Proliferation Of Squamous Cell Carcinoma Research Articles

Aberrant methylation-mediated downregulation of the LINC01554 gene accelerates the malignant progression and regulates the chemosensitivity of laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC) is diagnosed as a malignant tumor with a poor prognosis, the associated mechanisms still need to be further investigated. The LINC01554 gene is confirmed to participate in the tumorigenesis of hepatocellular carcinoma, but its role in LSCC has not been investigated. The aim of this study was to investigate the function and the potential mechanism of LINC01554 in LSCC, LINC01554 further was used as a molecular target for the diagnosis and molecular targeted therapy of LSCC. The microarray-based gene expression profiling of LSCC and its adjacent non-tumor tissue were used to identify the differentially expressed long non-coding RNAs (lncRNAs). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied to verify the expression levels of LINC01554 in tissue and LSCC cell lines. The DNA methylation level of the LINC01554 promoter was detected by the application of bisulfite genomic sequencing (BGS), and the bisulfite conversion-specific/methylation-specific polymerase chain reaction (BS-MSP) method. The effect of LINC01554 on the proliferation, migration, and invasion of squamous cell carcinoma was assessed by MTS, wound healing, transwell, RT-qPCR, Western blot in vitro-cultured TU177 cells, and AMC-HN-8 cells. The microarray-based gene expression profiling identified the differentially expressed lncRNAs, including LINC01554, with downregulation in the LSCC tissue vs. normal tissue. The RT-qPCR verified the downregulation of LINC01554 in the LSCC tissue (P=0.0049) and LSCC cell (P=0.0020). The BGS and BS-MSP exhibited the hypermethylation level of the LINC01554 promoter, which mediated the downregulation of LINC01554. A gain-of-function experiment showed that LINC01554 inhibited the proliferation, migration, and invasion of TU177 and AMC-HN-8. Subsequently, LINC01554 overexpression was shown to decrease cell viability in TU177 and AMC-HN-8 cells treated with cisplatin. Our findings indicated that the aberrant methylation-mediated downregulation of LINC01554 promoted malignant progression and cisplatin resistance in LSCC, and LINC01554 may serve as a potential diagnostic biomarker and a novel therapeutic target for LSCC.

Long non-coding RNA human leucocyte antigen complex group-18 HCG18 (HCG18) promoted cell proliferation and migration in head and neck squamous cell carcinoma through cyclin D1-WNT pathway

ABSTRACT Emerging evidence has demonstrated that long noncoding RNA (lncRNAs) play a vital role in the development of head and neck squamous cell carcinoma (HNSCC); however, the biological effects and underlying mechanisms of human leukocyte antigen complex group-18 HCG18 (HCG18) have not yet been reported in HNSCC. In this study, we detected the expression of the HCG18 in HNSCC cell lines and patient tissues. We observed that HCG18 was upregulated in HNSCC patient tissues and cell lines. Furthermore, silencing of HCG18 significantly inhibited proliferation, migration, and invasion of HNSCC cells, whereas the opposite effects were detected in the HCG18-overexpressed group. We also found that HCG18 directly binds to the functional protein cyclin D1. Upregulated cyclin D1 reversed the inhibitory effects of HCG18 in HNSCC cell lines and activated the WNT pathway-related proteins (AXIN2, survivin, c-Myc, and β-catenin) simultaneously. Knockdown of cyclin D1 could accelerate the inhibitory effects of HCG18 and decrease the expression of AXIN2, survivin, c-Myc, and β-catenin. This indicated that lncRNA HCG18 might be involved in the tumorigenesis of HNSCC via the cyclin D1-WNT pathway. These results suggest that lncRNA HCG18 could act as a promising prognostic biomarker and potential therapeutic target in HNSCC patients.

