scholarly journals Hypoxia-mediated YTHDF2 expression and activation of the mTOR/AKT axis in lung squamous cell carcinoma

2021 ◽  
Author(s):  
Peng Xu ◽  
Kang Hu ◽  
Zhi-Gang Sun ◽  
Nan Zhang
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Western Blotting ◽  
Squamous Cell ◽  
Critical Role ◽  
Lung Squamous Cell Carcinoma ◽  
Tumor Promoter ◽  
Domain Family ◽  
Yth Domain

Abstract Background N6-methyladenosine (m6A) is a dynamic and reversible internal RNA structure of eukaryotic mRNA. YTH domain family 2 (YTHDF2), an m6A-specific reader YTH domain family, plays fundamental roles in several types of cancer. However, the function of YTHDF2 in lung squamous cell carcinoma (LUSC) remains elusive. Methods Functionally, NCI-H226 and SK-MES-1 cells were exposed to hypoxia to detect the protein levels of hypoxia-inducible factor-1α (HIF-1α), endogenous YTHDF2, and phospho-AKT (Ser473) analyzed by western blotting and then the association of these proteins with LUSC was analyzed with a bioinformatics database. Next, we established stable YTHDF2 upregulation models in NCI-H226 and SK-MES-1 cells to explore the function of YTHDF2 in LUSC cells by performing in vitro and in vivo assays. Finally, we affirmed that YTHDF2 overexpression was involved in activating the mTOR/AKT signaling and inducing the EMT process in LUSC using western blotting. Clinically, immunohistochemical staining revealed the relationship between YTHDF2 expression levels and the clinicopathological characteristics of lung squamous cell carcinoma patients. Results The results showed that hypoxia-mediated YTHDF2, a tumor promoter, promoted cell proliferation and invasion by activating the mTOR/AKT axis and inducing the EMT process in LUSC. Moreover, YTHDF2 was closely associated with pN (pN– 37.0%, pN + 73.9%; P = 0.002) and pTNM stage (pI 50.0%, PII 43.3%, pIIIa 80.6%; P = 0.007), ultimately resulting in poor survival for LUSC patients. Conclusion In brief, the results highlight the critical role of YTHDF2 in both hypoxia exposure and the pathogenesis of LUSC.

scholarly journals Hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT axis

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Peng Xu ◽  
Kang Hu ◽  
Ping Zhang ◽  
Zhi-Gang Sun ◽  
Nan Zhang
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma ◽  
Akt Signaling ◽  
In Vitro Assays ◽  
Domain Family ◽  
Yth Domain

Abstract Background N6-methyladenosine (m6A) is a dynamic and reversible internal RNA structure of eukaryotic mRNA. YTH domain family 2 (YTHDF2), an m6A-specific reader YTH domain family, plays fundamental roles in several types of cancer. However, the function of YTHDF2 in lung squamous cell carcinoma (LUSC) remains elusive. Methods The knockdown and overexpression of YTHDF2 in LUSC cells were conducted to detect the biological characteristics of YTHDF2. In vivo assays, the role of YTHDF2 in tumor growth was further uncovered. In vitro assays, YTHDF2 was confirmed to be involved in activating the mTOR/AKT signaling and YTHDF2 overexpression induced the EMT process in LUSC. Clinically, immunohistochemical staining revealed the relationship between YTHDF2 expression levels and the clinicopathological characteristics of lung squamous cell carcinoma patients. Moreover, quantitative PCR (qPCR), western blot, CCK8 assay, transwell assay, and wound-healing assay were used to detect the expression level and function of YTHDF2 under hypoxia exposure in LUSC cells. Results The results showed that hypoxia-mediated YTHDF2 overexpression promotes cell proliferation and invasion by activating the mTOR/AKT axis, and YTHDF2 overexpression induces the EMT process in LUSC. Moreover, YTHDF2 is closely associated with pN (pN– 37.0%, pN + 73.9%; P = 0.002) and pTNM stage (pI 50.0%, PII 43.3%, pIIIa 80.6%; P = 0.007), ultimately resulting in poor survival for LUSC patients. Conclusion In brief, the results highlight high-YTHDF2 expression predicted a worse prognosis of LUSC, while hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT signaling pathway.

scholarly journals Design and Synthesis of Arf1-Targeting γ-Dipeptides as Potential Agents against Head and Neck Squamous Cell Carcinoma

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 286
Author(s):  
Yen Vo-Hoang ◽  
Sergio Paiva ◽  
Leilei He ◽  
Sébastien Estaran ◽  
Yong Teng
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Critical Role ◽  
In Vitro Cytotoxicity ◽  
Neck Squamous Cell Carcinoma ◽  
Protein Levels ◽  
Design And Synthesis

