Enhanced lipid biosynthesis in oral squamous cell carcinoma cancer-associated fibroblasts contributes to tumor progression: Role of IL8/AKT/p-ACLY axis.

Lipid metabolic reprogramming of tumor cells has been proven to play a critical role in tumor initiation and development. However, lipid metabolism in cancer-associated fibroblasts (CAFs) has rarely been studied, particularly in CAFs of oral squamous cell carcinoma (OSCC). Additionally, the molecular mechanism by which tumor cells regulate lipid metabolism in fibroblasts is unclear. In this study, we found that phosphorylated ATP citrate lyase (p-ACLY), a key lipid metabolic enzyme, was upregulated in OSCC CAFs. Compared to paracancerous normal fibroblasts, CAFs showed enhanced lipid synthesis, such as elevated cytosolic acetyl-CoA level and accumulation of lipid droplets. Conversely, reduction of p-ACLY level blocked this biological process. In addition, blocking lipid synthesis in CAFs or inhibiting fatty acid uptake by OSCC cells reduced the promotive effects of CAFs on OSCC cell proliferation, invasion, and migration. These findings suggested that CAFs are one of lipid sources required for OSCC progression. Mechanistically, AKT signaling activation was involved in the upregulation of p-ACLY level and lipid synthesis in CAFs. Interleukin-8 (IL8), an exocrine cytokine of OSCC cells, could activate AKT and then phosphorylate ACLY in fibroblasts. This study suggested that the IL8/AKT/p-ACLY axis could be considered as a potential target for OSCC treatment.

Prognostic value of tumor-stroma ratio in oral carcinoma: Role of cancer-associated fibroblasts.

OBJECTIVE: Tumor-stroma ratio (TSR) is a promising parameter representing the abundance of the stroma which has been validated in many solid tumors. However, it is still not clear which part of stroma mainly contribute to the prognostic value of TSR. The aim of this study is to confirm the prognostic value of TSR in a large cohort of oral squamous cell carcinoma (OSCC) and further demonstrated that cancer-associated fibroblasts (CAFs)-stroma ratio (CSR) contributed to the prognostic value of TSR. MATERIALS AND METHODS: TSR was evaluated on hematoxylin and eosin stained tissue samples from 581 patients with OSCC, which divides patients into high (>50%) and low (<50%) stroma. Then, CSR was estimated on immunohistochemical staining slides of 100 patients selected from 581 patients. RESULTS: In multivariate analysis, TSR was identified as an independent prognostic factor for disease-free survival (DFS) (p < 0.001) and oral cancer-specific survival (OCSS) (p < 0.001). The interaction term reached statistical significance for histological grade for DFS and OCSS separately. Furthermore, the high-stroma group had a higher CSR than the low-stroma group. CONCLUSION: The prognostic value of TSR is validated in OSCC particularly in moderate and high differentiation, and CSR plays its part in the prognosis of TSR.

Watching Food Videos Leads to Postparotidectomy Salivary Fistula.

Salivary fistula is a common postparotidectomy complication, and eating sour or spicy food ranks among the leading causes. Here we report a rare postparotidectomy salivary fistula case, a 31-year-old female patient who affirmed that she did not eat any irritating foods but admitted that she had been watching food videos for up to 4 hours every day since she left hospital. This case offers a cautionary tale about postparotidectomy precautions.

Melatonin inhibits EMT and PD-L1 expression through the ERK1/2/FOSL1 pathway and regulates anti-tumor immunity in HNSCC.