Biomimetic Nanosystems for the Synergistic Delivery of miR-144/451a for Oral Squamous Cell Carcinoma

Background:The miR-144/451a cluster acts as a tumor suppressor in various tumors by synergistically inhibiting the proliferation, migration, and invasion of oral squamous cell carcinoma (OSCC).Aims:To achieve the synergistic delivery of the miR-144/451a cluster for OSCC treatment by constructing chitosan nanoparticles (CAs) camouflaged with macrophage membranes.Study Design:A cell-culture study.Methods:CAs were prepared using the ionic cross-linking method, and biomimetic nanoparticles coloaded with the miR-144/451a cluster (miR-144-source of macrophage-derived exosomes [MEXO]/CA-miR-451a) were prepared using the uptake–efflux method. The MEXO was detected by a bicinchoninic acid assay. The as-prepared biomimetic nanoparticles were then characterized to determine their protective effects on microRNAs (miRNAs). Moreover, the influence of the miR-144-MEXO/CA-miR-451a nanoparticles on the proliferation, migration, and invasion of OSCCs was evaluated. Finally, the effects of the biomimetic system on the expression of calcium-binding protein 39 (CAB39) and migration inhibitory factor (MIF) were detected using the real-time polymerase chain reaction and Western blot.Results:After coating the CAs with MEXO, their particle size increased from 113.1 ± 3.4 nm to 143.2 ± 14 nm, and their surface potential decreased from 26.34 ± 0.4 mV to −10.3 ± 1.6 mV. The expression of the MEXO marker protein was also observed on the biomimetic nanoparticles’ surface. The system can protect miRNAs from RNase A degradation. Compared with the CAs cotransfected with free miR-144/451a cluster, CAs that are coloaded with miR-144-MEXO/CA-miR-451a nanoparticles substantially reduced the viability (p < 0.001), migration (p = 0.023), and invasion (p = 0.004) of OSCC. These findings revealed the successful construction of biomimetic nanoparticles coloaded with the miR-144/451a cluster. CAB39 and MIF expression in OSCC treated with miR-144-MEXO/CA-miR-451a nanoparticles have significantly decreased compared with the miR-144/451a group (p < 0.05). Thus, the nanoparticles can effectively improve the inhibitory effects of the miR-144/451a cluster on OSCC.Conclusion:This study provided a new idea for the application of gene cotransfection to tumor treatment.

NEDD4L inhibits glycolysis and proliferation of cancer cells in oral squamous cell carcinoma by inducing ENO1 ubiquitination and degradation

ABSTRACT Glycolysis contributes to cell metabolism and facilitates cell proliferation of oral squamous cell carcinoma (OSCC), the most common type of oral cancer. Understanding the regulatory mechanisms involved in the glycolysis of OSCC cells may provide important therapeutic inspirations. Immunohistochemistry was used to examine protein localization patterns in human OSCC tissues and Western blot was conducted to gauge protein level. Lentivirus transduction was used to overexpress or silence genes of interest. Cell proliferation was assessed by Cell Counting Kit (CCK)-8 assay while glycolysis was examined via measurement of extracellular acidification rate, oxygen consumption rate, and lactate and ATP production. In vivo cancer development was evaluated with a mouse tumor growth model. OSCC tissues displayed reduced expression of NEDD4L compared with normal tissues. NEDD4L expression positively correlated with 5-year patient survival rate, indicating that NEDD4L may be a prognosis marker for OSCC. NEDD4L overexpression suppressed proliferation, cell cycle transition, and glycolysis in OSCC cells, and inhibited in vivo tumor growth. UbiBrowser identified ENO1, an enzyme that catalyzes glycolysis, as a substrate of NEDD4L. Overexpression of NEDD4L resulted in the ubiquitination and subsequent degradation of ENO1 whereas overexpression of ENO1 reversed the functional effects of NEDD4L overexpression, restoring proliferation, cell cycle transition, and glycolysis in OSCC cells. NEDD4L elicits tumor-suppressive functions via inhibition of OSCC cell proliferation, cell cycle transition, and glycolysis by stimulating ENO1 ubiquitination and degradation. Our results unraveled a signaling axis important for OSCC cell survival and metabolism, which can serve as a potential therapeutic target.

