NFATc1 promotes epithelial-mesenchymal transition and facilitates colorectal cancer metastasis by targeting SNAI1

Shen, Tianli; Yue, Chenyang; Wang, Xingjie; Wang, Zijun; Wu, Yunhua; Zhao, Chenye; Chang, Peng; Sun, Xuejun; Wang, Wei

doi:10.1016/j.yexcr.2021.112854

Cited by 11 publications

(9 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Likely, gene copy number, epigenetic alterations, and microenvironment-derived stimulant regulate PD-1 expression in human cancer cells. [32][33][34][35][36] As c-Fos binds to the AP-1-binding site and activates Pdcd1 transcription in tumor-infiltrating T cells, 29 Fos reduction was retrieved among the genes regulated in NIVO-treated colon cancer cells. Also, FOXO4 and FOXO3 were regulated by NIVO treatment in human colon cancer cells, mechanism previously reported for FOXO1 in antigen-specific CD8 +T cells during chronic lymphocytic choriomeningitis virus infection.…”

Section: Discussionmentioning

confidence: 99%

In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies

Ieranò

Righelli

D’Alterio

et al. 2022

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundColorectal cancer (CRC) is one of the most prevalent and deadly tumors worldwide. The majority of CRC is resistant to anti-programmed cell death-1 (PD-1)-based cancer immunotherapy, with approximately 15% with high-microsatellite instability, high tumor mutation burden, and intratumoral lymphocytic infiltration. Programmed death-ligand 1 (PD-L1)/PD-1 signaling was described in solid tumor cells. In melanoma, liver, and thyroid cancer cells, intrinsic PD-1 signaling activates oncogenic functions, while in lung cancer cells, it has a tumor suppressor effect. Our work aimed to evaluate the effects of the anti-PD-1 nivolumab (NIVO) on CRC cells.MethodsIn vitro NIVO-treated human colon cancer cells (HT29, HCT116, and LoVo) were evaluated for cell growth, chemo/radiotherapeutic sensitivity, apoptosis, and spheroid growth. Total RNA-seq was assessed in 6–24 hours NIVO-treated human colon cancer cells HT29 and HCT116 as compared with NIVO-treated PES43 human melanoma cells. In vivo mice carrying HT29 xenograft were intraperitoneally treated with NIVO, OXA (oxaliplatin), and NIVO+OXA, and the tumors were characterized for growth, apoptosis, and pERK1/2/pP38. Forty-eight human primary colon cancers were evaluated for PD-1 expression through immunohistochemistry.ResultsIn PD-1+ human colon cancer cells, intrinsic PD-1 signaling significantly decreased proliferation and promoted apoptosis. On the contrary, NIVO promoted proliferation, reduced apoptosis, and protected PD-1+ cells from chemo/radiotherapy. Transcriptional profile of NIVO-treated HT29 and HCT116 human colon cancer cells revealed downregulation of BATF2, DRAM1, FXYD3, IFIT3, MT-TN, and TNFRSF11A, and upregulation of CLK1, DCAF13, DNAJC2, MTHFD1L, PRPF3, PSMD7, and SCFD1; the opposite regulation was described in NIVO-treated human melanoma PES43 cells. Differentially expressed genes (DEGs) were significantly enriched for interferon pathway, innate immune, cytokine-mediated signaling pathways. In vivo, NIVO promoted HT29 tumor growth, thus reducing OXA efficacy as revealed through significant Ki-67 increase, pERK1/2 and pP38 increase, and apoptotic cell reduction. Eleven out of 48 primary human colon cancer biopsies expressed PD-1 (22.9%). PD-1 expression is significantly associated with lower pT stage.ConclusionsIn PD-1+ human colon cancer cells, NIVO activates tumor survival pathways and could protect tumor cells from conventional therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies

Ieranò

Righelli

D’Alterio

et al. 2022

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…[32] Besides, SNAI1 have a positive effect on the development and invasion of various tumors through inducing EMT. [33][34][35] In addition, IRX1, a member of the iroquois homeobox transcription factor family, has been identified as a tumor suppressor in several cancers, including lung adenocarcinoma, gastric cancer and invasive ductal carcinoma. [36][37][38][39] In our study, we found that high expressions of CDKN2A, SCD and SNAI1 were closely related to the poor prognosis, which was consistent with previous studies.…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of a prognostic anoikis-related gene signature in papillary thyroid carcinoma by integrated analysis of single-cell and bulk RNA-sequencing

