Migration Of Squamous Cell Carcinoma Research Articles

Comparison of nanovesicles derived from Panax notoginseng at different size: physical properties, composition, and bioactivity.

Plant-derived nanovesicles have emerged as potential agents for combating tumors. In this study, we investigated the inhibitory effects of Panax notoginseng-derived nanovesicles (PnNVs) on the proliferation and migration of squamous cell carcinoma. Additionally, we explored the relationship between plant tuber size and the physical properties, composition and bioactivity of these nanovesicles. We isolated PnNVs from Panax notoginseng tubers of varying sizes: small-sized (s_PnNVs), medium-sized (m_PnNVs) and large-sized (l_PnNVs), and evaluated for size, potential, and morphology. Cellular uptake efficiency was assessed using confocal microscopy and flow cytometry. The ability of different PnNVs to inhibit oral squamous cell carcinoma cells was evaluated using plate cloning, CCK8 assay, and scratch healing assay. Off-target metabolomics was used to compare metabolic compounds of different PnNVs. Our findings revealed that s_PnNVs exhibited lower potential but had the highest cellular uptake efficiency, whereas m_PnNVs were characterized by the smallest size and lowest cellular uptake efficiency. Notably, m_PnNVs demonstrated the most effective inhibition of squamous cell carcinoma growth and migration. Compositional analyses showed that PnNVs were rich in proteins and contained lower levels of RNA, with l_PnNVs having the highest protein content. Furthermore, untargeted metabolomics analysis revealed a significant increase in the expression of specific antitumour-related metabolites in m_PnNVs compared to s_PnNVs and l_PnNVs. Overall, our results underscore the influence of plant tuber size on the bioactivity of the nanovesicles from which they are derived, emphasizing its importance for experimental design and study reproducibility.

Pinosylvin Inhibits Esophageal Squamous Cell Carcinoma Migration and Invasion by Regulating STX6/ITGA3/VASP Pathway

Pinosylvin Inhibits Esophageal Squamous Cell Carcinoma Migration and Invasion by Regulating STX6/ITGA3/VASP Pathway

Blimp-1 Upregulation by Multiple Ligands via EGFR Transactivation Inhibits Cell Migration in Keratinocytes and Squamous Cell Carcinoma.

B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor and plays a crucial role in the regulation of development and functions of various immune cells. Currently, there is limited understanding about the regulation of Blimp-1 expression and cellular functions in keratinocytes and cancer cells. Previously we demonstrated that EGF can upregulate Blimp-1 gene expression in keratinocytes, playing a negative role in regulation of cell migration and inflammation. Because it remains unclear if Blimp-1 can be regulated by other stimuli beyond EGF, here we further investigated multiple stimuli for their regulation of Blimp-1 expression in keratinocytes and squamous cell carcinoma (SCC). We found that PMA, TNF-α, LPS, polyIC, H2O2 and UVB can upregulate the protein and/or mRNA levels of Blimp-1 in HaCaT and SCC cells. Concomitant EGFR activation was observed by these stimuli, and EGFR inhibitor gefitinib and Syk inhibitor can block Blimp-1 gene expression caused by PMA. Reporter assay of Blimp-1 promoter activity further indicated the involvement of AP-1 in PMA-, TNF-α-, LPS- and EGF-elicited Blimp-1 mRNA expression. Confocal microscopic data indicated the nuclear loclization of Blimp-1, and such localization was not changed by stimuli. Moreover, Blimp-1 silencing enhanced SCC cell migration. Taken together, Blimp-1 can be transcriptionally upregulated by several stimuli in keratinocytes and SCC via EGFR transactivation and AP-1 pathway. These include growth factor PMA, cytokine TNF-α, TLR ligands (LPS and polyIC), and ROS insults (H2O2 and UVB). The function of Blimp-1 as a negative regulator of cell migration in SCC can provide a new therapeutic target in SCC.

Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis.

