FSCN1 Promotes Radiation Resistance in Patients With PIK3CA Gene Alteration

Li, Sisi; Huang, Xiaoting; Wang, Mengyao; Chen, Dongping; Li, Mingyi; Zhu, Yan-Yi; Yu, Yi; Zheng, Lu; Qi, Bin; Liu, Jin-quan

doi:10.3389/fonc.2021.653005

Cited by 7 publications

(9 citation statements)

References 36 publications

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“…International Publisher pathogenesis molecular mechanisms and new therapeutic targets are essential [8,9].…”

Section: Ivyspringmentioning

confidence: 99%

Integrative Analyses of m6A Regulators Identify that METTL3 is Associated with HPV Status and Immunosuppressive Microenvironment in HPV-related Cancers

Yu¹,

Ye²,

He³

et al. 2022

Int. J. Biol. Sci.

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Although m6A modifications are associated with tumor progression, and anti-tumor immune responses, the role of m6A regulators in HPV-related carcinogenesis has not been well resolved. To provide evidence for the role of m6A regulators in HPV-related carcinogenesis and identify potential therapeutic targets for HPV-related cancers, integrative analyses of m6A regulators in 1,485 head and neck squamous cell carcinoma (HNSC) patients and 507 cervical squamous cell carcinoma (CESC) patients was performed and identified that an m6A regulator, METTL3, was highly expressed in tumors and was related to the poor prognosis in HNSC and CESC. In HPV-positive tumors, METTL3 was positively associated with tumor HPV status, such as HPV integration status, E6 and unspliced-E6 expression, and p16 expression. Further analysis demonstrated that METTL3 high status was negatively correlated with tumor immune cell infiltrations and facilitated the expression of immunosuppressive immune checkpoint molecules (i.e., PD-L1). Cell-derived xenograft models demonstrated that METTL3 inhibitor combined with anti-PD1 therapy promoted immunotherapy of CESC in vivo. Overall, this study identified that METTL3 high status, is associated with poor prognosis and HPV status, and serves as a mediator of the immunosuppressive tumor microenvironment in HPV-associated cancer, which provides a promising therapeutic target for anti-cancer immunotherapy.

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“…International Publisher pathogenesis molecular mechanisms and new therapeutic targets are essential [8,9].…”

Section: Ivyspringmentioning

confidence: 99%

Integrative Analyses of m6A Regulators Identify that METTL3 is Associated with HPV Status and Immunosuppressive Microenvironment in HPV-related Cancers

Yu¹,

Ye²,

He³

et al. 2022

Int. J. Biol. Sci.

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“…The 13q12.3 amplification in C1 contained HMGB1, which could promote the development of MDSC and the metastasis of cancer cells ( Gorgulho et al, 2019 ; Ren et al, 2021 ). FSCN1 amplification at 7p22.1, Gab2 amplification at 11q14.1, and CD44 amplification at 11p13 were also associated with promoting tumor invasion ( Ke et al, 2007 ; Li et al, 2018 ; Rohani et al, 2019 ) and inducing tumor resistance to radiotherapy ( Li et al, 2021 ), suggesting that patients with C1 had high immune suppression, active EMT, and may not be suitable for radiation therapy. The 19q13.42 amplification of C2 contained NLRP3, which could upregulate the expression of PD-L1 to form immunosuppression ( Lu et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Multi-Omics Characterization of Tumor Microenvironment Heterogeneity and Immunotherapy Resistance Through Cell States–Based Subtyping in Bladder Cancer

Tao

et al. 2022

Front. Cell Dev. Biol.

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Due to the strong heterogeneity of bladder cancer (BC), there is often substantial variation in the prognosis and efficiency of immunotherapy among BC patients. For the precision treatment and assessment of prognosis, the subtyping of BC plays a critical role. Despite various subtyping methods proposed previously, most of them are based on a limited number of molecules, and none of them is developed on the basis of cell states. In this study, we construct a single-cell atlas by integrating single cell RNA-seq, RNA microarray, and bulk RNA-seq data to identify the absolute proportion of 22 different cell states in BC, including immune and nonimmune cell states derived from tumor tissues. To explore the heterogeneity of BC, BC was identified into four different subtypes in multiple cohorts using an improved consensus clustering algorithm based on cell states. Among the four subtypes, C1 had median prognosis and best overall response rate (ORR), which characterized an immunosuppressive tumor microenvironment. C2 was enriched in epithelial-mesenchymal transition/invasion, angiogenesis, immunosuppression, and immune exhaustion. Surely, C2 performed the worst in prognosis and ORR. C3 with worse ORR than C2 was enriched in angiogenesis and almost nonimmune exhaustion. Displaying an immune effective environment, C4 performed the best in prognosis and ORR. We found that patients with just an immunosuppressive environment are suitable for immunotherapy, but patients with an immunosuppressive environment accompanied by immune exhaustion or angiogenesis may resist immunotherapy. Furthermore, we conducted exploration into the heterogeneity of the transcriptome, mutational profiles, and somatic copy-number alterations in four subtypes, which could explain the significant differences related to cell states in prognosis and ORR. We also found that PD-1 in immune and tumor cells could both influence ORR in BC. The level of TGFβ in a cell state can be opposite to the overall level in the tissues, and the level in a specific cell state could predict ORR more accurately. Thus, our work furthers the understanding of heterogeneity and immunotherapy resistance in BC, which is expected to assist clinical practice and serve as a supplement to the current subtyping method from a novel perspective of cell states.