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer-related deaths and calls for new druggable targets. We have previously highlighted the critical role of ADP-ribosylation factor-1 (Arf1) activation in HNSCC. In the present study, we address the question whether targeting Arf1 could be proposed as a valuable strategy against HNSCC. Methods: We rationally designed and synthesized constrained ATC-based (4-amino-(methyl)-1,3-thiazole-5-carboxylic acid) γ-dipeptides to block Arf1 activation. We evaluated the effects of these γ-dipeptides in HNSCC cells: The cell viability was determined in 2D and 3D cell cultures after 72 h treatment and Arf1 protein levels and activity were assessed by GGA3 pull-down and Western blotting assays. Results: Targeting Arf1 offers a valuable strategy to counter HNSCC. Our new Arf1-targeting compounds revealed a strong in vitro cytotoxicity against HNSCC cells, through inhibiting Arf1 activation and its downstream pathways. Conclusions: Arf1-targeting γ-dipeptides developed in this study may represent a promising targeted therapeutic to improve managing the HNSCC disease.

scholarly journals Targeting SKA3 suppresses the proliferation and chemoresistance of laryngeal squamous cell carcinoma via impairing PLK1–AKT axis-mediated glycolysis

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Wei Gao ◽  
Yuliang Zhang ◽  
Hongjie Luo ◽  
Min Niu ◽  
Xiwang Zheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Laryngeal Squamous Cell Carcinoma ◽  
Critical Role ◽  
In Vivo Experiments ◽  
Potential Strategy

Abstract Spindle and kinetochore-associated complex subunit 3 (SKA3) is a well-known regulator of chromosome separation and cell division, which plays an important role in cell proliferation. However, the mechanism of SKA3 regulating tumor proliferation via reprogramming metabolism is unknown. Here, SKA3 is identified as an oncogene in laryngeal squamous cell carcinoma (LSCC), and high levels of SKA3 are closely associated with malignant progression and poor prognosis. In vitro and in vivo experiments demonstrate that SKA3 promotes LSCC cell proliferation and chemoresistance through a novel role of reprogramming glycolytic metabolism. Further studies reveal the downstream mechanisms of SKA3, which can bind and stabilize polo-like kinase 1 (PLK1) protein via suppressing ubiquitin-mediated degradation. The accumulation of PLK1 activates AKT and thus upregulates glycolytic enzymes HK2, PFKFB3, and PDK1, resulting in enhancement of glycolysis. Furthermore, our data reveal that phosphorylation at Thr360 of SKA3 is critical for its binding to PLK1 and the increase in glycolysis. Collectively, the novel oncogenic signal axis “SKA3-PLK1-AKT” plays a critical role in the glycolysis of LSCC. SKA3 may serve as a prognostic biomarker and therapeutic target, providing a potential strategy for proliferation inhibition and chemosensitization in tumors, especially for LSCC patients with PLK1 inhibitor resistance.

scholarly journals Vasohibin 2 Promotes Lymphangiogenesis of Lung Squamous Cell Carcinoma Through Snail-dependent VEGF-D Signaling Pathway

2020 ◽  
Author(s):  
Pengpeng Liu ◽  
Rui Zhang ◽  
Lei Han ◽  
Xiao Zhang ◽  
Yingnan Ye ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Endothelial Cells ◽  
Tumor Growth ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lymphatic Metastasis ◽  
Poor Prognosis ◽  
Lung Squamous Cell Carcinoma ◽  
Secondary Site

Abstract Backgroumd: Tumor metastasis is a process in which tumor cells enter the lymphatic vessels and blood vessels and then spread to the secondary site where they form secondary tumors. In vascular biology, angiogenesis and anti-angiogenesis therapy have been extensively studied, however, the molecular mechanisms involved in lymphangiogenesis and lymphatic metastasis remain unclear.Methods: We analyzed mRNA expression profiles of 937 primary lung squamous cell carcinoma (LUSC) samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to screen the most differentially expressed genes related to the poor prognosis of LUSC patients and validated in an independent Chinese LUSC cohort. We focused on Vasohibin 2 (VASH2) and investigated its biological functions in LUSC proliferation, apoptosis, migration, invasion, as well as lymphangiogenesis by forced over-expressing VASH2 in LUSC cell line H520 in vitro. We also investigated the anti-tumor efficacy of VASH2 target treatment in LUSC xenograft-bearing mice models.Results: We identified 12 genes closely related to poor prognosis of LUSC patients, among which VASH2 was validated in an independent Chinese LUSC cohort and displayed high potential of lymphatic metastasis. VASH2 promoted the proliferation and invasion of LUSC cells both in vitro and vivo. Forced over-expression of VASH2 in LUSC cells promoted the amplification and tube-formation of human umbilical vein endothelial cells (HUVECs) and human lymphatic endothelial cells (HLECs) cells via up-regulating vascular endothelial growth factor-D (VEGF-D) production which could be reversed by Snail inhibition. Furthermore, blocking VASH2/VEGF-D signaling using specific antibodies dramatically inhibited tumor growth in mice by interfering proliferation of cancer cells and lymphangiogenesis in tumor tissues. Conclusion: In conclusion, VASH2 facilitated lymphangiogenesis and tumor growth in a Snail-dependent manner which might serve as a novel biomarker for early diagnosis and prognosis prediction, as well as a potential therapeutic target in LUSC.Statement of conflict of interest: The authors declare no potential conflicts of interest.