Simple SummaryHead and neck squamous cell carcinomas (HNSCC) are among the most common cancers worldwide. In contrast to the advances in prevention and treatment of other types of cancer, the five-year survival rate for HNSCC is only about 50% and it has not changed for the past 50 years. This poor prognosis is mainly due to a shortage of suitable markers for early detection, delayed diagnosis and/or referral, and ineffectiveness of chemotherapy. The aim of this study was to explore the inhibitory role of LEKTI in matriptase-dependent squamous cell carcinogenesis and to investigate additional players operating in this pathway. We found that Kallikrein-5 is necessary for PAR-2-mediated IL-8 release, YAP1-TAZ/TEAD activation, and matriptase-mediated oral squamous cell carcinoma migration. This knowledge can contribute for the development of future targeted therapy in HNSCC.Head and neck squamous cell carcinoma remains challenging to treat with no improvement in survival rates over the past 50 years. Thus, there is an urgent need to discover more reliable therapeutic targets and biomarkers for HNSCC. Matriptase, a type-II transmembrane serine protease, induces malignant transformation in epithelial stem cells through proteolytic activation of pro-HGF and PAR-2, triggering PI3K-AKT-mTOR and NFKB signaling. The serine protease inhibitor lympho-epithelial Kazal-type-related inhibitor (LEKTI) inhibits the matriptase-driven proteolytic pathway, directly blocking kallikreins in epithelial differentiation. Hence, we hypothesized LEKTI could inhibit matriptase-dependent squamous cell carcinogenesis, thus implicating kallikreins in this process. Double-transgenic mice with simultaneous expression of matriptase and LEKTI under the keratin-5 promoter showed a prominent rescue of K5-Matriptase+/0 premalignant phenotype. Notably, in DMBA-induced SCC, heterotopic co-expression of LEKTI and matriptase delayed matriptase-driven tumor incidence and progression. Co-expression of LEKTI reverted altered Kallikrein-5 expression observed in the skin of K5-Matriptase+/0 mice, indicating that matriptase-dependent proteolytic pathway inhibition by LEKTI occurs through kallikreins. Moreover, we showed that Kallikrein-5 is necessary for PAR-2-mediated IL-8 release, YAP1-TAZ/TEAD activation, and matriptase-mediated oral squamous cell carcinoma migration. Collectively, our data identify a third signaling pathway for matriptase-dependent carcinogenesis in vivo. These findings are critical for the identification of more reliable biomarkers and effective therapeutic targets in Head and Neck cancer.

LncRNA GACAT1 induces tongue squamous cell carcinoma migration and proliferation via miR-149.

Recent studies have observed that lncRNAs (long non‐coding RNAs) are involved in the progression of various tumours including tongue squamous cell carcinoma (TSCC). Recently, a new lnRNA, GACAT1, has been firstly identified in gastric cancer. However, its potential role in TSCC remains unknown. In this reference, we observed that GACAT1 was overexpressed in TSCC samples and cell lines. Of 25 TSCC specimens, GACAT1 expression was overexpressed in 18 patients (18/25, 72%) compared to non‐tumour specimens. Ectopic expression of GACAT1 induced cell growth and migration and promoted epithelial to mesenchymal transition in TSCC. In addition, ectopic expression of GACAT1 decreased miR‐149 expression in SCC1 cell. We observed that miR‐149 expression was down‐regulated in TSCC cell lines. Moreover, we observed that GACAT1 expression was negatively correlated with miR‐149 expression. GACAT1 overexpression induced TSCC cell growth and migration via regulating miR‐149 expression. These data provided that GACAT1 played an oncogenic role in the progression of TSCC partly through modulating miR‐149 expression.

The Level of Mesenchymal-Epithelial Transition Autophosphorylation is Correlated with Esophageal Squamous Cell Carcinoma Migration

Background:The MET receptor is a critical member of cancer-associated RTKs and plays an important role in different biological activities, including differentiation, migration, and cell proliferation. Methods:In this study, novel MET inhibitors were introduced and applied on esophageal squamous carcinoma cell line KYSE-30, and the level of proliferation and migration, as well as the activated form of MET receptor protein were assessed in the examined cells. The human KYSE-30 cell line was cultured according to ATCC recommendations. The mRNA level of the MET gene was measured in the examined cell line using the quantitative RT-PCR assay. Cytotoxicity evaluation test was performed at different concentrations of heterocyclic anti-MET compounds (i.e. D1, D2, D5, D6, D7, and D8). Finally, the capability of these compounds in MET receptor inhibition was evaluated using the migration assay and Western blot. All experiments were performed in triplicate and repeated three times with similar results. Results:Cell growth and proliferation were significantly inhibited (p ≤ 0.05) by all the above-mentioned compounds. Moreover, the majority of compounds significantly prevented the cell migration (p ≤ 0.05) and inhibited MET autophosphorylation. Interestingly, the level of phosphorylated MET was significantly correlated with KYSE-30 cell migration. Conclusion:The obtained data introduced and confirmed the biological activities of the mentioned novel compounds in KYSE-30 cells and proposed that the therapeutic inhibition of MET with these compounds may be a powerful approach for inhibiting cancer cell migration and proliferation although some structural optimizations are needed to improve their inhibitory functions.