Melatonin is an endogenous hormone with various biological functions and possesses anti-tumor properties in multiple malignancies. Immune evasion is one of the most important hallmarks of head and neck squamous cell carcinoma (HNSCC) and is closely related to tumor progression. However, as an immune modulator under physiological conditions, the roles of melatonin in tumor immunity in HNSCC remains unclear. In this study, we found that the endogenous melatonin levels in patients with HNSCC were lower than those in patients with benign tumors in head and neck. Importantly, lower melatonin levels were related to lymph node metastasis among patients with HNSCC. Moreover, melatonin significantly suppressed programmed death-ligand 1 (PD-L1) expression and inhibited epithelial-mesenchymal transition (EMT) of HNSCC through the ERK1/2/FOSL1 pathway in vitro and in vivo. In SCC7/C3H syngeneic mouse models, anti-programmed death-1 (PD-1) antibody combined with melatonin significantly inhibited tumor growth and modulated anti-tumor immunity by increasing CD8+ T cell infiltration and decreasing the regulatory T cell (Treg) proportion in the tumor microenvironment. Taken together, melatonin inhibited EMT and downregulated PD-L1 expression in HNSCC through the ERK1/2/FOSL1 pathway and exerted synergistic effects with anti-PD-1 antibody in vivo, which could provide promising strategies for HNSCC treatment.

HSP90/IKK-rich small extracellular vesicles activate pro-angiogenic melanoma-associated fibroblasts via the NF-κB/CXCL1 axis.

Hypoxia is a main feature of most solid tumors, but how melanoma cells under hypoxic conditions exploit tumor microenvironment (TME) to facilitate tumor progression remains poorly understood. In this study, we found that hypoxic melanoma-derived small extracellular vesicles (sEVs) could improve the proangiogenic capability of cancer-associated fibroblasts (CAFs). This improvement was due to the activation of the IKK/IκB/NF-κB signaling pathway and upregulation of CXCL1 expression and secretion in CAFs. By proteomic analysis, we verified that hypoxia could promote enrichment of chaperone HSP90 and client protein phosphorylated IKKα/ß (p-IKKα/ß) in melanoma-derived sEVs. Delivery of the HSP90/p-IKKα/ß complex by sEVs could activate the IKK/IκB/NF-κB/CXCL1 axis in CAFs and promote angiogenesis in vitro and in vivo. Taken together, these findings deepen the understanding of hypoxic response in melanoma progression and provide potential targets for melanoma treatment.

Glycometabolic reprogramming-mediated proangiogenic phenotype enhancement of cancer-associated fibroblasts in oral squamous cell carcinoma: role of PGC-1α/PFKFB3 axis.

BACKGROUND: Angiogenesis is a key rate-limiting step in the process of tumour progression. Cancer-associated fibroblasts (CAFs), the most abundant component OSCC stroma, play important roles in pro-angiogenesis. Recently, the stroma "reverse Warburg effect" was proposed, and PFKFB3 has been brought to the forefront as a metabolic enzyme regulating glycometabolism. However, it remains unclear whether glycometabolism reprogramming is involved in promoting the angiogenesis of CAFs. METHODS: CAFs and paracancerous fibroblasts (PFs) were isolated from OSCC and adjacent tissues. We detected the pro-angiogenesis and glycometabolism phenotype of three pairs of fibroblasts. Targeted blockage of PFKFB3 or activation of PGC-1α signal was used to investigate the effect of glycolysis on regulating angiogenesis of CAFs in vitro and vivo. RESULTS: CAFs exhibited metabolic reprogramming and enhanced proangiogenic phenotype compared with PFs. Inhibition of PFKFB3-dependent glycolysis impaired proangiogenic factors (VEGF-A, PDGF-C and MMP9) expression in CAFs. Furthermore, CAFs proangiogenic phenotype was regulated by glycometabolism through the PGC-1α/PFKFB3 axis. Consistently, PGC-1α overexpression or PFKFB3 knockdown in CAFs slowed down tumour development by reducing tumour angiogenesis in the xenograft model. CONCLUSION: CAFs of OSCC are characterised with glycometabolic reprogramming and enhanced proangiogenic phenotypes. Our findings suggest that activating PGC-1α signalling impairs proangiogenic phenotype of CAFs by blocking PFKFB3-driven glycolysis.

Salivary Porphyromonas gingivalis predicts outcome in oral squamous cell carcinomas: a cohort study.