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“…High FSCN1 expression has been revealed to be associated with worse outcomes in HCC ( 48 ). Increasing evidence showed that FSCN1 is involved in cell proliferation, apoptosis, motility, chemotherapeutic resistance, tumor growth, and metastasis of several malignancies ( 49 , 50 ). PI3K/AKT pathway was revealed by several reports to be a critical downstream target of FSCN1 ( 51 , 52 ).…”

Section: Resultsmentioning

confidence: 99%

“…Conversely to ADORA2A-AS1, high expression of FSCN1 was correlated with poor outcome of HCC patients (48). FSCN1 was documented to exert oncogenic roles in several malignancies, including HCC (49,50). For example, FSCN1 was reported to promote HCC cellular proliferation, migration, and invasion, inhibit HCC cellular apoptosis, and increase HCC cellular doxorubicin resistance (55)(56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

ADORA2A-AS1 Restricts Hepatocellular Carcinoma Progression via Binding HuR and Repressing FSCN1/AKT Axis

Zhang

Wang

et al. 2021

Front. Oncol.

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BackgroundHepatocellular carcinoma (HCC) is one of the most aggressive malignancies. Increasing evidence revealed that long noncoding RNAs (lncRNAs) were frequently involved in various malignancies. Here, we explored the clinical significances, roles, and mechanisms of lncRNA ADORA2A antisense RNA 1 (ADORA2A-AS1) in HCC.MethodsThe clinical significances of ADORA2A-AS1 in HCC were analyzed using RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) project. The expressions of ADORA2A-AS1, Fascin Actin-Bundling Protein 1 (FSCN1), Matrix Metallopeptidase 2 (MMP2), and Baculoviral IAP Repeat Containing 7 (BIRC7) in HCC tissues and cells were measured by qRT-PCR. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2’-deoxyuridine (EdU), caspase-3 activity assay, transwell migration and invasion assays, and xenograft growth and metastasis experiments were performed to evaluate the roles of ADORA2A-AS1 in HCC. RNA pull-down, RNA immunoprecipitation, qRT-PCR, Western blot, and RNA stability assay were performed to elucidate the mechanisms of ADORA2A-AS1 in HCC.ResultsADORA2A-AS1 was identified as an HCC-related lncRNA, whose low expression was correlated with advanced stage and poor outcome in HCC. Gain- and loss-of functional experiments demonstrated that ADORA2A-AS1 inhibited HCC cell proliferation, induced cell apoptosis, repressed cell migration and invasion, and repressed xenograft growth and metastasis in vivo. Mechanistically, ADORA2A-AS1 competitively bound HuR (Hu Antigen R), repressed the binding of HuR to FSCN1 transcript, decreased FSCN1 transcript stability, and downregulated FSCN1 expression. The expression of FSCN1 was negatively correlated with ADORA2A-AS1 in HCC tissues. Through downregulating FSCN1, ADORA2A-AS1 repressed AKT pathway activation. Functional rescue assays showed that blocking of FSCN1/AKT axis abrogated the roles of ADORA2A-AS1 in HCC.ConclusionLow-expression ADORA2A-AS1 is correlated with poor survival of HCC patients. ADORA2A-AS1 exerts tumor-suppressive roles in HCC via binding HuR and repressing FSCN1/AKT axis.

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FSCN1 Promotes Radiation Resistance in Patients With PIK3CA Gene Alteration

Cited by 7 publications

References 36 publications

Integrative Analyses of m6A Regulators Identify that METTL3 is Associated with HPV Status and Immunosuppressive Microenvironment in HPV-related Cancers

Integrative Analyses of m6A Regulators Identify that METTL3 is Associated with HPV Status and Immunosuppressive Microenvironment in HPV-related Cancers

Multi-Omics Characterization of Tumor Microenvironment Heterogeneity and Immunotherapy Resistance Through Cell States–Based Subtyping in Bladder Cancer

ADORA2A-AS1 Restricts Hepatocellular Carcinoma Progression via Binding HuR and Repressing FSCN1/AKT Axis

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