DMP-1 promoter-associated antisense strand non-coding RNA, panRNA-DMP-1, physically associates with EGFR to repress EGF-induced squamous cell carcinoma migration.

Accumulating evidence suggests that specific non-coding RNAs exist in many types of malignant tissues, and are involved in cancer invasion and metastasis. However, little is known about the precise roles of non-coding RNAs in squamous cell carcinoma (SQCC) invasion and migration. Recently, the dentin matrix protein-1 (DMP-1) gene locus was identified as a transcriptionally active site in squamous cell carcinoma (SQCC) tissue and cells. However, it is unclear whether RNA associated with cell migration exist at the DMP-1 gene locus in SQCC cells. We identified a novel promoter-associated non-coding RNA in the antisense strand of DMP-1 gene locus, promoter-associated non-coding RNA (panRNA)-DMP-1, by the RACE method in SQCC cells and tissues, and characterized the functions of panRNA-DMP-1 in EGF-driven SQCC cell migration. The inhibition of endogenous panRNA-DMP-1 expression by specific siRNAs and exogenous over-expression of panRNA-DMP-1 resulted in increased and suppressed cellular migration toward EGF in SQCC cells, respectively, and nuclear expression of panRNA-DMP-1 was induced by EGF stimulation. Mechanistically, suppression of panRNA-DMP-1 expression increased EGFR nuclear localization upon EGF treatment and nuclear panRNA-DMP-1 physically interacted with EGFR, which was confirmed by RNA immunoprecipitation assay using a bacteriophage-delivered PP7 RNA labeling system. Furthermore, co-immunoprecipitation assay revealed that suppression of panRNA-DMP-1 stabilized EGFR interaction with STAT3, a known co-transcription factors of EGFR, to induce migratory properties in many cancer cells. Based on these findings, panRNA-DMP-1 is an EGFR-associating RNA that inhibits the EGF-induced migratory properties of SQCC possibly by regulating EGFR nuclear localization and EGFR binding to STAT3.

MiR-770 promotes oral squamous cell carcinoma migration and invasion by regulating the Sirt7/Smad4 pathway.

Oral squamous cell carcinoma (OSCC) is a common malignant cancer with unfavorable prognosis, and the epithelial-to-mesenchymal transition (EMT) is a critical contributor to OSCC metastasis. Recently, we have shown that sirtuin 7 (Sirt7) is associated with EMT and OSCC metastasis by acetylating small mother against decapentaplegic 4 (Smad4). Nonetheless, the mechanism of Sirt7 downregulation in OSCC cells remains unknown. This study analyzed the potential microRNAs that were predicted to regulate Sirt7 expression by online databases. We identified miR-770 as an upstream regulator of Sirt7 that targets its 3'-untranslated region. The expression of miR-770 was observed to be negatively correlated with the mRNA expression of Sirt7 in metastatic OSCC tumors, and higher miR-770 expression was correlated with poorer OSCC patient survival. Our in vitro data indicated that miR-770 promoted OSCC cell migration and invasion, and this process was dependent on Sirt7/Smad4 signaling. Furthermore, in vivo metastasis experiments indicated that miR-770 overexpression led to more prominent OSCC metastasis and downregulated Sirt7 expression. Collectively, our results revealed a new role of Sirt7 downregulation in metastatic OSCC and suggested that miR-770 is a potential target in counteracting OSCC metastasis.