Hsa_circ_0072008 regulates cell proliferation, migration, and invasion in cervical squamous cell carcinoma via miR-1305/helicase, lymphoid specific (HELLS) axis

ABSTRACT Cervical squamous cell carcinoma (CESC) is one of the most common cancers in women. Recent studies have proved that circular RNAs (circRNAs) could regulate the progress of CESC, but the mechanism is still indistinct. In this work, we explored the roles of circ_0072008 in CESC. The expression levels of circ_0072008, microRNA-1305 (miR-1305) and mRNA of HELLS (helicase, lymphoid specific) were detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) in CESC tissues. Meanwhile, the level of HELLS was quantified by western blot analysis. Besides, the cell functions were examined by colony formation assay, 5-Ethynyl-2’-deoxyuridine (EdU) assay, wound healing assay, flow cytometry assay and western blot. Furthermore, the interaction between miR-1305 and circ_0072008 or HELLS was detected by dual-luciferase reporter assay. The function of circ_0072008 in CESC has also been further verified in vivo by xenograft model experiments. The levels of circ_0072008 and HELLS were upregulated, and the miR-1305 level was decreased in CESC tissues in contrast to that in normal tissues. For functional analysis, silencing circ_0072008 inhibited cell proliferation and cell migration, whereas enhanced cell apoptosis in CESC cells. In mechanism, circ_0072008 acted as a miR-1305 sponge to regulate the level of HELLS. Moreover, miR-1305 was confirmed to repress the progression of CESC cells by suppressing HELLS. Meanwhile, knockdown of circ_0072008 inhibited CESC cells growth in vivo. In conclusion, circ_0072008 facilitated CESC cell proliferation, migration, and invasion through increasing HELLS expression by regulating miR-1305, which also offered an underlying targeted therapy for CESC treatment.

MiR-23a-3p Regulates Runx2 to Inhibit the Proliferation and Metastasis of Oral Squamous Cell Carcinoma.

Objective To investigate the effects of microRNA-23a (miR-23a-3p) and Runx2 on malignant progression of oral cancer cells and their possible molecular mechanisms. Methods Fluorescence quantitative PCR (qPCR) was used to detect the expression of miR-23a-3p and Runx2 in human oral squamous cell carcinoma tissues and paracancerous tissues. The dual luciferase reporter assay was used to evaluate the targeted regulation of miR-23a-3p on Runx2. A subcutaneous xenograft model was established to investigate the tumor-suppressive effect of miR-23a-3p. Cells were transfected with miR-23a-3p mimics and negative control NC. CCK-8 assay, EDU assay, Transwell assay, and clone formation assay were used to detect malignant evolution of cells. Western blotting was used to detect the expression of Runx2, PTEN, and PI3K/Akt. The cells were simultaneously transfected with miR-23a-3p mimics and Runx2 to detect the malignant evolution of cells. Results The expression of miR-23a-3p was downregulated in oral squamous cell carcinoma tissues, while the expression of Runx2 was upregulated. Overexpression of miR-23a-3p or inhibition of Runx2 inhibited the malignant progression of oral squamous cell carcinoma CAL-27 and TSCCA. Overexpression of miR-23a-3p inhibits the growth of oral cancer tumors. miR-23a-3p inhibits the PTEN/PI3K/Akt signaling pathway through Runx2. Overexpression of Runx2 reverses the tumor-suppressive effect of miR-23a-3p. Conclusion miR-23a-3p can inhibit the PI3K/Akt signaling pathway by targeting Runx2 and inhibit the malignant evolution of oral cancer.

MiR-186-5p inhibits the progression of oral squamous cell carcinoma by targeting ITGA6 to impair the activity of the PI3K/AKT pathway.

