PKD3 promotes metastasis and growth of oral squamous cell carcinoma through positive feedback regulation with PD-L1 and activation of ERK-STAT1/3-EMT signalling

AbstractOral squamous cell carcinoma (OSCC) has a high incidence of metastasis. Tumour immunotherapy targeting PD-L1 or PD-1 has been revolutionary; however, only a few patients with OSCC respond to this treatment. Therefore, it is essential to gain insights into the molecular mechanisms underlying the growth and metastasis of OSCC. In this study, we analysed the expression levels of protein kinase D3 (PKD3) and PD-L1 and their correlation with the expression of mesenchymal and epithelial markers. We found that the expression of PKD3 and PD-L1 in OSCC cells and tissues was significantly increased, which correlated positively with that of mesenchymal markers but negatively with that of epithelial markers. Silencing PKD3 significantly inhibited the growth, metastasis and invasion of OSCC cells, while its overexpression promoted these processes. Our further analyses revealed that there was positive feedback regulation between PKD3 and PD-L1, which could drive EMT of OSCC cells via the ERK/STAT1/3 pathway, thereby promoting tumour growth and metastasis. Furthermore, silencing PKD3 significantly inhibited the expression of PD-L1, and lymph node metastasis of OSCC was investigated with a mouse footpad xenograft model. Thus, our findings provide a theoretical basis for targeting PKD3 as an alternative method to block EMT for regulating PD-L1 expression and inhibiting OSCC growth and metastasis.

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PKD3 promotes metastasis and growth of oral squamous cell carcinoma through positive feedback regulation with PD-L1 and activation of ERK -STAT1/3-EMT signaling

10.21203/rs.3.rs-28178/v1 ◽

2020 ◽

Author(s):

Bomiao Cui ◽

Jiao Chen ◽

Min Luo ◽

Yiying Liu ◽

Hongli Chen ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Tumor Growth ◽

Western Blot ◽

Cell Carcinoma ◽

Squamous Cell ◽

Positive Feedback ◽

Feedback Regulation ◽

Mesenchymal Transition ◽

Epithelial Markers

Abstract Background: Oral squamous cell carcinoma (OSCC) has a high incidence of metastasis. Tumor immunotherapy targeting programmed death ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) is revolutionary; however, only a few patients with OSCC respond to this treatment. Therefore, it is necessary to understand the molecular mechanisms of OSCC growth and metastasis to identify new therapeutic targets. Methods: In this study, we first analyzed the expression level of protein kinase D3 (PKD3) and PD-L1, and their correlation with mesenchymal and epithelial markers through UALCAN database, UCSC Xena, western blot, and immunostaining of human OSCC tissue sections. We knocked down and overexpressed PKD3 in OSCC cell lines and analyzed cell growth, migration, and invasion using western blot, cell proliferation assays, wound healing assays, and Transwell assays. A mouse footpad xenograft model was used to study the effects of PKD3 on tumor growth and lymph node metastasis in vivo. Results: The expression of PKD3 and PD-L1 in OSCC cells and tissues was significantly increased, and correlated positively with mesenchymal markers but negatively with epithelial markers. Silencing PKD3 significantly inhibited the growth, metastasis, and invasion of OSCC cells, while its overexpression promoted these processes. PKD3 regulated PD-L1 expression through the ERK/STAT1/3 signaling pathway, forming a positive feedback regulatory loop with PD-L1 to induce epithelial-mesenchymal transition (EMT) in OSCC. Conclusions: There is a positive feedback regulation between PKD3 and PD-L1, which can drive the EMT of OSCC cells through the ERK/STAT1/3 pathway, thereby promoting tumor growth and metastasis. Our findings provide a theoretical basis for targeting PKD3 as an alternative method to block EMT for regulating PD-L1 expression and inhibiting OSCC growth and metastasis . Keywords: OSCC, PKD3, PD-L1, EMT, tumor growth, metastasis

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Long Non-Coding RNA (lncRNA) in Oral Squamous Cell Carcinoma: Biological Function and Clinical Application

Cancers ◽

10.3390/cancers13235944 ◽

2021 ◽

Vol 13 (23) ◽

pp. 5944

Author(s):

