normal tissues to clarify its distribution in tumor epithelial cells. Using TROP2 overexpression/knockdown to assess its effects on HPSCC cell progression phenotypes and pyroptosis. Applying molecular biology techniques to analyze TROP2’s regulation of the NLR signaling pathway, pyroptosis-related proteins and the PI3K/AKT pathway. And verifying via chromatin immunoprecipitation (ChIP) the binding of transcription factor JUND to the TROP2 promoter and its role in activating TROP2 expression. We showed that TROP2 is significantly upregulated in HPSCC, particularly in tumor epithelial cell. Our study revealed that TROP2 promotes HPSCC progression by suppressing pyroptosis. Mechanistically, TROP2 was found to regulate NOD-like receptor (NLR) signaling pathway and downregulate key pyrotosis-related protein, including GSDMD-N, Cleaved Caspase-1 (p20), IL18 and IL-1β. Additionally, we identified that PI3K/AKT signaling pathway is critically involved in TROP2-mediated inhibition of pyroptosis. Upstream analysis further revealed that the transcription factor JUND directly binds to and activates the TROP2 promoter, thereby contributing to its overexpression in HPSCC. Our findings highlight the JUND-TROP2-PI3K/AKT-pyrotosis axis as a potential therapeutic target for the treatment of HPSCC.
Oncogenic KRAS mutations are highly prevalent in colorectal cancer. Phosphorylation of KRAS at Ser181 regulates several of its oncogenic properties. Using CRISPR-edited SW480 cells expressing either the phosphorylatable (S181) or non-phosphorylatable (S181A) forms of oncogenic KRAS, we demonstrate that this post-translational modification modulates the invasive and metastatic capacity of the cells. To elucidate the underlying mechanism, we analyzed the secretome composition and identified 290 differentially secreted proteins. Notably, secretion of lysosomal proteins was specifically reduced in S181A cells. Among these, cathepsin B, a protein associated with invasiveness, was the most abundantly secreted in S181 cells. Protein kinase C (PKC) activity modulated cathepsin B secretion in S181 cells but had a diminished effect in S181A cells. Intracellular levels of cathepsin B and lysosomes were not significantly affected, indicating that secretion is the step regulated by KRAS phosphorylation. Cathepsin B secretion was also dependent on PI3K activity, which was lower in S181A cells, suggesting that KRAS phosphorylation facilitates cathepsin B secretion via PI3K activation. These findings indicate that KRAS phosphorylation by PKC regulates the invasive and metastatic potential of colorectal cancer cells by controlling secretion of lysosomal proteins, particularly cathepsin B.
Breast cancer is the most frequently diagnosed malignancy among women worldwide, affecting more than 2 million people annually. Despite significant advances in diagnosis and treatment, the mortality rate has increased in recent years. Patient mortality is primarily attributed to disease recurrence, metastasis, and resistance to therapy. It is known that cancer stem cells (CSCs) in cancer tissues, which can self-renew and generate heterogeneous cancer cell lineages, play an essential role in the initiation, progression, metastasis, and treatment resistance. Therefore, their ablation is a practical approach to the treatment of BC. Using natural compounds has been proposed as a promising and effective strategy to eliminate stem cells. Natural products include plant metabolites such as polyphenols, flavonoids, alkaloids, and isothiocyanates, which can directly or indirectly affect CSCs due to their distinct biological characteristics, including antioxidant, anti-inflammatory, and pro-apoptotic activities, as well as the regulation of cell signaling pathways. These compounds often suppress the growth of CSC cells by targeting cellular markers such as ALDH1, CD44, and CXCRs, and critical signaling pathways such as Notch, Wnt/β-catenin, and Hedgehog, which are involved in the self-renewal and proliferation of CSCs. Finally, developing and using natural compounds as complementary or alternative therapies is a promising step to improve BC treatment. This study investigates the latest knowledge of BCSCs, emphasizing their biomarkers, signaling pathways, and drug resistance mechanisms, and then highlights the importance and mechanism of action of plant compounds in destroying them.
The CXCL13 chemokine expression is developmentally restricted to few cell types including T, B and dendritic cells. Aberrant amplification of CXCL13 expression and subsequent CXCR5-CXCL13 signaling occurs in multiple cancers, including germinal center (GC) derived B-lymphomas (GCDBL), and several solid cancers including of colorectal adenocarcinoma (COAD), and liver hepatocellular carcinoma (LIHC), however the molecular mechanisms underlying abnormal CXCL13 transcription in cancers remains elusive. Chromosomal conformation capture (3C) analysis reveals a distal super-enhancer located near CCNG2 that interacts with the CXCL13 promoter in GCDBL, suggesting enhancer-hijacking drives aberrant CXCL13 expression in cancer cells. Notably, internal CXCL13 in the GCDBL line Raji disrupts CXCR5-dependent migration, suggesting that elevated CXCL13 in GCDBL impairs light-zone migration, thus restricting GCDBL B-cell survival, a quality-control step preceding affinity maturation and high-affinity antibody production. Functional validation in cancer cells revealed CXCR5-CXCL13 signaling suppresses p53 and its target genes in COAD, LIHC and lymphoma cells. Together, these findings uncover a mechanism of aberrant CXCL13 transcription via super-enhancer hijacking in cancer cells that drives proliferation through p53 dysregulation in CXCR5-CXCL13-positive cancers, while CXCL13 expression in GCDBL can quality assure high affinity antibody production and B-lymphoma elimination during the GC reaction.
Pseudopodium-enriched atypical kinase 1 (PEAK1), initially identified in the pseudopodia of motile cells, is a signaling scaffold and a focal adhesion-linked pseudokinase. Experimental studies link PEAK1 to extracellular matrix sensing, integrin and receptor-mediated signal transduction, cytoskeletal reorganization, epithelial-mesenchymal plasticity, angiogenesis, metastatic progression and responses to therapy. Pro-tumorigenic activities have been described in models of pancreatic, breast, lung, melanoma, anaplastic thyroid and colorectal cancers. However, gastric and colorectal studies indicate that its effects depend on the biological context. Outside of oncology, mechanistic inquiries have characterized PEAK1 in the endothelial GATA2-VEGFR2 signaling pathways and in the maintenance of the intestinal epithelial barrier by protecting ZO-1 from degradation by autophagy. Therefore, instead of being a ubiquitous oncogenic driver, PEAK1 is better characterized as a context dependent regulator that orchestrates signaling networks associated with cell adhesion and growth factors. The following narrative review presents the identification and the molecular features of PEAK1, and summarizes the data concerning its functions in both oncogenic and non-malignant biological contexts. It also explores the upstream regulatory mechanisms, the downstream signaling effectors, the phenotypes related to metastasis and drug resistance, and new therapeutic perspectives. More specifically, the review distinguishes causal functional evidence from expression correlations. It explains which unresolved mechanistic questions must be addressed before clinical translation.