microRNAs (miRNAs) are pivotal regulators of multiple biological processes. miR-186-5p functions as a tumor suppressor in a variety of cancers and promotes the malignant proliferation of oral squamous cell carcinoma (OSCC). This study aimed to clarify the role and regulatory mechanism of miR-186-5p in OSCC. The levels of miR-186-5p and integrin subunit alpha 6 (ITGA6) were investigated in clinical specimens and OSCC cell lines by reverse transcription-quantitative polymerase chain reaction. The effects of miR-186-5p and ITGA6 on the cell migration, proliferation, and phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (AKT) pathway activity were evaluated by transwell assay, cell counting kit 8 assay, and western blotting, respectively. A xenograft model was used to analyze the effect of miR-186-5p on tumor growth. Bioinformatic analyses were conducted to identify the putative targets of miR-186-5p in OSCC. Decreased miR-186-5p expression levels were observed in OSCC tumor tissues and cell lines. The overexpression of miR-186-5p suppressed the proliferation and migration of OSCC cells, and weakened the phosphorylation of PI3K and AKT. Moreover, the overexpression of miR-186-5p in xenograft tumor models impedes tumor growth. miR-186-5p is bound to ITGA6 and negatively related to ITGA6 expression in tumor tissues. The forced expression of ITGA6 promoted OSCC cell proliferation and migration and enhanced the phosphorylation levels of PI3K and AKT, while additional miR-186-5p enrichment partly abolished these effects. miR-186-5p binds to ITGA6 to impair the activity of the PI3K/AKT signaling pathway, thereby blocking the development of OSCC. This study provides insight to understand the pathogenesis of OSCC.

MiR-195 Inhibits Proliferation and Enhances Apoptosis of OSCC Cells via Targeting TLR4.

The aim of this research was to assess the function of microribonucleic acid (miR)-195 in the apoptosis and proliferation of oral squamous cell carcinoma (OSCC) cells as well as its action mechanism. The downstream target protein of miR-195 was predicted using the biological software. A quantitative polymerase chain reaction (qPCR) was implemented to examine the changes in expressions of miR-195 and its target protein toll-like receptor 4 (TLR4) in OSCC cell lines (TSCCA, Tca8223, Tb3.1, and CAL-27) and normal adult human gingival fibroblasts (HGFs), and the relation between their expressions was assessed. The expressions of phosphorylated proteins in nuclear factor-κB (NF-κB) pathway were determined through western blotting. miR-195 was expressed at a noticeably lower level in four OSCC cells than in HGFs, and the lowest level appeared in CAL-27 cells. Compared with miR-195 control, the miR-195 mimic could obviously raise the expression of miR-195. In CAL-27 cells with high expression of miR-195, the proliferation was inhibited and the apoptosis was evidently enhanced. OSCC cells exhibited evidently reduced protein and mRNA expression of TLR4, and miR-195 expression was inversely associated with TLR4 expression. It was uncovered from the dual-luciferase reporter assay that cells with wild-type TLR4 had prominently weakened luciferase activity relative to cells with mutant-type TLR4, revealing that the direct target of miR-195 is TLR4. The NF-κB pathway was impeded in cells that lowly expressed TLR4. miR-195 blocks the NF-κB pathway via inhibiting the expression of TLR4 in OSCC cells, thereby exerting an antitumor effect.

Ubiquitin specific peptidase 47 promotes proliferation of lung squamous cell carcinoma

Ubiquitin specific peptidase 47 (USP47) is a kind of deubiquitinase, which has been reported to play oncogenic roles in several malignancies including colorectal cancer and breast cancer. Here we aimed to investigate the clinical significance of USP47 in lung squamous cell carcinoma (LUSC). We retrospectively enrolled a cohort of LUSC patients who underwent surgical resection in our hospital (n = 280) and conducted immunohistochemistry staining for their tumor tissues targeting USP47. The correlations between USP47 expression and clinicopathological characteristics were evaluated by Chi-square test. Univariate and multivariate analyses were conducted to assess the prognostic predictive role of USP47 in LUSC. Cell lines and mice models were utilized to explore the tumor-related functions of USP47 in vitro and in vivo, respectively. Among the 280 cases, there were 127 cases classified as high-USP47 expression and 153 cases with low-USP47 expression. Statistical analyses revealed that higher USP47 expression was independently correlated with larger tumor size, advanced T stage, and unfavorable prognosis. Knockdown of USP47 by shRNA resulted in impaired proliferation of LUSC cell lines and reduced nucleus beta-catenin level. Furthermore, xenograft assays demonstrated that silencing USP47 can inhibit LUSC tumor growth in vivo. Our research established a novel tumor-promoting effect and prognostic predictive role of USP47 in LUSC, thereby providing evidence for further therapeutic development.