BACKGROUND: Studies suggest Porphyromonas gingivalis (Pg) increased the incidence of oral squamous cell carcinoma (OSCC). However, fimA genotypes distribution of Pg, the origination of Pg in tissue, and its prognostic value are inconclusive. We aimed to investigate the frequency of fimA genotypes in OSCC patients, study the association between Pg and OSCC, and explore the prognostic value of Pg. METHODS: The abundance of Pg in saliva from the OSCC group and the OSCC-free group was analysed by qPCR. The presence of Pg was explored in OSCC tissue and para-cancerous tissue by in situ hybridization. The frequency of fimA genotypes in saliva and OSCC tissue was determined by PCR, then PCR products were sequenced and compared. Clinical data were extracted, and patients followed up for a median period of 23 months. Clinicopathological variables were compared with the abundance of Pg using Pearson Chi-square test or Fisher's exact test. The disease-free survival (DFS) rate was calculated by Kaplan-Meier method with log-rank tests. RESULTS: Comparing the OSCC-free group, 95 patients with OSCC showed a high abundance of Pg in saliva (P = 0.033), and OSCC tissue showed strong in situ expression of Pg compared with paired normal tissue. Patients with OSCC showed a dominant distribution of Pg with genotype I + Ib (21.1%), II (31.6%), and IV (21.1%). FimA genotypes detected in saliva were in accordance with those in OSCC tissue, there was, moreover, a significant similarity in amplified Pg fragments. Of the 94 responsive OSCC patients, the recurrence rate was 26.6% (25/94). Overabundance of Pg in saliva showed advanced pathologic staging (P = 0.008), longer disease-free time (P = 0.029) and lower recurrence rate (P = 0.033). The overabundance of Pg in saliva was associated with improved disease-free survival (P = 0.049). CONCLUSIONS: This study indicated that Pg might involve in the pathogenesis of OSCC, Pg carrying fimA I, Ib, II, and IV were prevalent genotypes in patients with OSCC, the provenance of Pg in OSCC tissue might be from the salivary microbial reservoir, and the abundance of Pg in saliva might consider as a favorable potential prognostic indicator in OSCC.

CCL21/CCR7 interaction promotes EMT and enhances the stemness of OSCC via a JAK2/STAT3 signaling pathway.

Chemokines and their receptors show a strong relationship with poor clinical outcomes in various cancers. However, their underlying mechanisms remain to be fully elucidated. In our research, we found C-C chemokine receptor 7 (CCR7) and its ligand chemokine ligand 21 (CCL21) were abnormally abundant in oral squamous cell carcinoma (OSCC) tissues, and CCR7 expression was correlated with poor prognosis of OSCC. After exogenous CCL21 stimulation, epithelial-mesenchymal transition (EMT) was promoted in OSCC cells, and cancer stem cell-related markers CD133, CD44, BMI1, ALDH1A1, and OCT4 increased. The migration, invasion, tumorsphere formation, and colony formation abilities of OSCC cells were enhanced, indicating that the stemness of OSCC cells was also improved. The knockdown and overexpression of CCR7 efficiently affected the CCL21-induced EMT and stemness of OSCC cells. When treated with CCL21, the phospho-JAK2 and phospho-STAT3 markedly increased. The inhibitor of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) significantly suppressed CCL21-induced EMT and stemness of OSCC cells. In conclusion, CCL21/CCR7 axis regulated EMT progress and promoted the stemness of OSCC by activating the JAK2/STAT3 signaling pathway. CCL21/CCR7 might be an effective target for OSCC prevention and treatment.

Tumoral microvesicle-activated glycometabolic reprogramming in fibroblasts promotes the progression of oral squamous cell carcinoma.