The Leader Position of Mesenchymal Cells Expressing N-Cadherin in the Collective Migration of Epithelial Cancer

Understanding how heterogeneous cancer cell populations migrate collectively is of paramount importance to arrest metastasis. Here, we applied 3D culture-based approaches for in vitro modeling of the collective migration of squamous carcinoma cells and examine the impact of epithelial and mesenchymal cell interactions on this type of migration. We show that both mesenchymal N-cadherin-expressing cancer cells and cancer-associated fibroblasts cooperate in collective migration of epithelial cancer cells by leading their collective migration. This was consistent with the observed distribution of E-cadherin/N-cadherin in the human carcinoma tissues of head and neck. The presence of “leader” mesenchymal cancer cells or “leader” fibroblasts was significantly associated with metastasis development, recurrent disease and low overall disease survival in head and neck squamous cell carcinomas (HNSCC). In silico analysis of independent public datasets revealed that increased N-cadherin expression in the heterogeneous cancer tissues is associated with disease progression not only in HNSCC but also in other prevalent tumors, such as colorectal, breast and lung cancer. Collectively, our data highlight the importance of mesenchymal cells in collective cell migration and disease progression, findings that may have a broad significance in cancer, especially in those in which aberrant N-cadherin expression negatively impacts disease survival.

Upregulation of circFLNA contributes to laryngeal squamous cell carcinoma migration by circFLNA\u2013miR-486-3p-FLNA axis

BackgroundAccumulating evidence shows that circular RNAs (circRNAs) plays vital roles in tumor progression. However, the biological functions of circRNAs in laryngeal squamous cell carcinoma (LSCC) metastasis is still unclear.MethodsqRT-PCR was used to detect circFLNA, miRNAs and FLNA mRNA expression. Transwell assay and western blot were performed to evaluate cell migration ability and to detect FLNA, MMP2 and MLK1 protein expression, respectively. RNA pull-down analysis was used to find the binding-miRNAs of circFLNA. Luciferase reporter assay was used to examine the effect of circFLNA on miRNAs and miR-486-3p on FLNA expression.ResultsIn this study, we confirmed that a Filamin A (FLNA)-derived hsa_circ_0092012 known as circFLNA, was upregulated in LSCC, and the higher expression of circFLNA was correlated with LSCC lymph node metastasis. Increased circFLNA facilitates LSCC cell migration ability through upregulating FLNA and MMP2 protein expression. Mechanistically, we find that circFLNA sponges miR-486-3p in LSCC cells, relieving miR-486-3p-induced repression of FLNA which promotes LSCC cell migration. Accordingly, FLNA mRNA is overexpressed in LSCC tissues and a higher FLNA level is correlated with poor survival. Dysregulation of the circFLNA/miR-486-3p/FLNA regulatory pathway contributes to LSCC migration.ConclusionsIn summary, our study sheds light on the regulatory mechanism of circFLNA in LSCC migration via sponging miR‐486-3p, which downregulates the FLNA protein expression. Targeting circFLNA/miR-486-3p/FLAN axis provides a potential therapeutic target for aggressive LSCC.

Blimp-1 transcriptionally induced by growth factors, TNF-α and TLR ligands inhibits keratinocyte migration and inflammation but enhances cell migration in squamous cell carcinoma

Abstract B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor, and plays a crucial role in the regulation of development and functions of various immune cells. Currently, there is limited understanding about the regulation of Blimp-1 expression and cellular functions in keratinocytes and cancer cells. The aim of the study was to investigate the regulation and functional link between EGFR and Blimp-1 in human epidermal keratinocytes and squamous cell carcinoma (SCC). We found that EGF, PMA, TNF-α, LPS (TLR4 activator) and polyIC (TLR3 activator) can upregulate the protein and mRNA levels of Blimp-1 in NHEK and/or HaCaT cells. This effect of EGF was dependent on PKC, p38, and ERK activation, and Syk is also involved in the action of PMA. Additionally, the stability of Blimp-1 protein was under the control of the proteasome and lysosome degradation systems. PMA, LPS and polyIC also can activate EGFR and Syk in HaCaT cells. In addition, Blimp-1 knockdown enhanced the EGFR-mediated IL8, CXCL5 and IL6 gene expression and keratinocyte migration, but reduced the EGFR-mediated suppression of differentiation marker K10. On the other hand, EGF, TNF-α, TGF-β and PMA could also upregulate Blimp-1 expression in SCC, and EGFR activation by TNF-α and PMA was observed. Unlike the action of Blimp-1 in keratinocytes, Blimp-1 silencing reduces SCC cell migration either in the absence or presence of TNF-α and PMA. Taken together, Blimp-1 can be upregulated by several growth factors, innate immune receptors and PKC signaling pathway. Blimp-1 is a negative regulator of EGF-induced inflammation and migration in keratinocytes, but mediates cell migration in SCC.