Metallothionein-like 5 expression is correlated with poor prognosis and promotes proliferation of cervical squamous cell carcinoma

ABSTRACT Cervical cancer represents one of the most important female genital cancers. Cervical squamous cell carcinoma (CESC) accounts for about 90% of all cervical malignancies and the prognosis are unsatisfied. Here we aimed to investigate the clinical relevance of metallothionein-like 5 (MTL5), a novel metallothionein-like protein, in CESC. RT-qPCR and immunohistochemistry staining showed that MTL5 was upregulated in CESC tissues than nontumorous cervix tissues, which is consistent with the data from TCGA database. Kaplan–Meier survival analysis revealed that higher MTL5 can help predict worse prognosis. In addition, Cox hazard regression analysis verified an independent predictive role of MTL5 in CESC. To further investigate the involvement of MTL5 in CESC, we conducted knockdown experiments in two CESC cell lines. As a result, silencing MTL5g significantly inhibited proliferation of CESC cells. Finally, we validated that silencing MTL5 can suppress CESC tumor growth in vivo using the mice subcutaneous xenografts model. Taken together, higher MTL5 indicates worse survival of CESC after surgical resection. Targeting MTL5 represents a potential therapy of CESC by inhibiting tumor growth, which deserves further investigations.

The Overexpression of Kinesin Superfamily Protein 2A (KIF2A) Was Associated with the Proliferation and Prognosis of Esophageal Squamous Cell Carcinoma [Retraction

[This retracts the article DOI: 10.2147/CMAR.S248008.].

HA1077 inhibits cell proliferation of oral squamous cell carcinoma in vitro

Oral squamous cell carcinoma is a common malignant lesion. ROCKs proteins are associated with pathogenesis and progression of human tumours. This study aimed to evaluate the functional role of ROCKs in the regulation of cell proliferation of oral squamous cell carcinoma in vitro. BrdU incorporation assays and KI-67 immunoexpression were performed by using SCC-4 cell line from oral squamous cell carcinoma. Control and treated cells: HA-1077 (25, 50 and 100 μmol/l), 50 μmol HA-1077 and Y-27632 30 μmol/l, Y-27632 30 μmol/l were cutured for 6 h. The number of SCC-4 cells treated with: HA-1077 (25, 50 and 100 μmol/l), HA-1077 50 μmol/l and/or Y-27632 30 μmol/l was significantly lower than control cells in BrdU assay [F (5.17) = 443.818, p&lt;0.0001] and in KI-67 assay [F = 192.595, d.f. = 5,17; p&lt;0.0001]. The results obtained suggest that the pathways that evolve ROCKs proteins play an important functional role in the positive regulation of cell proliferation in oral squamous cell carcinoma.

Lidocaine represses proliferation and cisplatin resistance in cutaneous squamous cell carcinoma via miR-30c/SIRT1 regulation

ABSTRACT This study aimed to determine the effects of lidocaine on cell proliferation and cisplatin resistance in A431 human cutaneous squamous cell carcinoma (cSCC) cells and elucidate the underlying mechanism. Cell proliferation, colony numbers, and cisplatin resistance were determined in A431 or cisplatin-resistant A431 (A431-R) cells that were first transfected with miR-30c-inhibitor or miR-30c-mimic, respectively, and then treated with different concentrations of lidocaine, cisplatin, or both. The expression levels of miR-30c and Sirtuin 1 (SIRT1) in A431 and A431-R cells were determined by quantitative real-time polymerase chain reaction and Western blotting. Lidocaine suppressed A431 cell proliferation and cisplatin resistance in a dose- and time-dependent manner via the miR-30c/SIRT1 pathway. MiR-30c overexpression also suppressed cell proliferation and cisplatin resistance in A431 cells by directly targeting and downregulating SIRT1, thus enhancing the protective effects of lidocaine. Conversely, SIRT1 upregulation or miR-30c inhibition antagonized the inhibitory effects of lidocaine. Our results suggest that lidocaine may suppress the progression of cSCC by activating the miR-30c/SIRT1 pathway, indicating its promising potential as a treatment strategy for cSCC.

