The Hippo pathway has emerged as a fundamental regulator in tissue growth, organ size and stem cell functions, and tumorigenesis when deregulated. However, its roles and associated molecular mechanisms underlying oral squamous cell carcinoma (OSCC) initiation and progression remain largely unknown. Here, we identified TAZ, the downstream effector of Hippo signaling, as a novel bona fide oncogene by promoting cell proliferation, migration/invasion and chemoresistance in OSCC. TAZ promoted epithelial‐to‐mesenchymal transition (EMT) and also was involved in TGF‐β1‐induced EMT in oral cancer cells. Furthermore, enriched TAZ sustained self‐renewal, maintenance, tumor‐seeding potential of oral cancer stem cells (CSCs). Remarkably, enforced TAZ overexpression conferred CSCs‐like properties on differentiated non‐CSCs and fueled phenotypic transition from non‐CSCs to CSCs‐like cells. Mechanistically, TAZ‐TEADs binding and subsequent transcriptional activation of EMT mediators and pluripotency factors are presumably responsible for TAZ‐mediated EMT and non‐CSCs‐to‐CSCs conversion. Importantly, aberrant TAZ overexpression was found to be associated with tumor size, pathological grade and cervical lymph node metastasis, as well as unfavorable prognosis. Pharmacological repression of TAZ by simvastatin resulted in potent anti‐cancer effects against OSCC. Taken together, our findings have revealed critical links between TAZ, EMT and CSCs in OSCC initiation and progression, and also established TAZ as a novel cancer biomarker and viable druggable target for OSCC therapeutics.

Emerging evidence has demonstrated that circular RNAs (circRNA) are involved in cancer metastasis. Further elucidation of the role of circRNAs in oral squamous cell carcinoma (OSCC) could provide insights into mechanisms driving metastasis and potential therapeutic targets. Here, we identify a circRNA, circFNDC3B, that is significantly upregulated in OSCC and is positively associated with lymph node (LN) metastasis. In vitro and in vivo functional assays showed that circFNDC3B accelerated the migration and invasion of OSCC cells and the tube-forming capacity of human umbilical vein endothelial cells and human lymphatic endothelial cells. Mechanistically, circFNDC3B regulated ubiquitylation of the RNA-binding protein FUS and the deubiquitylation of HIF1A through the E3 ligase MDM2 to promote VEGFA transcription, thereby enhancing angiogenesis. Meanwhile, circFNDC3B sequestered miR-181c-5p to upregulate SERPINE1 and PROX1, which drove epithelial–mesenchymal transition (EMT) or partial-EMT (p-EMT) in OSCC cells and promoted lymphangiogenesis to accelerate LN metastasis. Overall, these findings uncovered the mechanistic role of circFNDC3B in orchestrating cancer cell metastatic properties and vasculature formation, suggesting circFNDC3B could be a potential target to reduce OSCC metastasis. Significance: Dual functions of circFNDC3B in enhancing the metastatic ability of cancer cells and promoting vasculature formation through regulation of multiple pro-oncogenic signaling pathways drive lymph node metastasis of OSCC.

EZH2, a core member of the Polycomb Repressor Complex 2 (PRC2), mediates transcriptional silencing by catalyzing the trimethylation of histone 3 lysine 27 (H3K27), which plays key roles in cancer initiation and progression. Here, we investigated the expression pattern and biological roles of EZH2 in tongue tumorigenesis by loss-of-function assays using small interference RNA and EZH2 inhibitor DZNep. Also we determined the therapeutic efficiency of DZNep against tongue cancer in vivo. We found that aberrantly overexpressed EZH2 was associated with pathological grade, cervical nodes metastasis and Ki-67 expression in tongue cancers. Elevated EZH2 correlated with shorter overall survival and showed significant and independent prognostic importance in patients with tongue cancer. Both genetic and pharmacological depletion of EZH2 inhibited cell proliferation, migration, invasion and colony formation and decreased CD44+ subpopulation probably in part through modulating p16, p21 and E-caherin. Moreover, DZNep enhanced the anticancer effects of 5-Fluorouracil. Furthermore, intratumoral EZH2 inhibition induced by DZNep intraperitoneal administration significantly attenuated tumor growth in a tongue cancer xenograft model. Taken together, our results indicate that EZH2 serves as a key driver with multiple oncogenic functions during tongue tumorigenesis and a new biomarker for tongue cancer diagnosis and prognostic prediction. These findings open up possibilities for therapeutic intervention against EZH2 in tongue cancer.

Deregulated inflammation and immune deficit both intricately associate with cancer initiation and progression, which have been increasingly exploited as prognostic biomarkers and therapeutic targets. Recently, systemic immune-inflammation index (SII) based on peripheral neutrophil, lymphocyte and platelet counts serves as a novel and powerful cancer biomarker with prognostic significance in multiple types of malignancies. Here, we sought to evaluate the prognostic value of preoperative SII in patients with primary oral squamous cell carcinoma (OSCC) after curative resection. Two independent cohorts with a total number of 309 patients with OSCC from two tertiary referral hospitals were included and defined as training (Nanjing, 138) and validation (Wuxi, 171) cohort, respectively. Preoperative SII in both cohorts was calculated and its optimal cutoff value was initially determined by X-tile software in the training cohort and then verified in the validation cohort. Our data indicated that high SII (≥ 484.5) was significantly associated with larger tumor size (P < 0.05, Chi square test), reduced overall and disease-free survival (Kaplan–Meir, P < 0.05, Log-rank test). Univariate and multivariate analyses further revealed that SII was an independent prognostic predictor for patient survival. Moreover, the area under receiver operating characteristic curve of SII for survival was significantly greater or comparable to other well-established prognostic parameters, indicative of its satisfactory prediction accuracy and specificity. Our findings reveal that high preoperative SII associates with poor outcome and serves as a non-invasive, low-cost and powerful prognostic predictor for patients with OSCC. This inflammation/immune-related biomarker holds translational potentials to supplement currently prognostic regime to better stratification of patients and treatment planning.

Cell-based drug delivery systems have shown tremendous advantages in cancer treatment due to their distinctive properties. For instance, delivery of therapeutics using tumor-tropic cells like neutrophils, lymphocytes and mesenchymal stem cells can achieve specific tumor targeting due to the “Trojan Horse” effect. Other circulatory cells like erythrocytes and platelets can greatly improve the circulation time of nanoparticles due to their innate long circulation property. Adipocytes, especially cancer-associated adipocytes, play key roles in tumor development and metabolism, therefore, adipocytes are regarded as promising bio-derived nanoplatforms for anticancer targeted drug delivery. Nanomaterials are important participants in cell-based drug delivery because of their unique physicochemical characteristics. Therefore, the integration of various nanomaterials with different cell types will endow the constructed delivery systems with many attractive properties due to the merits of both. In this review, a number of strategies based on nanomaterial-involved cell-mediated drug delivery systems for cancer treatment will be summarized. This review discusses how nanomaterials can be a benefit to cell-based therapies and how cell-derived carriers overcome the limitations of nanomaterials, which highlights recent advancements and specific biomedical applications based on nanomaterial-mediated, cell-based drug delivery systems.