Metabolic reprogramming is a hallmark of cancer. Stromal cells could function as providers of energy metabolites for tumor cells by undergoing the "reverse Warburg effect," but the mechanism has not been fully elucidated. The interaction between the tumoral microvesicles (TMVs) and stroma in the tumor microenvironment plays a critical role in facilitating cancer progression. In this study, we demonstrated a novel mechanism for the TMV-mediated glycometabolic reprogramming of stromal cells. After being incubated with TMVs, normal human gingival fibroblasts exhibited a phenotype switch to cancer-associated fibroblasts and underwent a degradation of caveolin 1 (CAV1) through the ERK1/2-activation pathway. CAV1 degradation further induced the metabolic switch to aerobic glycolysis in the fibroblasts. The microvesicle-activated fibroblasts absorbed more glucose and produced more lactate. The migration and invasion of oral squamous cell carcinoma (OSCC) were promoted after being cocultured with the activated fibroblasts. Fibroblast-cancer cell glycometabolic coupling ring mediated by monocarboxylate transporter (MCT) 4 and MCT1 was then proved in the tumor microenvironment. Results indicated a mechanism for tumor progression by the crosstalk between tumor cells and stromal cells through the reverse Warburg effect via TMVs, thereby identifying potential targets for OSCC prevention and treatment.-Jiang, E., Xu, Z., Wang, M., Yan, T., Huang, C., Zhou, X., Liu, Q., Wang, L., Chen, Y., Wang, H., Liu, K., Shao, Z., Shang, Z. Tumoral microvesicle-activated glycometabolic reprogramming in fibroblasts promotes the progression of oral squamous cell carcinoma.

Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling.

Chewing areca nut is closely associated with oral squamous cell carcinoma (OSCC). The current study aimed to investigate potential associations between areca nut extract (ANE) and cisplatin toxicity in OSCC cells. OSCC cells (Cal-27 and Scc-9) viability and apoptosis were analyzed after treatment with ANE and/or cisplatin. The expressions of proteins associated with autophagy and the AMP-activated protein kinase (AMPK) signaling network were evaluated. We revealed that advanced OSCC patients with areca nut chewing habits presented higher LC3 expression and poorer prognosis. Reactive oxygen species (ROS)-mediated autophagy was induced after pro-longed treatment of ANE (six days, 3 µg). Cisplatin toxicity (IC50, 48 h) was decreased in OSCC cells after ANE treatment (six days, 3 µg). Cisplatin toxicity could be enhanced by reversed autophagy by pretreatment of 3-methyladenine (3-MA), N-acetyl-l-cysteine (NAC), or Compound C. Cleaved-Poly-(ADP-ribose) polymerase (cl-PARP) and cleaved-caspase 3 (cl-caspase 3) were downregulated in ANE-treated OSCC cells in the presence of cisplatin, which was also reversed by NAC and Compound C. Collectively, ANE could decrease cisplatin toxicity of OSCC by inducing autophagy, which involves the ROS and AMPK/mTOR signaling pathway.

L-cysteine contributes to destructive activities of odontogenic cysts/tumor.

BACKGROUND: Odontogenic cysts/tumor can cause severe bone destruction, which affects maxillofacial function and aesthetics. Meanwhile, metabolic reprogramming is an important hallmark of diseases. Changes in metabolic flow affect all aspects of disease, especially bone-related diseases. At present, the researches on pathogenesis of odontogenic cysts/tumor are mainly focused on the level of gene regulation, but the effects of metabolic alterations on odontogenic cysts/tumor have still underexplored. MATERIALS AND METHODS: Imaging analysis was used to evaluate the lesion size of different odontogenic lesions. Tartrate resistant acid phosphatase (TRAP) and immunohistochemistry (IHC) assays were utilized to detect the differences in bone destruction activity in odontogenic cysts and tumors. Furthermore, metabolomics and weighted gene co-expression network analysis (WGCNA) were conducted for the metabolomic features and key metabolite screening, respectively. The effect of ferroptosis inhibition on bone destruction was confirmed by IHC, immunofluorescence, and malondialdehyde colorimetric assay. RESULTS: The bone destruction activity of ameloblastoma (AM) was the strongest and the weakest in odontogenic cysts (OC). High-throughput targeted metabolomics was used to map the metabolomic profiles of OC, odontogenic keratocyst (OKC) and AM. WGCNA and differential analysis identified L-cysteine in OKC and AM. Cystathionine γ-lyase (CTH) was further screened by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The functions of L-cysteine were further validated. Finally, we confirmed that CTH affected destructive activities by regulating the sensitivity of epithelial cells to ferroptosis. CONCLUSION: High-throughput targeted metabolomics performed on diseased tissue confirmed the unique alteration of metabolic profiles in OKC and AM. CTH and its metabolite L-cysteine are the key factors regulating destructive activities.

