Jingtao Luo

Active surveillance is increasingly adopted for low-risk papillary thyroid microcarcinoma (PTMC ≤1 cm). However, a subset of tumors exhibit tracheal or recurrent laryngeal nerve (RLN) invasion, resulting in upstaging and functional morbidity. Reliable preoperative predictors are needed to optimize patient selection. This retrospective study analyzed 10,112 consecutive PTMC patients (mean age, 44.7 years; 73.8% female) who underwent surgery at a high-volume center between June 2021 and February 2025. Preoperative high-resolution ultrasonography was performed for all the patients. The shortest distances from the tumor to the trachea and posterior thyroid capsule were measured and categorized. Tracheal and RLN invasion were confirmed intraoperatively. Odds ratios (ORs) were calculated across risk groups. Tracheal invasion occurred in 1.5% of the patients and was not observed when the tumor-trachea distance exceeded 3 mm. Among tumors ≤1 mm from the trachea, invasion rates increased with tumor-trachea angle (acute 7.6%, right 11.3%, obtuse 17.2%), corresponding to a 47.9-fold higher risk (95% confidence interval, 29.5-77.7) compared with tumors larger than 1 mm. Recurrent laryngeal nerve invasion occurred in 2.3% of the patients and was rare when the tumor-capsule distance exceeded 3 mm (0.05%). Tumors ≤2 mm from the posterior capsule with capsular disruption showed a 34.6% invasion rate, including 9.8% clinically significant RLN invasion, with significantly increased risks of any RLN invasion (OR 45.6) and clinically significant RLN invasion (OR, 66.2). Preoperative ultrasound assessment of tumor proximity and interface with adjacent structures robustly predicts tracheal and RLN invasion in PTMC. These parameters may improve selection for active surveillance and guide surgical decision-making.

Cancer cells and the nervous system engage in a dynamic interplay, significantly influencing initiation and progression in head and neck squamous cell carcinoma (HNSCC). Our findings highlight that cancer cells drive an increase in caveolin-2 (Cav2) expression within trigeminal ganglia and associated neural fibers in the tumor milieu, fostering a reciprocal attractant relationship between tumor cells and nerves. Notably, the knockout of Cav2, either globally or specifically in sensory neurons or glial cells, markedly attenuates the growth of orthotopically implanted tongue tumors. Moreover, Cav2-expressing nerves are implicated in shifting cancer cell metabolism towards mitochondrial oxidative phosphorylation, a process involved in maintenance of cancer stem cells (CSCs). Our results also demonstrate that Cav2-expressing nerves confer stemness properties to cancer cells. Disruption of Cav2 expression, both globally and in specific neural cell types, impedes tumorigenesis and progression in a 4-NQO-induced HNSCC mouse model. This interplay observed between cancer cells, neurons, and glial cells suggests a potential mechanism through which tumor-associated nerves might influence cancer stemness via metabolic reprogramming. This highlights a possible direction for anticancer therapy that warrants further investigation.

Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer with alarmingly high morbidity. The cancer-associated fibroblasts (CAFs) play a pivotal role in tumor development, while their specific mechanisms in OSCC remains largely unclear. Our object is to explore a CAFs-related biomarker in OSCC. Single-cell RNA sequencing (ScRNA-seq) analysis was used to pinpoint CAF clusters in OSCC samples. Differentially expressed genes and Cox regression analyses were used to identify candidate genes, and their functions were evaluated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The prognostic performance of the identified biomarker was evaluated using receiver operating characteristic analysis. The qPCR and western blot were used to assess gene expression. The hub gene related immune characteristics were analyzed in independent cohorts, and gene expression differences between different immunotherapy response groups were investigated using Pearson correlation analysis. Desmoglein-2 (DSG2) was identified as a CAFs-related biomarker in OSCC exhibiting elevated expression compared to controls and being associated with poor prognosis. Enrichment analyses revealed that DSG2 was involved in signal transduction pathways like focal adhesion. The Area Under Curve values of DSG2 in predicting prognosis exceeded 0.6 in both training-set and validation-set. Furthermore, patients with low DSG2 expression were more likely to benefit from immunotherapy than those DSG2 highly expressed patients. Our study identified DSG2 as a reliable CAFs-related prognostic biomarker in OSCC, providing a new reference for the mechanistic understanding and target therapy of this malignancy.

More than half of HNSCC patients are diagnosed with advanced disease. Locally advanced HNSCC is characterized by tumors with marked local invasion and evidence of metastasis to regional lymph nodes. CAV2 is a major coat protein of caveolins, important components of the plasma membrane. In this study, CAV2 was found to profoundly promote invasion and stimulate metastasis in vivo and in vitro. CAV2 was demonstrated to be a key regulator of S100 protein expression that upregulates the proteins levels of S100s, which promotes the invasion and migration and downregulates the expression of tumor suppressors. Mechanistically, CAV2 directly interacts with S100s in HNSCC cells, and CAV2 reduces S100A14 protein expression by promoting its ubiquitylation and subsequent degradation via the proteasome. Moreover, we discovered that CAV2 promotes the interaction between S100A14 and the E3 ubiquitin ligase TRIM29 and increases TRIM29 expression. Taken together, our findings indicate that CAV2 promotes HNSCC invasion and metastasis by regulating the expression of S100 proteins, presenting a novel potential target for anticancer therapy in HNSCC.