Jianfei Tang ◽

Xiaodan Fang ◽

Juan Chen ◽

Haixia Zhang ◽

Zhangui Tang

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Molecular Mechanisms ◽

Non Coding Rna ◽

Potential Applications ◽

Non Coding Rnas ◽

Long Non Coding Rna

Oral squamous cell carcinoma (OSCC) is a type of malignancy with high mortality, leading to poor prognosis worldwide. However, the molecular mechanisms underlying OSCC carcinogenesis have not been fully understood. Recently, the discovery and characterization of long non-coding RNAs (lncRNAs) have revealed their regulatory importance in OSCC. Abnormal expression of lncRNAs has been broadly implicated in the initiation and progress of tumors. In this review, we summarize the functions and molecular mechanisms regarding these lncRNAs in OSCC. In addition, we highlight the crosstalk between lncRNA and tumor microenvironment (TME), and discuss the potential applications of lncRNAs as diagnostic and prognostic tools and therapeutic targets in OSCC. Notably, we also discuss lncRNA-targeted therapeutic techniques including CRISPR-Cas9 as well as immune checkpoint therapies to target lncRNA and the PD-1/PD-L1 axis. Therefore, this review presents the future perspectives of lncRNAs in OSCC therapy, but more research is needed to allow the applications of these findings to the clinic.

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NF-κB-mediated lncRNA AC007271.3 promotes carcinogenesis of oral squamous cell carcinoma by regulating miR-125b-2-3p/Slug

Cell Death and Disease ◽

10.1038/s41419-020-03257-4 ◽

2020 ◽

Vol 11 (12) ◽

Author(s):

Ze-nan Zheng ◽

Guang-zhao Huang ◽

Qing-qing Wu ◽

Heng-yu Ye ◽

Wei-sen Zeng ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Molecular Mechanisms ◽

Nuclear Factor Κb ◽

Underlying Mechanisms ◽

E Cadherin

AbstractOral squamous cell carcinoma (OSCC) is the most common oral cancer. The molecular mechanisms of this disease are not fully understood. Our previous studies confirmed that dysregulated function of long non-coding RNA (lncRNA) AC007271.3 was associated with a poor prognosis and overexpression of AC007271.3 promoted cell proliferation, migration, invasion, and inhibited cell apoptosis in vitro, and promoted tumor growth in vivo. However, the underlying mechanisms of AC007271.3 dysregulation remained obscure. In this study, our investigation showed that AC007271.3 functioned as competing endogenous RNA by binding to miR-125b-2-3p and by destabilizing primary miR-125b-2, resulted in the upregulating expression of Slug, which is a direct target of miR-125b-2-3p. Slug also inhibited the expression of E-cadherin but N-cadherin, vimentin, and β-catenin had no obvious change. The expression of AC007271.3 was promoted by the canonical nuclear factor-κB (NF-κB) pathway. Taken together, these results suggested that the classical NF-κB pathway-activated AC007271.3 regulates EMT by miR-125b-2-3p/Slug/E-cadherin axis to promote the development of OSCC, implicating it as a novel potential target for therapeutic intervention in this disease.

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Peptide functionalized upconversion/NIR II luminescent nanoparticles for targeted imaging and therapy of oral squamous cell carcinoma

Biomaterials Science ◽

10.1039/d0bm01737j ◽

2021 ◽

Author(s):

Bi Lin ◽

Jun Wu ◽

Yanxing Wang ◽

Song Sun ◽

Ying Yuan ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Early Diagnosis ◽

Cell Carcinoma ◽

Squamous Cell ◽

Poor Prognosis ◽

Targeted Imaging ◽

Invasion And Metastasis ◽

High Incidence ◽

Luminescent Nanoparticles

Early diagnosis is critical and challenging for tongue squamous cell carcinoma (TSCC), which is a kind of tumor with high malignancy, poor prognosis, and a high incidence of invasion and metastasis.

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Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma

ISRN Oncology ◽

10.5402/2012/681469 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 21

Author(s):

Suttichai Krisanaprakornkit ◽

Anak Iamaroon

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Signaling Pathways ◽

Squamous Cell ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Large Body ◽

Invasion And Metastasis ◽

Mesenchymal Transition

Oral cancer is one of the drastic human cancers due to its aggressiveness and high mortality rate. Of all oral cancers, squamous cell carcinoma is the most common accounting for more than 90%. Epithelial-mesenchymal transition (EMT) is suggested to play an important role during cancer invasion and metastasis. Recently, emerging knowledge on EMT in carcinogenesis is explosive, tempting us to analyze previous studies on EMT in oral squamous cell carcinoma (OSCC). In this paper, we have first addressed the general molecular mechanisms of EMT, evidenced by alterations of cell morphology during EMT, the presence of cadherin switching, turning on and turning off of many specific genes, the activation of various signaling pathways, and so on. The remaining part of this paper will focus on recent findings of the investigations of EMT on OSCC. These include the evidence of EMT taking place in OSCC and the signaling pathways employed by OSCC cells during their invasion and metastasis. Collectively, with the large body of new knowledge on EMT in OSCC elaborated here, we are hopeful that targeting treatment for OSCC will be developed.