A retrospective study of the malignant change of odontogenic keratocyst.

The odontogenic keratocyst (OKC) is a common cystic lesion of the maxilla and mandible. Squamous cell carcinoma (SCC) arising from OKC or dysplasia occurring in OKC is rare. This study aimed to explore the incidence and clinical features of the dysplasia and malignant transformation of OKC. In this study, 544 patients diagnosed with OKC were collected. Among them, 3 patients were diagnosed as SCC arising from OKC, and 12 patients were diagnosed as OKC with dysplasia. The incidence was calculated. Clinical features were analyzed by chi-square test. In addition, a representative case reconstructing mandible with vascularized fibula flap under general anesthesia was reported. And cases reported before were reviewed. The incidence of the dysplasia and malignant transformation of OKC, which are highly associated with the clinical features of swelling and chronic inflammation, is about 2.76%. But the relevance between the dysplasia and malignant transformation and age, gender together with pain is not statistically high. All in all, the clinical features of swelling and chronic inflammation can be considered as characteristics of the dysplasia and malignant transformation of OKC. Although the pain isn't statistically relevant, it may be a dangerous clew. Also, combined with earlier literatures, the dysplasia and malignant transformation of OKC shows unique features of radiographs and histopathology.

Roles of Mitochondria in Oral Squamous Cell Carcinoma Therapy: Friend or Foe?

Oral squamous cell carcinoma (OSCC) therapy is unsatisfactory, and the prevalence of the disease is increasing. The role of mitochondria in OSCC therapy has recently attracted increasing attention, however, many mechanisms remain unclear. Therefore, we elaborate upon relative studies in this review to achieve a better therapeutic effect of OSCC treatment in the future. Interestingly, we found that mitochondria not only contribute to OSCC therapy but also promote resistance, and targeting the mitochondria of OSCC via nanoparticles is a promising way to treat OSCC.

Autophagy regulates the cancer stem cell phenotype of head and neck squamous cell carcinoma through the noncanonical FOXO3/SOX2 axis.

Autophagy is an essential catabolic process that orchestrates cellular homeostasis and plays dual roles in tumor promotion and suppression. However, the mechanism by which autophagy affects the self-renewal of cancer stem cells (CSCs) remains unclear. In this study, we investigated whether autophagy activation contributes to CSC properties of head and neck squamous cell carcinoma (HNSCC). The results showed that the autophagy level and CSC properties of HNSCC cells were elevated in response to several adverse conditions, including treatment with cisplatin, starvation, and hypoxia. Pretreatment with autophagy inhibitors, such as 3-MA and chloroquine, diminished the CSC properties acquired under adverse conditions. In addition, the isolated CSCs were endowed with stronger autophagic activity than non-CSCs, and the CSC properties were dampened when autophagy was inhibited either by 3-MA, chloroquine, or Beclin1 knockdown. Notably, the tumor-initiating activity of CSCs was decreased upon knocking down Beclin1. Further study revealed that FOXO3, a substrate for autophagy, was enriched in the nucleus of cells with lower autophagy levels. Nuclear FOXO3 directly bound to the promoter region of SOX2 and negatively regulated its transcriptional activity. Overexpression of FOXO3 decreased the expression of SOX2 and thereby impaired the CSC phenotype both in vitro and in vivo. Taken together, our findings suggest that the activation of autophagy is essential for the acquisition of CSC properties in adverse conditions and the self-renewal of CSCs. We clarify the role of autophagy in regulating the CSC phenotype and demonstrate that the noncanonical FOXO3/SOX2 axis is the intrinsic regulatory mechanism.

Cancer cells corrupt normal epithelial cells through miR-let-7c-rich small extracellular vesicle-mediated downregulation of p53/PTEN.