The actin cytoskeletal architecture provides the structural underpinnings for crucial cellular behaviors. In cancer cells, changes in the actin cytoskeleton may serve as prerequisites for proliferation, invasion, and metastatic dissemination. However, the underlying mechanisms remain largely unknown. Here, we show that MICAL2, which is increased in head and neck squamous cell carcinoma (HNSCC) and inversely associated with patient survival, promotes HNSCC growth, invasion, and migration. MICAL2 serves as a flavoprotein monooxygenase and directly induces actin filament depolymerization by specifically oxidizing the methionine 44 and 47 residues of F-actin. The kinase ARG interacts with MICAL2 and augments MICAL2-mediated actin disassembly. Direct phosphorylation assay and mass spectrometry confirmed that ARG phosphorylates MICAL2 at Tyr445, Tyr463, and Tyr488. Substitution of the Tyr445 or Tyr463 residue of purified recombinant MICAL2-redox with phenylalanine (generating a non-phosphorylatable mutant) abolishes the enhanced MICAL2-mediated F-actin disassembly induced by ARG. Consistently, ectopic expression of non-phosphorylatable MICAL2 mutants (MICAL2^Y445F and MICAL2^Y463F, not MICAL2^Y488F) failed to ameliorate HNSCC cell growth, whereas expression of wild-type MICAL2 or MICAL2^Y488F rescued the impaired proliferation induced by MICAL2 knockdown. Moreover, CCG-1423, an inhibitor of MICAL2, was shown to inhibit HNSCC cell proliferation, invasion, and migration. Taken together, our findings indicate that phosphorylation of MICAL2 at Tyr445 and Tyr463 by ARG mediates F-actin disassembly and promotes HNSCC progression.

Breast cancer anti-estrogen resistance protein 3 (BCAR3) is involved in anti-estrogen resistance and other important aspects of breast cancer. However, the role of BCAR3 in other solid tumors remains unclear. The relationship between the clinicopathologic characteristics of head and neck squamous cell carcinoma (HNSCC) patients and BCAR3 was analyzed using the Wilcoxon’s signed-rank test and logistic regression. The association between BCAR3 expression and clinicopathologic features and survival was analyzed using Cox regression and the Kaplan–Meier method. In vivo and in vitro assays were performed to validate the effect of BCAR3 on HNSCC growth. BCAR3-related mRNAs were determined by calculating the Pearson’s correlation coefficient based on The Cancer Genome Atlas (TCGA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and gene set enrichment analysis (GSEA) were used to predict the potential functions of BCAR3. BCAR3 expression is overexpressed in HNSCC and was shown to be associated with perineural invasion (PNI) and poor survival. BCAR3 silencing significantly attenuated the proliferation of HNSCC cells, whereas BCAR3 depletion inhibited tumor growth in vitro. GO and KEGG functional enrichment analyses, and GSEA showed that BCAR3 expression in HNSCC was associated with biological processes, such as cell adhesion, actin binding, cadherin binding, and angiogenesis. BCAR3, which promotes HNSCC growth, is associated with perineural invasion and may be a potential molecular prognostic marker of poor survival in HNSCC.

Background: Glutamine is an abundant and versatile nutrient in cancer cells. Head and neck squamous cell carcinoma (HNSCC) was reported to be dependent on mainly glucose, not glutamine, for producing the energy required for survival and proliferation.Methods: The roles of ASCT2 (SLC1A5) and associated glutamine metabolism were determined by the MTT, colony formation, glutamine uptake, intracellular glutathione, ROS detection, immunofluorescence, immunohistochemistry, and apoptosis enzyme-linked immunosorbent assays as well as animal studies.Results: We found that glutamine is also critical for HNSCC. In this study, ASCT2, an amino acid transporter responsible for glutamine transport, in addition to LAT1 and GLS, is overexpressed in HNSCC and associated with poor survival. Using both in vivo and in vitro models, we found that knocking down ASCT2 by shRNAs or miR-137 or the combination of silencing ASCT2 and pharmacologically inhibiting SNAT2 via a small-molecule antagonist called V-9302 significantly suppressed intracellular glutamine levels and downstream glutamine metabolism, including glutathione production; these effects attenuated growth and proliferation, increased apoptosis and autophagy, and increased oxidative stress and mTORC1 pathway suppression in HNSCC. Additionally, silencing ASCT2 improved the response to cetuximab in HNSCC.Conclusions: In summary, ASCT2-dependent glutamine uptake and subsequent glutamine metabolism are essential for HNSCC tumorigenesis, and the combination of glutamine uptake inhibitors and cetuximab presents a promising strategy for improving the outcomes of HNSCC patients.

Introduction: Aberrant activation of Semaphorin3C(SEMA3C) is widespread in human cancers. We aimed to analyze SEMA3C expression in cervical cancer and investigate the role of SEMA3C in cervical cancer and its underlying mechanism, which is important for exploring new therapeutic targets and prognostic factors. Materials and Methods: The expression of SEMA3C was examined in paraffin-embedded cervical cancer specimens. In vivo and in vitro assays were performed to validate the effect of SEMA3C on cervical cancer cell proliferation and p-ERK pathway activation. Gene Set Enrichment Analysis (GSEA) was performed using The Cancer Genome Atlas (TCGA) data set. Results: SEMA3C expression was associated with poor survival in both the TCGA cohort and our cohort. Silencing of SEMA3C suppressed cervical cancer cell proliferation, colony formation ability, and the activation of the p-ERK signaling pathway in vitro. SEMA3C depletion inhibited tumor growth in vitro. GSEA also showed that the epithelial mesenchymal transition (EMT), TGFβ signaling pathway, angiogenesis, and extracellular matrix (ECM) receptor interactions are associated with a high SEMA3C expression phenotype. Conclusion: SEMA3C is correlated with poor prognosis of cervical cancer patients and promotes tumor growth via the activation of the p-ERK pathway.