Resident adipocytes under a hypoxic tumor microenvironment exert an increasingly important role in cell growth, proliferation, and invasion in cancers. However, the communication between adipocytes and cancer cells during nasopharyngeal carcinoma (NPC) progression is poorly understood. Here, we demonstrate that hypoxic adipocyte‐derived exosomes are key information carriers that transfer low expression of miR‐433‐3p into NPC cells. In addition, luciferase reporter assays detected that hypoxia inducible factor‐1α (HIF‐1α) induced miR‐433‐3p transcription through five binding sites at its promoter region. Concordantly, the low expression of miR‐433‐3p promoted proliferation, migration, and lipid accumulation in NPC cells via targeting stearoyl‐CoA desaturase 1 (SCD1) are suggested by functional studies. Consistent with these findings, in tumor‐bearing mice, NPC cells with low HIF‐1α expression, high miR‐433‐3p expression, and low SCD1 expression were equally endowed with remarkably reduced potential of tumorigenesis. Collectively, our study highlights the critical role of the HIF‐1α‐miR‐433‐3p‐SCD1 axis in NPC progression, which can serve as a mechanism‐based potential therapeutic approach.

In head and neck squamous cell carcinoma (HNSCC), perineural invasion (PNI) is a distinctive clinicopathologic feature associated with poor survival. To improve patient prognosis, our investigation delved into the underlying mechanism of PNI in HNSCC, especially laryngeal cancer and hypopharyngeal carcinoma. Based on data from the Cancer Genome Atlas (TCGA), genes were categorized into two groups based on the presence or absence of PNI. Plasminogen activator urokinase (PLAU) was screened out as the key molecular. Next, a tissue microarray comprising 68 patients with HNSCC was used to explore the association between PLAU and nerve growth factor (NGF), a positive control of PNI. Then, the co-culture model and cell damage function experiments were used to investigate the carcinogenic effect of PLAU. CCK8 and Transwell assays confirmed the role of PLAU in promoting proliferation and metastasis. The PC12 neurite growth assay and the co-culture system suggested that PLAU influences malignant behaviors by facilitating PNI. Moreover, introducing small molecule compounds to impede PLAU and NGF can effectively revert tumor progression in vivo. PLAU promotes tumor malignancy by facilitating PNI in HNSCC, offering a novel reference for clarifying the molecular mechanisms underlying PNI and identifying potential therapeutic targets for HNSCC.

Protein serine/threonine phosphatase 2A (PP2A) regulates diverse cellular processes via the formation of ~100 heterotrimeric holoenzymes. However, a scarcity of knowledge on substrate recognition by various PP2A holoenzymes has greatly prevented the deciphering of PP2A function in phosphorylation-mediated signaling in eukaryotes. The review summarized the contribution of B56 phosphorylation to PP2A-B56 function and proposed strategies for intervening B56 phosphorylation to treat diseases associated with PP2A-B56 dysfunction; it especially analyzed recent advancements in LxxIxEx B56-binding motifs that provide the molecular details of PP2A-B56 binding specificity and, on this basis, explored the emerging role of PP2A-B56 in the mitosis process, virus attack, and cancer development through LxxIxE motif-mediated PP2A-B56 targeting. This review provides theoretical support for discriminatingly targeting specific PP2A holoenzymes to guide PP2A activity against specific pathogenic drivers.

Anoikis resistance is a phenomenon wherein cells survive under anchorage-independent conditions, which is critical for cancer cell dissemination and metastasis. To identify strategies to overcome anoikis resistance, we used a 3D suspension culture model combined with proteomic screening, identifying a relationship between dynamin-related protein 1 (Drp1) and anoikis resistance in nasopharyngeal carcinoma (NPC). Drp1 facilitated the generation of new mitochondria and the removal of damaged ones by regulating fission and mitophagy, thereby enabling tumor cells to overcome anoikis. Furthermore, the interaction of Drp1 and BIP was enhanced during anoikis resistance, which increased formation of mitochondria-associated endoplasmic reticulum membranes (MAM) to maintain mitochondrial dynamic equilibrium. Mechanistically, CaMKKβ activated the AMPK–MFF–Drp1 and AMPK–mTOR–Drp1 pathways through O-GlcNAcylation modification, thus recruiting Drp1 to MAMs. Notably, the Drp1–BIP complex served as a prognostic indicator for NPC clinical outcome and metastatic risk. Collectively, these results elucidate a mechanism by which Drp1 regulates anoikis resistance through mitochondrial dynamics and provide a feasible treatment strategy for managing NPC. Significance: Drp1 translocation to MAMs and interaction with BIP induces mitochondrial remodeling and anoikis resistance to support metastasis in NPC, highlighting the potential of Drp1 as a therapeutic target.

The Forkhead-box (FOX) transcription factors, as one of the largest gene families in humans, play key roles in cancer. Although studies have suggested that several FOX transcription factors have a significant impact on cancer, the functions of most of the FOX genes in cancer remain elusive. In the study, the expression of 43 FOX genes in 63 kinds of cancer diseases (including many subtypes of same cancer) and in response to 60 chemical substances was obtained from the Gene Expression Atlas database of the European Bioinformatics Institute. Based on the high degree of overlap in FOXO family members differentially expressed in various cancers and their particular responses to chemotherapeutic drugs, our data disclosed the FOX genes that played an important role in the development and progression of cancer. More importantly, we predicted the role of one or several combinatorial FOX genes in the diagnosis and prognostic assessment of a specific cancer and evaluated the potential of a certain anticancer drug therapy for this type of cancer by integrating patterns of FOX genes expression with anticancer drugs sensitivity.

Lentiviruses, plasmids, and siRNA.