Targeting Wee1 kinase to suppress proliferation and survival of cisplatin-resistant head and neck squamous cell carcinoma.

We investigated the role of Wee1 kinase in cisplatin-resistant head and neck squamous cell carcinoma (HNSCC) in multiple cisplatin-resistant HNSCC cell lines and determined the efficacy of either Wee1 inhibitor, AZD1775 alone, or in combination with cisplatin, on cisplatin-resistant HNSCC inhibition. Phosphorylation and total protein levels of cells were assessed by Western blot analysis. Cell viability and apoptosis were examined by MTS assay and flow cytometry, respectively. Wee1 kinase protein expression levels in five cisplatin-resistant HNSCC cell types were higher than those in their parental cisplatin-sensitive partners. Importantly, Wee1 knockdown inhibited cell proliferation and re-sensitized cells to cisplatin treatment. Interestingly, previous studies have also shown that Wee1 inhibitor AZD1775 synergizes with cisplatin to suppress cell proliferation of cisplatin-sensitive HNSCC. We found that AZD1775 inhibited both cisplatin-sensitive and resistant HNSCC with similar IC50 values, which suggested that AZD1775 could overcome cisplatin resistance in cisplatin-resistant HNSCC. Mechanistically, AZD1775 and cisplatin cooperatively induced DNA damage and apoptosis. Wee1 inhibitor, AZD1775, and cisplatin coordinately suppressed proliferation and survival of HNSCC.

SP1-Mediated Upregulation of circFAM126A Promotes Proliferation and Epithelial-Mesenchymal Transition of Oral Squamous Cell Carcinoma via Regulation of RAB41.

BackgroundAccumulating evidence indicates that circular RNAs have major roles in the progression of human cancers. Nevertheless, the molecular mechanism and effects of circFAM126A in oral squamous cell carcinoma (OSCC) remain unclear.MethodsQuantitative real-time PCR (qRT-PCR) was used to detect expression levels of circFAM126A in OSCC tumor tissues and cell lines; the effects of circFAM126A small hairpin RNA (shRNA) on the proliferation, migration, and invasion of OSCC cells were detected by MTT, colony formation, and transwell assays; xenograft mouse models were used to determine the effects of circFAM126A shRNA on the growth of OSCC tumors in vivo; the expression of miR-186 and RAB41 in OSCC tissues and cells was examined by qRT-PCR; the targeting relationship between circFAM126A and miR-186 was verified by dual-luciferase reporter and RNA pull-down assays; and the relationship between miR-186 and RAB41 was explored.ResultsThe expression of circFAM126A was significantly upregulated in OSCC tissues and cells. The transcription factor SP1 transcriptionally activated circFAM126A. However, knockdown of circFAM126A markedly suppressed the proliferation, migration, and invasion of OSCC cells in vitro and inhibited tumor growth and distant metastasis in vivo. Moreover, circFAM126A increased the expression of RAB41 and promoted its mRNA stability via binding to miR-186 and RNA-binding protein FUS. Overexpression of RAB41 antagonized the effects of circFAM126A knockdown and induced an aggressive phenotype of OSCC cells.ConclusionSP1 transcriptionally activated circFAM126A modulated the growth, epithelial-mesenchymal transition (EMT) of OSCC cells via targeting the miR-186/FUS/RAB41 axis, suggesting that circFAM126A is a potential biomarker for the treatment of OSCC.

TUSC3 inhibits cell proliferation and invasion in cervical squamous cell carcinoma via suppression of the AKT signalling pathway.