Tumor volume increases continuously in the advanced stage, and aside from the self-renewal of tumor cells, whether the oncogenic transformation of surrounding normal cells is involved in this process is currently unclear. Here, we show that oral squamous cell carcinoma (OSCC)-derived small extracellular vesicles (sEVs) promote the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of normal epithelial cells but delay their apoptosis. In addition, nuclear-cytoplasmic invaginations and multiple nucleoli are observed in sEV-treated normal cells, both of which are typical characteristics of premalignant lesions of OSCC. Mechanistically, miR-let-7c in OSCC-derived sEVs is transferred to normal epithelial cells, leading to the transcriptional inhibition of p53 and inactivation of the p53/PTEN pathway. In summary, we demonstrate that OSCC-derived sEVs promote the precancerous transformation of normal epithelial cells, in which the miR-let-7c/p53/PTEN pathway plays an important role. Our findings reveal that cancer cells can corrupt normal epithelial cells through sEVs, which provides new insight into the progression of OSCC.

LncRNA FENDRR in Carcinoma-Associated Fibroblasts Regulates the Angiogenesis of Oral Squamous Cell Carcinoma Through the PI3K/AKT Pathway.

Angiogenesis is essential for the development of tumors. Studies have shown that carcinoma-associated fibroblasts (CAFs) are involved in regulating tumor angiogenesis, but the mechanism remains unclear. Recently, long noncoding RNAs (lncRNAs) have been proved to play an important role in the angiogenesis of various tumors. However, there is currently no research involving the regulation of CAFs on the angiogenesis of oral squamous cell carcinoma (OSCC) mediated by lncRNAs. By analyzing microarray data, we identified that the expression of lncRNA FOXF1 adjacent noncoding developmental regulatory RNA (FENDRR) in OSCC patients is downregulated, compared to that in normal tissues. Quantitative polymerase chain reaction (qPCR) results demonstrated that FENDRR expression is lower in CAFs compared to normal fibroblasts (NFs) of OSCC patients. KEGG pathway analysis revealed that some genes differentially expressed between CAFs and NFs of HNSCC patients are enriched to the PI3K/AKT pathway. Further experiments confirmed that the downregulation of FENDRR can activate the PI3K/AKT pathway in NFs and enhances the expression of matrix metalloproteinase 9 (MMP9). The overexpression of FENDRR had the opposite effect. Besides, we co-cultured human umbilical vein endothelial cells (HUVECs) with CAFs, and the tube-forming ability of HUVECs co-cultured with CAFs overexpressing FENDRR decreased significantly. However, activation of the AKT pathway of CAFs overexpressing FENDRR can weaken the inhibitory effect of FENDRR on angiogenesis. In summary, our experiments are focused on the influence of lncRNAs in CAFs on OSCC angiogenesis for the first time and prove that FENDRR mediates CAFs' regulation of OSCC angiogenesis through the PI3K/AKT pathway.

Osteosarcoma Cell-Derived Small Extracellular Vesicles Enhance Osteoclastogenesis and Bone Resorption Through Transferring MicroRNA-19a-3p.

Osteosarcoma (OS) is the most common primary bone cancer characterized by an aggressive phenotype with bone destruction. The prognosis of OS patients remains unoptimistic with the current treatment strategy. Recently, osteoclasts are believed to play a crucial role in cancer bone metastasis. Thus, osteoclast could be a target both in bone destruction and cancer progression in OS. However, mechanisms governing osteoclastogenesis in OS remain poorly understood. miRNA delivered by small extracellular vesicles (sEVs) could mediate cellular communications. In this study, we investigated the effects of sEVs on osteoclastogenesis and osteoclast function, also clarified the underlying mechanism. We herein found that sEVs promoted pre-osteoclast migration, osteoclastogenesis and resorption by exposing RAW264.7 cells to sEVs derived from OS cells. Bioinformatics analysis showed that phosphatase tension homologue (PTEN), and miR-19a-3p were involved in OS progression. Overexpression of miR-19a-3p or sEVs' miR-19a-3p promoted osteoclast formation and function through PTEN/PI3K/AKT signaling pathway, while inhibition of miR-19a-3p showed the contrary results. The bone marrow macrophages (BMMs) were used to verify the results. OS mice, which were established by subcutaneous injection of OS cells, exhibited increased levels of sEVs' miR-19a-3p in blood. Moreover, micro-computed tomography (CT) and histomorphometry analysis demonstrated that OS mice exhibited osteopenia with increased number of osteoclasts. In conclusion, miR-19a-3p delivery via OS cell-derived sEVs promotes osteoclast differentiation and bone destruction through PTEN/phosphatidylinositol 3 -kinase (PI3K)/protein kinase B (AKT) signaling pathway. These findings highlight sEVs packaging of miR-19a-3p as a potential target for prevention and treatment of bone destruction and cancer progression in OS patients. And this finding provides a novel potentially therapeutic target for the bone metastasis.