MIR205HG facilitates carcinogenesis of lung squamous cell carcinoma in vitro revealed by long noncoding RNA profiling

2020 ◽  
Vol 52 (4) ◽  
pp. 371-381 ◽  
Author(s):  
Yan Chang ◽  
Xinying Xue ◽  
Chunsun Li ◽  
Wei Zhao ◽  
Yongfu Ma ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Noncoding Rna ◽  
Lung Squamous Cell Carcinoma ◽  
Clinical Samples ◽  
Lung Cancers ◽  
Rna Profiling ◽  
Whole Transcriptome Sequencing

Abstract As a subtype of non-small-cell lung cancer, lung squamous cell carcinoma (LUSC) accounts for one-fifth of all lung cancers. Unfortunately, no specific targetable aberration has yet been identified. Hence, it is of huge urgency and potential to identify aberrantly regulated genes in LUSC. Here, five pairs of LUSC samples and their corresponding adjacent tissues were subject to whole transcriptome sequencing. Our results showed that CTD-2562J17.6 and FENDRR were significantly downregulated while MIR205HG, LNC_000378, RP11-116G8.5, RP3-523K23.2, and RP5-968D22.1 were significantly upregulated in all five LUSC samples. Importantly, MIR205HG was upregulated in LUSC clinical samples as well as in LUSC cell lines. Interestingly, our results demonstrated that the expression level of MIR205HG is positively correlated with the malignancy. In addition, MIR205HG is required for LUSC cell growth and cell migration. Most importantly, our results showed that MIR205HG prohibits LUSC apoptosis via regulating Bcl-2 and Bax. Taken together, our data shed lights on the lncRNA regulatory nexus that controls the carcinogenesis of LUSC and provided potential novel diagnostic markers and therapeutic targets for LUSC.

Evaluation of the in vitro Chemosensitivity and Correlation with Clinical Outcomes in Lung Cancer using the ATP-TCA

2018 ◽  
Vol 18 (1) ◽  
pp. 139-145 ◽  
Author(s):  
Zhiyao Chen ◽  
Shichao Zhang ◽  
Sheng Ma ◽  
Chang Li ◽  
Chun Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Clinical Outcomes ◽  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma ◽  
Lung Cancer Patients ◽  
In Vitro Chemosensitivity

Background and Objective: Multiple drug resistance (MDR) to chemotherapeutic agents often leads to a failure to respond to chemotherapy. We utilized an in vitro chemosensitivity test to identify sensitive and effective chemotherapeutic drugs and further elucidated the correlation between the in vivo chemosensitivity and clinical outcomes. Methods: Here, we evaluated the in vitro chemosensitivity and MDR of 120 lung cancer patients to eight singledrug chemotherapies and of 291 lung cancer patients to seven chemotherapy regimens using an ATP-based tumor chemosensitivity assay (ATP-TCA). Additionally, the chemosensitivity profiles of lung adenocarcinoma patients (284 cases) and lung squamous cell carcinoma patients (90 cases) to these single-drug and chemotherapy regimens were compared. Furthermore, the correlations between the chemosensitivity and clinical outcomes were investigated in 16 stage III squamous cell carcinoma patients. Results and Conclusion: PTX (51.7%), TXT (43.3%), GEM (12.5%), PTX+DDP (62.5%), TXT+L-OHP (54.3%) and VP-16+DDP (16.2%) had the highest in vitro chemosensitivity rates. Approximately 31.7% of patients developed resistance to all eight single-drug chemotherapies, and 25.8% of patients displayed resistance to all seven chemotherapy regimens. In addition, lung squamous cell carcinoma was significantly more sensitive to GEM and MTA+DDP than lung adenocarcinoma (P<0.05). Further analysis showed that patients with higher drug sensitivity tended to have longer disease-free survival (18 months vs. 8.5 months) than patients displaying drug resistance (P<0.05). These results suggest that the implementation of in vitro drug susceptibility testing before chemotherapy can effectively prevent the occurrence of primary drug resistance and inappropriate drug treatment.

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