The decreased expression of tumour suppressor candidate 3 (TUSC3) is associated with proliferation in several types of cancer, leading to an unfavourable prognosis. The present study aimed to assess the cellular and molecular function of TUSC3 in patients with cervical squamous cell carcinoma (CSCC). Levels of mRNA expressions of TUSC3 were analysed in CSCC tissues and six cell lines using qRT‐PCR. Immunohistochemistry(IHC) was used to evaluate the protein expression level of TUSC3 in four paired specimens, 220 paraffin‐embedded CSCC specimens and 60 cases of normal cervical tissues(NCTs), respectively. Short hairpin RNA interference was employed for TUSC3 knockdown. Cell proliferation, migration and invasion were evaluated using growth curve, MTT assay, wound healing, transwell assay and xenograft tumour model, respectively. The results demonstrated that TUSC3 mRNA and protein expression levels were downregulated in CSCC samples. Multivariate and univariate analyses indicated that TUSC3 was an independent prognostic factor for patients with CSCC. Decreased TUSC3 expression levels were significantly associated with proliferation and an aggressive phenotype of cervical cancer cells both in vitro and in vivo. Moreover, the knockdown of TUSC3 promoted migration and invasion of cancer cells, while the increased expression of TUSC3 exhibited the opposite effects. The downregulation of TUSC3 facilitated proliferation and invasion of CSCC cells through the activation of the AKT signalling pathway. Our data demonstrated that the downregulation of TUSC3 promoted CSCC cell metastasis via the AKT signalling pathway. Therefore, TUSC3 may serve as a novel prognostic marker and potential target for CSCC.

Circ-PKD2 promotes Atg13-mediated autophagy by inhibiting miR-646 to increase the sensitivity of cisplatin in oral squamous cell carcinomas

Autophagy is an evolutionally conserved catabolic process that degrades cells to maintain homeostasis. Cisplatin-activated autophagy promotes the expression of circ-PKD2, which plays a role as a tumor suppressor gene in the proliferation, migration, and invasion in oral squamous cell carcinoma (OSCC). However, the role of circ-PKD2 in regulating the sensitivity of OSCC patients to cisplatin remains to be elucidated. Overexpression of circ-PKD2 increased the formation of autophagosomes in OSCC cells and activation of proteins, such as LC3 II/I. Its activation effect on autophagy was, however, alleviated by 3-MA. Bioinformatics analyses and double luciferases reporter assays conducted in this study confirmed the existence of targeted relationships between circ-PKD2 and miR-646 and miR-646 and Atg13. Functional experiments further revealed that miR-646 reversed the autophagy and apoptosis effects of circ-PKD2 in OSCC cells treated with cisplatin. In addition, circ-PKD2 promoted the expression of ATG13 by adsorption of miR-646. Its interference with Atg13 alleviated the activation effects of circ-PKD2 on autophagy and apoptosis of miR-646. Notably, the in vivo animal experiments also confirmed that circ-PKD2 inhibited tumor proliferation and activated autophagy in OSCC cells. This study provides a theoretical basis for using circ-PKD2 as a target to regulate the sensitivity of OSCC patients to cisplatin, thus increasing its chemotherapeutic effects.

Oxethazaine inhibits esophageal squamous cell carcinoma proliferation and metastasis by targeting aurora kinase A

Esophageal squamous cell carcinoma (ESCC), a malignant neoplasm with high incidence, is a severe global public health threat. The current modalities used for treating ESCC include surgery, chemotherapy, and radiotherapy. Although ESCC management and treatment strategies have improved over the last decade, the overall 5-year survival rate remains <20%. Therefore, the identification of novel therapeutic strategies that can increase ESCC patient survival rates is urgently needed. Oxethazaine, an amino-amide anesthetic agent, is mainly prescribed in combination with antacids to relieve esophagitis, dyspepsia, and other gastric disorders. In the present study, we found that oxethazaine inhibited the proliferation and migration of esophageal cancer cells. According to the results of in vitro screening and binding assays, oxethazaine binds directly to AURKA, suppresses AURKA activity, and inhibits the downstream effectors of AURKA. Notably, we found that oxethazaine suppressed tumor growth in three patient-derived esophageal xenograft mouse models and tumor metastasis in vivo. Our findings suggest that oxethazaine can inhibit ESCC proliferation and metastasis in vitro and in vivo by targeting AURKA.