Research Achievements of Oral Submucous Fibrosis: Progress and Prospect.

Oral submucous fibrosis (OSMF) is a kind of chronic, insidious disease, and it is categorized into potentially malignant disorders (PMD), which poses a global and regional problem to public health. It is considered to be a multifactorial disease, such as due to areca nut chewing, trace element disorders, and genetic susceptibility. However, there is still no unanimous conclusion on its pathogenesis, diagnosis, and treatment strategies. Hence, this article provides a comprehensive review and prospect of OSMF research, providing scholars and clinicians with a better perspective and new ideas for the research and treatment of OSMF.

The acoustic droplet printing of functional tumor microenvironments.

The fabrication of functional tissue is important for tissue engineering, regenerative medicine, and biological research. However, current 3D bioprinting technologies mean it is hard to precisely arrange bioinks (composed of cells and materials) in a high-fidelity 3D structure and print cells of multiple types with sufficient concentrations and superior viabilities; this can severely constrain cell growth, interactions, and functions. Here, an acoustic droplet printing method is introduced to solve these problems in 3D bioprinting. Being nozzle-free, the acoustic printer stably enables high-concentration cells, or even cell spheroids, to be printed without clogging. Cell viability (>94%) using post acoustic printing is higher than those obtained with currently used inkjet-based (>85%) and extrusion-based (40-80%) bioprinting methods. Also, this method involves a small printer that can be flexibly integrated, allowing different kinds of bioinks to be printed. Moreover, the limited printability of low-concentration gelatin methacryloyl (5% (w/v) GelMA) materials is overcome by determining the positioning, fluidity (e.g., spreading), and 3D morphology of the GelMA droplets; therefore, high-fidelity 3D constructs can be fabricated. As a proof of concept, a tumor microenvironment consisting of one tumor spheroid surrounded by a high concentration of cancer-associated fibroblasts (CAFs) was constructed; this was able to establish a dynamic tumor invasion function modulated by reciprocal tumor cell-CAF interactions. The nozzle-free, contact-free, and low cell-damage merits of this method will advance bioprinting, allowing the creation of more functional native tissues, organoids, or disease models.

Long Noncoding RNAs in the Metastasis of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a common malignant tumor worldwide. Metastasis is the main cause of the death of OSCC patients. Long noncoding RNAs (lncRNAs), one of the key factors affecting OSCC metastasis, are a subtype of RNA with a length of more than 200 nucleotides that has little or no coding potential. In recent years, the important role played by lncRNAs in biological processes, such as chromatin modification, transcription regulation, RNA stability regulation, and mRNA translation, has been gradually revealed. More and more studies have shown that lncRNAs can regulate the metastasis of various tumors including OSCC at epigenetic, transcriptional, and post-transcriptional levels. In this review, we mainly discussed the role and possible mechanisms of lncRNAs in OSCC metastasis. Most lncRNAs act as oncogenes and only a few lncRNAs have been shown to inhibit OSCC metastasis. Besides, we briefly introduced the research status of cancer-associated fibroblasts-related lncRNAs in OSCC metastasis. Finally, we discussed the research prospects of lncRNAs-mediated crosstalk between OSCC cells and the tumor microenvironment in OSCC metastasis, especially the potential research value of exosomes and lymphangiogenesis. In general, lncRNAs are expected to be used for screening, treatment, and prognosis monitoring of OSCC metastasis, but more work is still required to better understand the biological function of lncRNAs.