Snail-induced claudin-11 prompts collective migration for tumour progression.

Epithelial-mesenchymal transition (EMT) is a pivotal mechanism for cancer dissemination. However, EMT-regulated individual cancer cell invasion is difficult to detect in clinical samples. Emerging evidence implies that EMT is correlated to collective cell migration and invasion with unknown mechanisms. We show that the EMT transcription factor Snail elicits collective migration in squamous cell carcinoma by inducing the expression of a tight junctional protein, claudin-11. Mechanistically, tyrosine-phosphorylated claudin-11 activates Src, which suppresses RhoA activity at intercellular junctions through p190RhoGAP, maintaining stable cell-cell contacts. In head and neck cancer patients, the Snail-claudin-11 axis prompts the formation of circulating tumour cell clusters, which correlate with tumour progression. Overexpression of snail correlates with increased claudin-11, and both are associated with a worse outcome. This finding extends the current understanding of EMT-mediated cellular migration via a non-individual type of movement to prompt cancer progression.

Long non-coding RNA PICSAR decreases adhesion and promotes migration of squamous carcinoma cells by downregulating α2β1 and α5β1 integrin expression.

ABSTRACTLong non-coding RNAs (lncRNAs) regulate various cellular processes, and they have emerged as potential biomarkers and therapeutic targets in cancer. We have previously characterized the oncogenic role of lncRNA PICSAR (p38 inhibited cutaneous squamous cell carcinoma associated lincRNA) in cutaneous squamous cell carcinoma (cSCC), the most common metastatic skin cancer. In this study, we show that knockdown of PICSAR in cSCC cells upregulates expression of α2, α5 and β1 integrins, resulting in increased cell adhesion and decreased cell migration on collagen I and fibronectin. In contrast, overexpression of PICSAR in cSCC cells downregulates expression of α2, α5 and β1 integrins on cell surface, resulting in decreased cell adhesion on collagen I and fibronectin and increased cell migration. These results demonstrate a novel mechanism for regulation of the expression of collagen and fibronectin binding integrins by lncRNA PICSAR, leading to altered adhesion and migration of cSCC cells.This article has an associated First Person interview with the first author of the paper.

Long Noncoding RNA LOC441178 Reduces the Invasion and Migration of Squamous Carcinoma Cells by Targeting ROCK1.

In recent years, long noncoding RNAs (lncRNAs) have been reported to have significant regulating effect in human cancer development. Previous studies suggested that dysregulation of lncRNA 441178 (LOC441178) is possibly associated with oral squamous cell carcinoma (OSCC). The postoperative survival time was significantly prolonged in the high-grade OSCC patients with high LOC441178 expression compared with those with low LOC441178 expression, which indicated that LOC441178 may act as a prognostic marker and as a potential tumor suppressor for OSCC. However, the biological molecular mechanisms behind these phenomena remain almost unknown. Here, our studies revealed that LOC441178 suppressed the invasion and migration of squamous carcinoma cells (SCCs). Furthermore, we found that rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) is one of the functionally relevant targets of LOC441178 in squamous cells, which is negatively correlated with LOC441178 in tumor tissues from OSCC patients. In conclusion, our findings demonstrated the inhibition effect of LOC441178 on tumor in OSCC and might have potential implications for OSCC gene therapy. In conclusion, these results suggest that LOC441178 could represent a prognostic indicator for OSCC and be a new target for the diagnosis and treatment of OSCC.

Odd-skipped related transcription factor 1 (OSR1) suppresses tongue squamous cell carcinoma migration and invasion through inhibiting NF-κB pathway

Tongue squamous cell carcinoma (TSCC) is the most common cancers of oral, owing to the high invasive and metastatic ability, patients with TSCC have poor prognosis, it's important to explore the regulatory mechanism of TSCC invasion and metastasis. Previous studies suggest OSR1 suppresses the progression of gastric cancer and renal cell carcinoma, but its role in TSCC hasn’t been studied. Here, we found OSR1 was downregulated in TSCC cells and specimens, Transwell and 3D spheroid invasion assay suggested OSR1 overexpression inhibited TSCC cell migration and invasion, while its knockdown promoted TSCC cell migration and invasion. Mechanism analysis found OSR1 expression was negatively correlated with NF-κB pathway and its targets. Western blot and NF-κB activity analysis suggested OSR1 inhibited NF-κB activity. Double inhibition of OSR1 and NF-κB significantly inhibited TSCC cell migration and invasion. These findings suggested OSR1 inhibited TSCC cell migration and invasion through inhibiting NF-κB pathway.