Phytochemically Derived Zingerone Nanoparticles Inhibit Cell Proliferation, Invasion and Metastasis in Human Oral Squamous Cell Carcinoma.

Due to its aggressiveness and high mortality rate, oral cancer still represents a tough challenge for current cancer therapeutics. Similar to other carcinomas, cancerous invasion and metastasis are the most important prognostic factors and the main obstacles to therapy for human oral squamous cell carcinoma (OSCC). Fortunately, with the rise of the nanotechnical era and innovative nanomaterial fabrication, nanomaterials are widely used in biomedicine, cancer therapeutics, and chemoprevention. Recently, phytochemical substances have attracted increasing interest as adjuvants to conventional cancer therapy. The ginger phenolic compound zingerone, a multitarget pharmacological and bioactive phytochemical, possesses potent anti-inflammatory, antioxidant, and anticancer activities. In our previous study, we generated phytochemically derived zingerone nanoparticles (NPs), and documented their superior antitumorigenic effect on human hepatoma cells. In the present study, we further investigated the effects of zingerone NPs on inhibiting the invasiveness and metastasis of human OSCC cell lines. Zingerone NPs elicited significant cytotoxicity in three OSCC cell lines compared to zingerone. Moreover, the lower dose of zingerone NPs (25 µM) markedly inhibited colony formation and colony survival by at least five-fold compared to zingerone treatment. Additionally, zingerone NPs significantly attenuated cell motility and invasiveness. In terms of the signaling mechanism, we determined that the zingerone NP-mediated downregulation of Akt signaling played an important role in the inhibition of cell viability and cell motility. Zingerone NPs inhibited matrix metalloproteinase (MMP) activity, which was highly correlated with the attenuation of cell migration and cell invasion. By further detecting the roles of zingerone NPs in epithelial–mesenchymal transition (EMT), we observed that zingerone NPs substantially altered the levels of EMT-related markers by decreasing the levels of the mesenchymal markers, N-cadherin and vimentin, rather than the epithelial proteins, ZO-1 and E-cadherin, compared with zingerone. In conclusion, as novel and efficient phytochemically derived nanoparticles, zingerone NPs may serve as a potent adjuvant to protect against cell invasion and metastasis, which will provide a beneficial strategy for future applications in chemoprevention and conventional therapeutics in OSCC treatment.

MiR-34c-3p upregulates erastin-induced ferroptosis to inhibit proliferation in oral squamous cell carcinomas by targeting SLC7A11

BackgroundMiRNA is a small molecule RNA that plays an important role in a variety of physiological and pathological processes., and miR-34c-3p has been demonstrated to be closely related to the occurrence of tumors. Ferroptosis is a new form of cell death characterized by lipid-based reactive oxygen species accumulation. However, it is still unclear how miR-34c-3p influences the development of oral squamous cell carcinoma (OSCC) by regulating ferroptosis. Therefore, the main objective of this study was to explore the role and mechanism of miR-34c-3p in OSCC. Materials and methodsThe expression of miR-34c-3p in OSCC and matched normal tissues was detected by quantitative real-time PCR (qRT-PCR). Subsequently, the effect of miR-34c-3p overexpression on cell proliferation and ferroptosis was evaluated using CCK8, colony formation assays, Live/Dead staining, Western blotting analysis, ROS, MDA, and GSH assay. ResultsThe results showed lower expression of miR-34c-3p in OSSC compared with normal tissues. Overexpression of miR-34c-3p in SCC-25 cells suppressed cell proliferation. In addition, the overexpression of miR-34c-3p promoted ferroptosis by increasing ROS, MDA, and iron and decreasing GSH and GPX4 levels in SCC-25 cells. ConclusionOur findings revealed a novel strategy to upregulate erastin-induced ferroptosis in OSCC through the miR-34c-3p/SLC7A11 axis, suggesting new insights into OSCC and a potentially useful therapeutic strategy for OSCC.