Zheng,

Zhang,

et al. 2024

Medicine

View full text Add to dashboard Cite

Papillary thyroid carcinoma (PTC) prognosis may be deteriorated due to the metastases, and anoikis palys an essential role in the tumor metastasis. However, the potential effect of anoikis-related genes on the prognosis of PTC was unclear. The mRNA and clinical information were obtained from the cancer genome atlas database. Hub genes were identified and risk model was constructed using Cox regression analysis. Kaplan–Meier (K–M) curve was applied for the survival analysis. Immune infiltration and immune therapy response were calculated using CIBERSORT and TIDE. The identification of cell types and cell interaction was performed by Seurat, SingleR and CellChat packages. GO, KEGG, and GSVA were applied for the enrichment analysis. Protein-protein interaction network was constructed in STRING and Cytoscape. Drug sensitivity was assessed in GSCA. Based on bulk RNA data, we identified 4 anoikis-related risk signatures, which were oncogenes, and constructed a risk model. The enrichment analysis found high risk group was enriched in some immune-related pathways. High risk group had higher infiltration of Tregs, higher TIDE score and lower levels of monocytes and CD8 T cells. Based on scRNA data, we found that 4 hub genes were mainly expressed in monocytes and macrophages, and they interacted with T cells. Hub genes were significantly related to immune escape-related genes. Drug sensitivity analysis suggested that cyclin dependent kinase inhibitor 2A may be a better chemotherapy target. We constructed a risk model which could effectively and steadily predict the prognosis of PTC. We inferred that the immune escape may be involved in the development of PTC.

show abstract

“…Genes that appear to have interactions with the SNAI1 network in the STRING analysis have been reported to induce drug resistance, SNAI1 upregulation/activation, antitumor immune suppression and p53 antitumor mechanisms inhibition: the drug resistance genes set SORT1, 31–33 INPP4B, 32,34,35 PADI4, 36,37 AKT3, 38,39 EPAS1 (HIF2‐ α ), 40,41 TUBB2A, 42–44 ALOX5, 45 SPP1, 46 LMO4, 47,48 S100B 49 and JUN 50 ; and the immunomodulatory genes CCL23, 51 DPP4, 52,53 IL15, 54 MAF, 55 NFATC1, 56 STAT1, 57 CXCL10, 58 IRF1, 59 GZMB, 60 IDO1 61 and FoxP3, 62 except for MRC1, 63 PD‐L1 64 and BCL2, 65 which were upregulated by SNAI1, and PTEN, which was downregulated by SNAI1 65 . It seems that the upregulation of SNAI1 by these drug resistance and immunomodulatory genes is due to its synergetic effect in targeting and inhibiting p53 66 as well as the important role of SNAI1 in activating PI3K and ERKs signaling pathways responsible for developing intrinsic drug resistance and antitumor immune response suppression phenotypes 67 .…”

Section: Discussionmentioning

confidence: 99%

Bone marrow overexpression of SNAI1 is an early indicator of intrinsic drug resistance in patients with de novo acute myeloid leukemia

Gouda

Hassan

Kandil

2023

The Journal of Gene Medicine

View full text Add to dashboard Cite

Background: The lack of effectiveness of acute myeloid leukemia (AML) treatment remains a major challenge and resembles a principal cause of AML-related mortality owing to chemotherapy resistance. SNAI1 has been proved to be a leading factor in drug resistance in many cancer types. However, its relation to chemoresistance in AML is not well understood.Methods: In addition to standard lab work, the expression level of SNAI1 was determined in bone marrow samples of 109 adult and pediatric patients with de novo acute myeloid leukemia using RT-qPCR. The relation between SNAI1 and AML drug resistance and immunomodulatory genes was investigated using the STRING tool.Results: The SNAI1 expression level was upregulated in AML patients in particular samples with promyelocytic leukemia subtype against control cases. In the treatment response, SNAI1 was significantly higher in resistant patients in comparison with the complete remission group. SNAI1 overexpression was associated with high initial blasts and total leukocyte counts, but with HLA class II histocompatibility antigen DR downregulation. STRING analysis showed that multiple drug resistance and immunomodulatory genes of AML induce SNAI upregulation and activation. Kaplan-Meier analysis indicated that there was no relation between SNAI1 expression level and patient survival status. Conclusion:We conclude that the SNAI1 expression level may be a predictor of intrinsic drug resistance incidence in AML patients.acute myeloid leukemia (AML), drug resistance, HLA class II histocompatibility antigen DR (HLA-DR), immune suppression, promyelocytic leukemia (APL, AML-M3), retinoic acid receptor alpha (RAR-α), zinc finger protein SNAI1 | INTRODUCTIONAcute myeloid leukemia (AML) is a very heterogeneous malignant disease that exhibits uncontrolled clonal expansion of immature myeloid cells and ends in failure of normal hematopoiesis. 1 Leukemogenesis is thought to principally result from the accumulation of many genomic translocations and genetic mutations in hematopoietic stem cells during aging. 2 The AML incidence rate is considered to be three to five cases per 100,000 population and 68 years is the median age of diagnosis. The AML incidence rate does not change regarding race and ethnicity, but it is more common in men than women. Despite the advances in understanding the molecular mechanisms of AML development and in therapies that target it, standard AML induction regimens have remained unchanged for decades. A few years ago, new

show abstract

NFATc1 promotes epithelial-mesenchymal transition and facilitates colorectal cancer metastasis by targeting SNAI1

Cited by 11 publications

References 37 publications

In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies

In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies

Identification and validation of a prognostic anoikis-related gene signature in papillary thyroid carcinoma by integrated analysis of single-cell and bulk RNA-sequencing

Bone marrow overexpression of SNAI1 is an early indicator of intrinsic drug resistance in patients with de novo acute myeloid leukemia

Contact Info

Product

Resources

About