ERK1/2 Signaling Induces Upregulation of ANGPT2 and CXCR4 to Mediate Liver Metastasis in Colon Cancer

Urosevic, Jelena; Blasco, Maria; Lope, Alicia Llorente; Bellmunt, Anna; Berenguer‐Llergo, Antoni; Guiu, Marc; Cañellas, Adrià; Fernández, Esther; Burkov, Ivan; Clapés, Maria; Cartanà, Mireia; Figueras-Puig, Cristina; Batlle, Eduard; Nebreda, Ángel R.; Gomis, Roger R.

doi:10.1158/0008-5472.can-19-4028

Cited by 40 publications

(31 citation statements)

References 60 publications

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“… 39 , 40 In addition, CXCR4 has a role in cancer metastasis via activating the mitogen-activated protein kinase (MAPK) pathway. 41 Increased expression of CXCR4 in stromal cells and TME is also related to epithelial-mesenchymal transition and drug resistance. 42 The unexpected inhibitory effects of USMB-shMincle in the protumoral activities of TME should be investigated further, which may represent important information for its translational development.…”

Section: Discussionmentioning

confidence: 99%

USMB-shMincle: a virus-free gene therapy for blocking M1/M2 polarization of tumor-associated macrophages

Xue

Chung

Tang

et al. 2021

Molecular Therapy - Oncolytics

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Mincle is essential for tumor-associated macrophage (TAM)-driven cancer progression and represents a potential immunotherapeutic target for cancer. Nevertheless, the lack of a specific inhibitor has largely limited its clinical translation. Here, we successfully developed a gene therapeutic strategy for silencing Mincle in a virus-free and tumor-specific manner by combining RNA interference technology with an ultrasound-microbubble-mediated gene transfer system (USMB). We identified a small hairpin RNA (shRNA) sequence shMincle that can silence not only Mincle expression but also the protumoral effector production in mouse bone marrow- and human THP-1-derived macrophages in the cancer setting in vitro . By using our well-established USMB system (USMB-shMincle), the shMincle-expressing plasmids were delivered in a tissue-specific manner into xenografts of human lung carcinoma A549 and melanoma A375 in vivo . Encouragingly, we found that USMB-shMincle effectively inhibited the protumoral phenotypes of TAMs as well as the progression of both A549 and A375 xenografts in a dose-dependent manner in mice without significant side effects. Mechanistically, we identified that USMB-shMincle markedly enhanced the anticancer M1 phenotype of TAMs in the A549 and A375 xenografts by blocking the protumoral Mincle/Syk/nuclear factor κB (NF-κB) signaling axis. Thus, USMB-shMincle may represent a clinically translatable novel and safe gene therapeutic approach for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

USMB-shMincle: a virus-free gene therapy for blocking M1/M2 polarization of tumor-associated macrophages

Xue

Chung

Tang

et al. 2021

Molecular Therapy - Oncolytics

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“…ERK1/2 (extracellular regulated protein kinase 1/2) is a member of MAPK (mitogen activated protein kinase) family. p-ERK1/2 (phosphorylated ERK1/2) can transfer to the nucleus, regulate the activity of transcription factors, and ultimately change the metabolism and function of cells and participate in forming malignant tumor cells [54][55][56]. In lung cancer, tumor cell-intrinsic PD-1 is a tumor suppressor that inhibits the activation of AKT and ERK1/2 and thereby inhibits tumor cell growth [57].…”

Section: Tumor Cell-intrinsic Pd-1 Inhibits Akt and Erk1/2 Pathwaysmentioning

confidence: 99%

New insights into the important roles of tumor cell-intrinsic PD-1

Zheng¹,

Ning²,

Zhan³

et al. 2021

Int. J. Biol. Sci.

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PD-1 (Programmed cell death protein-1) is mainly expressed in various immune cells, while its ligands PD-L1/PD-L2 (Programmed death ligand-1/Programmed death ligand-2) are mostly expressed in tumor cells. Generally, the binding of PD-L1/PD-L2 and PD-1 could lead to the tumor immune evasion. However, some recent studies showed that PD-1 could also be expressed in tumor cells and could activate mTOR (Mammalian Target of Rapamycin) or Hippo signaling pathway, therefore facilitating tumor proliferation independent of the immune system. While there was evidence that tumor cell-intrinsic PD-1 inhibited the activation of AKT and ERK1/2 pathways, thereby inhibiting tumor cell growth. Based on TCGA and CCLE database, we found that PD-1 was expressed in a variety of tumors and was associated with patient's prognosis. Besides, we found that PD-1 may be involved in many carcinogenic signaling pathway on the basis of PD-1 gene enrichment analysis of cancer tissues and cancer cells. Our understanding of the tumor cell-intrinsic PD-1 function is still limited. This review is aimed at elaborating the potential effects of tumor cell-intrinsic PD-1 on carcinogenesis, providing a novel insight into the effects of anti-PD-1/PD-L1 immunotherapy, and helping to open a major epoch of combination therapy.

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“…Breast cancer was characterized by down-regulation of catalase and concomitant overexpression of SOD (Wang et al 2017). On the other hand, upregulation of ANGPT2 was associated with liver metastasis in colon cancer (Urosevic et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion

et al. 2021

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TP53 (p53) is a pivotal player in tumor suppression with fifty percent of all invasive tumors displaying mutations in the TP53 gene. In the present study, we characterized colon cancer cells (HCT116 p53 −/−) with TP53 deletion, a sub-line derived from HCT116-p53 +/+ cells. RNA sequencing and network analyses were performed to identify novel drug resistance mechanisms. Chromosomal aberrations were identified by multicolor fluorescence in situ hybridization (mFISH) and array comparative genomic hybridization (aCGH). Numerous genes were overexpressed in HCT116 p53 −/− cells: RND3/RhoE (235.6-fold up-regulated), DCLK1 (60.2-fold up-regulated), LBH (31.9-fold up-regulated), MYB (28.9-fold up-regulated), TACSTD2 (110.1-fold down-regulated), NRIP1 (81.5-fold down-regulated) and HLA-DMB (69.7-fold down-regulated) are among the identified genes with potential influence on multidrug resistance (MDR) and they are associated with cancer progression and tumorigenesis, according to previously published studies. Probably due to TP53 deletion, disturbances in DNA repair and apoptosis are leading to aberrancies in cellular and organismal organization, ultimately increasing tumorigenesis and cancer progression potential. With NFκB, PI3K and HSP70, being at the center of merged protein network, and TH1-2 pathways, being among the influenced pathways, it can be speculated that the inflammatory pathway contributes to a resistance phenotype together with cell cycle regulation and heat-shock response. HCT116-p53 −/− cells have more chromosomal aberrations, gains and losses in copy numbers than HCT116-p53 +/+ cells. In conclusion, numerous genomic aberrations, which might be associated with yet unknown drug resistance mechanisms, were identified. This may have important implications for future treatment strategies.

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ERK1/2 Signaling Induces Upregulation of ANGPT2 and CXCR4 to Mediate Liver Metastasis in Colon Cancer

Cited by 40 publications

References 60 publications

USMB-shMincle: a virus-free gene therapy for blocking M1/M2 polarization of tumor-associated macrophages

USMB-shMincle: a virus-free gene therapy for blocking M1/M2 polarization of tumor-associated macrophages

New insights into the important roles of tumor cell-intrinsic PD-1

Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion

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