MicroRNA-153 suppresses human laryngeal squamous cell carcinoma migration and invasion by targeting the SNAI1 gene.

Human laryngeal squamous cell carcinoma (LSCC) is a malignant cancer type. Epithelial-mesenchymal transition marker Snail family transcriptional repressor 1 (SNAI1) is associated with the occurrence, development, invasion and metastasis of numerous tumor types, such as lung, liver and ovarian cancer. Previous studies have indicated that microRNA-153 (miR-153) may serve as a novel tumor suppressor, which is involved in tumor metastasis; however, the role and clinical significance of miR-153 in LSCC are not fully understood. The aim of the present study was to determine the role of miR-153 in the growth and aggressiveness of LSCC cells. Bioinformatics prediction method, western blot analysis, Matrigel invasion assay and immunofluorescence were used to analyze whether SNAI1 can be regulated and controlled by miR-153 in LSCC cells. An inverse association between miR-153 and SNAI1 was observed in LSCC tissues. It was demonstrated that SNAI1 is a direct target of miR-153 in LSCC. In addition, the results indicated that miR-153 knockdown inhibited PCI-13 cell migration and invasion by targeting SNAI1, which may be a potential marker that can reflect the degree of malignancy in patients with LSCC. Furthermore, miR-153 knockdown decreased Twist family BHLH transcription factor 1 and metastasis-associated 1 family member 3 expression in LSCC cells. In conclusion, these data indicated that miR-153 regulates LSCC migration via the targeting of SNAI1 gene, which may be a potential predictor for patients with LSCC.

Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration.

Aging is associated with a rising incidence of cutaneous squamous cell carcinoma (cSCC), an aggressive skin cancer with the potential for local invasion and metastasis. Acquisition of a senescence-associated secretory phenotype (SASP) in dermal fibroblasts has been postulated to promote skin cancer progression in elderly individuals. The underlying molecular mechanisms are largely unexplored. We show that Chemerin, a previously unreported SASP factor released from senescent human dermal fibroblasts, promotes cSCC cell migration, a key feature driving tumor progression. Whereas the Chemerin abundance is downregulated in malignant cSCC cells, increased Chemerin transcripts and protein concentrations are detected in replicative senescent fibroblasts in vitro and in the fibroblast of skin sections from old donors, indicating that a Chemerin gradient is built up in the dermis of elderly. Using Transwell® migration assays, we show that Chemerin enhances the chemotaxis of different cSCC cell lines. Notably, the Chemerin receptor CCRL2 is remarkably upregulated in cSCC cell lines and human patient biopsies. Silencing Chemerin in senescent fibroblasts or the CCRL2 and GPR1 receptors in the SCL-1 cSCC cell line abrogates the Chemerin-mediated chemotaxis. Chemerin triggers the MAPK cascade via JNK and ERK1 activation, whereby the inhibition impairs the SASP- or Chemerin-mediated cSCC cell migration.Taken together, we uncover a key role for Chemerin, as a major factor in the secretome of senescent fibroblasts, promoting cSCC cell migration and possibly progression, relaying its signals through CCRL2 and GPR1 receptors with subsequent MAPK activation. These findings might have implications for targeted therapeutic interventions in elderly patients.

Role for the Aryl Hydrocarbon Receptor and Diverse Ligands in Oral Squamous Cell Carcinoma Migration and Tumorigenesis.