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M1-like tumor-associated macrophages cascade a mesenchymal/stem-like phenotype of oral squamous cell carcinoma via the IL6/Stat3/THBS1 feedback loop

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02222-z ◽

2022 ◽

Vol 41 (1) ◽

Author(s):

Yuanhe You ◽

Zhuowei Tian ◽

Zhong Du ◽

Kailiu Wu ◽

Guisong Xu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Feedback Loop ◽

Molecular Mechanisms ◽

Bioinformatics Analysis ◽

Rna Seq ◽

Stat3 Pathway ◽

Functional Roles

Abstract Background Tumor-associated macrophages (TAMs) have a leading position in the tumor microenvironment. Previously, we have demonstrated that M1-like TAMs activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma (OSCC). However, the functional roles and associated molecular mechanisms of the activated M1-like TAMs need to be further clarified in OSCC. Methods Conditioned Media (CM) were harvested from the exosome activated M1-like TAMs. We measured the malignant behaviors of OSCC under the treatment of CM from M1-like TAMs by performing colony forming assays, invasion assays, wound-healing assays, spheroid forming assays and in vivo xenograft experiments. The underlying mechanisms were investigated by RNA-seq, cytokines analysis, intracellular signaling pathway analysis, ChIP assays, bioinformatics analysis and validation. Results M1-like TAMs significantly promoted the epithelial-mesenchymal transition (EMT) process, and induced the cancer-stem like cells (CSCs) by upregulating the expression of MME and MMP14 in OSCC cells. Cytokine analysis revealed a shark increase of IL6 secretion from M1-like TAMs. Blocking IL6 in the CM from M1-like TAMs could significantly weaken its effects on the colony forming, invasion, migration, microsphere forming and xenograft forming abilities of OSCC cells. Cellular signaling assays indicated the activation of Jak/Stat3 pathway in the OSCC cells treated by the CM from M1-like TAMs. Blocking the activation of the Jak/Stat3 pathway could significantly weaken the effects of M1-like TAMs on the colony forming, invasion, migration, microsphere forming and xenograft forming abilities of OSCC cells. Further RNA-seq analysis and bioinformatics analysis revealed an increased expression of THBS1 in the OSCC cells treated by M1-like TAMs. Bioinformatics prediction and ChIP assays revealed the activation of Stat3 by CM from M1-like TAMs could directly promote the transcription of THBS1 in OSCC cells. Conclusions We proposed that M1-like TAMs could cascade a mesenchymal/stem-like phenotype of OSCC via the IL6/Stat3/THBS1 feedback loop. A better understanding on the functional roles and associated molecular mechanisms of M1-like TAMs might facilitate the development of novel therapies for supplementing the current treatment strategies for OSCC patients.

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LncRNA MCM3AP-AS1 promotes proliferation, migration and invasion of oral squamous cell carcinoma cells via regulating miR-204-5p/FOXC1

Journal of Investigative Medicine ◽

10.1136/jim-2020-001415 ◽

2020 ◽

Vol 68 (7) ◽

pp. 1282-1288

Author(s):

Hui Li ◽

Junhong Jiang

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Molecular Mechanisms ◽

Cell Counting ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Qrt Pcr ◽

Gene Assay

Oral squamous cell carcinoma (OSCC) is a lethal malignancy. It is reportedly demonstrated that long non-coding RNA (lncRNA) participates in the development of OSCC. The purpose of this study was to clarify the function and possible molecular mechanisms of lncRNA MCM3AP antisense RNA 1 (lncRNA MCM3AP-AS1) in OSCC. Quantitative real-time PCR (qRT-PCR) was adopted to investigate MCM3AP-AS1 expressions in OSCC tissues and cells. The proliferation, migration and invasion of HN-6 and SCC-9 cells were probed by cell counting kit-8 and Transwell assays, respectively. Dual luciferase reporter gene assay, Pearson’s correlation analysis, qRT-PCR and western blot were used to detect the binding relationship among miR-204-5 p, MCM3AP-AS1 and forkheadbox C1 (FOXC1). MCM3AP-AS1 expression was elevated in OSCC tissues and cell lines. Overexpression of MCM3AP-AS1 facilitated the proliferation, migration and invasion of OSCC cells, while the knockdown of MCM3AP-AS1 suppressed these malignant phenotypes. Besides, MCM3AP-AS1 impeded miR-204-5 p by binding with it. MCM3AP-AS1 could also upregulate the expression of FOXC1 via repressing miR-204-5 p.MCM3AP-AS1 promotes the progression of OSCC cells by adsorbing miR-204-5 p and upregulating FOXC1 expressions.

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