Over 45,000 new cases of oral and pharyngeal cancers are diagnosed and account for over 8,000 deaths a year in the United States. An environmental chemical receptor, the aryl hydrocarbon receptor (AhR), has previously been implicated in oral squamous cell carcinoma (OSCC) initiation as well as in normal tissue-specific stem cell self-renewal. These previous studies inspired the hypothesis that the AhR plays a role in both the acquisition and progression of OSCC, as well as in the formation and maintenance of cancer stem-like cells. To test this hypothesis, AhR activity in two oral squamous cell lines was modulated with AhR prototypic, environmental and bacterial AhR ligands, AhR-specific inhibitors, and phenotypic, genomic and functional characteristics were evaluated. The data demonstrate that: (i) primary OSCC tissue expresses elevated levels of nuclear AhR as compared with normal tissue, (ii) AhR mRNA expression is upregulated in 320 primary OSCCs, (iii) AhR hyperactivation with several ligands, including environmental and bacterial ligands, significantly increases AhR activity, ALDH1 activity, and accelerates cell migration, (iv) AhR inhibition blocks the rapid migration of OSCC cells and reduces cell chemoresistance, (v) AhR knockdown inhibits tumorsphere formation in low adherence conditions, and (vi) AhR knockdown inhibits tumor growth and increases overall survival in vivo These data demonstrate that the AhR plays an important role in development and progression of OSCC, and specifically cancer stem-like cells. Prototypic, environmental, and bacterial AhR ligands may exacerbate OSCC by enhancing expression of these properties. This study, for the first time, demonstrates the ability of diverse AhR ligands to regulate AhR activity in oral squamous cell carcinoma cells, as well as regulate several important characteristics of oral cancer stem cells, in vivo and in vitro Mol Cancer Res; 14(8); 696-706. ©2016 AACR.

ΔNp63α induces the expression of FAT2 and Slug to promote tumor invasion.

Tumor invasion can be induced by changes in gene expression that alter cell phenotype. The transcription factor ΔNp63α promotes basal-like breast cancer (BLBC) migration by inducing the expression of the mesenchymal genes Slug and Axl, which confers cells with a hybrid epithelial/mesenchymal state. However, the extent of the ΔNp63α regulated genes that support invasive behavior is not known. Here, using gene expression analysis, ChIP-seq, and functional testing, we find that ΔNp63α promotes BLBC motility by inducing the expression of the atypical cadherin FAT2, the vesicular binding protein SNCA, the carbonic anhydrase CA12, the lipid binding protein CPNE8 and the kinase NEK1, along with Slug and Axl. Notably, lung squamous cell carcinoma migration also required ΔNp63α dependent FAT2 and Slug expression, demonstrating that ΔNp63α promotes migration in multiple tumor types by inducing mesenchymal and non-mesenchymal genes. ΔNp63α activation of FAT2 and Slug influenced E-cadherin localization to cell-cell contacts, which can restrict spontaneous cell movement. Moreover, live-imaging of spheroids in organotypic culture demonstrated that ΔNp63α, FAT2 and Slug were essential for the extension of cellular protrusions that initiate collective invasion. Importantly, ΔNp63α is co-expressed with FAT2 and Slug in patient tumors and the elevated expression of ΔNp63α, FAT2 and Slug correlated with poor patient outcome. Together, these results reveal how ΔNp63α promotes cell migration by directly inducing the expression of a cohort of genes with distinct cellular functions and suggest that FAT2 is a new regulator of collective invasion that may influence patient outcome.

Overexpression of glypican-5 inhibits proliferation, migration and invasion of lung squamous carcinoma cell line SK-MES-1

Objective To investigate the effects of the up-regulated expression of glypican-5 (GPC5) on the proliferation,migration and invasion of lung squamous carcinoma cell line SK-MES-1.Methods Lentivirus-induced GPC5 over-expression was used for in vitro functional analyses in lung squamous carcinoma cell line SK-MES-1,including migration and invasive assay,proliferation assay as well as cell cycle analysis.Results Compared to the control,the expression of GPC5 was increased by 86 times in GPC5-SK-MES-1,whose length of cell migration spacing was longer [(729.89 ±46.15) vs.(438.33 ±19.77)] and number of penetrating the membrane was significantly reduced [(33 ± 3) vs.(128 ± 3)].The relative cell proliferation activity was significantly decreased,and the cell cycle analysis showed that the ratio of S-phase cells was markedly increased in GPC5-SK-MES-1 cells as compared with controls [(50.32 ± 0.97) ％ vs.(32.59 ± 1.54) ％] (P ＜ 0.05).Conclusion Up-regulation of GPC5 can inhibit the proliferation,migration and invasion of lung squamous carcinoma cells. Key words: Lung squamous cell carcinoma; Cell proliferation; Cell migration; Cell invasion ; Glypican-5