Oncogenes in immune cells as potential therapeutic targets

Zakiryanova, Gulnur K.; Wheeler, Sarah; Shurin, Michael R.

doi:10.2147/itt.s150586

Cited by 16 publications

(9 citation statements)

References 86 publications

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“…Assuming that the defects in the immune system may, at least in certain cases, precede the appearance of cancer, we hypothesized that proto-oncogenes in immune cells may also be associated with immune defects in cancer [5]. For example, the c-Myc proto-oncogene is frequently activated in a diversity of malignant cells and plays an important role in cellular differentiation, proliferation, apoptosis and cell cycle progression [6].…”

Section: Introductionmentioning

confidence: 99%

Abnormal Expression of c-Myc Oncogene in NK Cells in Patients with Cancer

Zakiryanova

Kustova

Urazalieva

et al. 2019

IJMS

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Natural killer (NK) cells have received a lot of attention in recent years for the roles they play in immunity and particularly in antitumor immune responses. Although defects in NK cell functions are recognized as important mechanisms for immune evasion of malignant cells, molecular pathways regulating NK cell dysfunction and exhaustion in cancer are largely unknown. Here we tested whether the c-myc proto-oncogene, known to promote cell proliferation, growth, differentiation, and apoptosis by regulating the expression of numerous target genes, may be involved in the mechanism of NK cell abnormalities in patients with lung and gastric cancer. Analysis of c-myc mRNA and protein expression in peripheral blood NK cells, mitogen-activated protein kinase (MAPK) activity, cell cycle, and cell longevity revealed a significantly decreased expression of c-myc mRNA and protein and mitotic arrest of NK cells in different phases of cell cycle. In addition, a significant decrease of NK cell death was also detected. These data allow the suggestion that defects of NK cell-mediated tumor surveillance may be associated with disturbed c-myc expression in NK cells in cancer patients. A better understanding of the mechanisms of NK cell dysfunction in cancer will help in the NK cell-mediated therapeutic eradication of primary and metastatic cancer cells and prolong patient survival.

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Section: Introductionmentioning

confidence: 99%

Abnormal Expression of c-Myc Oncogene in NK Cells in Patients with Cancer

Zakiryanova

Kustova

Urazalieva

et al. 2019

IJMS

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“…c-MYC is one of the most studied final targets of the Wnt/β-catenin pathway. It is a protooncogene involved in cell cycle progression [ 51 ] whose deregulation has been linked to an aberrant Wnt/β-catenin pathway expression in CRC [ 52 ]. WISP1 has been identified as an oncogene in several cancer types such as glioblastoma [ 53 ], CRC [ 54 ], and colon cancer [ 55 ], with involvement in tumor proliferation, migration, and poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

5-aza-2′-deoxycitidine inhibits cell proliferation, extracellular matrix formation and Wnt/β-catenin pathway in human uterine leiomyomas

Carbajo-García

Corachán

Segura-Benítez

et al. 2021

Reprod Biol Endocrinol

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Background Uterine leiomyoma is a benign tumor with unclear pathogenesis and inaccurate treatment. This tumor exhibits altered DNA methylation related to disease progression. DNMT inhibitors as 5-aza-2′-deoxycytidine (5-aza-CdR), have been suggested to treat tumors in which DNA methylation is altered. We aimed to evaluate whether DNA methylation reversion with 5-aza-CdR reduces cell proliferation and extracellular matrix (ECM) formation in uterine leiomyoma cells to provide a potential treatment option. Methods Prospective study using uterine leiomyoma and adjacent myometrium tissues and human uterine leiomyoma primary (HULP) cells (n = 16). In tissues, gene expression was analyzed by qRT-PCR and DNMT activity by ELISA. Effects of 5-aza-CdR treatment on HULP cells were assessed by CellTiter, western blot, and qRT-PCR. Results DNMT1 gene expression was higher in uterine leiomyoma vs myometrium. Similarly, DNMT activity was greater in uterine leiomyoma and HULP cells (6.5 vs 3.8 OD/h/mg; 211.3 vs 63.7 OD/h/mg, respectively). After 5-aza-CdR treatment on HULP cells, cell viability was reduced, significantly so at 10 μM (85.3%). Treatment with 10 μM 5-aza-CdR on HULP cells significantly decreased expression of proliferation marker PCNA (FC = 0.695) and of ECM proteins (COLLAGEN I FC = 0.654; PAI-1, FC = 0.654; FIBRONECTIN FC = 0.733). 5-aza-CdR treatment also decreased expression of Wnt/β-catenin pathway final targets, including WISP1 protein expression (10 μM, FC = 0.699), c-MYC gene expression (2 μM, FC = 0.745 and 10 μM, FC = 0.728), and MMP7 gene expression (5 μM, FC = 0.520 and 10 μM, FC = 0.577). Conclusions 5-aza-CdR treatment inhibits cell proliferation, ECM formation, and Wnt/β-catenin signaling pathway targets in HULP cells, suggesting that DNA methylation inhibition is a viable therapeutic target in uterine leiomyoma.

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“…We Colorectal cancer is a heterogeneous disease caused by the interaction of many different oncogenes (4). And the immune system is also regulated by these oncogenes, which promotes tumor immune escape and reduces the effectiveness of immunosuppressive agents (43).…”

Section: Discussionmentioning

confidence: 99%

The pathological significance of abnormal RON and PD-L1 expression in colorectal cancer

Liu¹,

Han²,

Shi³

et al. 2020

Preprint

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Background: PD-L1 immunotherapy remains poorly efficacious in colorectal cancer. The RON receptor tyrosine kinase plays an important role in regulating tumor immunity. Here, we identify patterns of RON and PD-L1 expression and explore the clinical significance of these patterns in colorectal cancer. Methods: Gene expression data were obtained from the Gene Expression Omnibus database (GEO; n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZUSM; n = 381) and were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor cells and the tumor microenvironment of colorectal cancer. Human colorectal cancer cell lines were treated with BMS-777607 to explore the relationship between RON activity and PD-L1 protein expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and western blot. Results: In the GEO cohort, cut-off values for RON and PD-L1 expression of 7.70 and 4.30, respectively, were determined. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 associated with poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and in tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121 (32%), 43 (11%), 91 (24%), and 51 (13.4%), respectively. High expression of RON and high expression of PD-L1 in the tumor cell compartment was significantly correlated (p < 0.001). High expression of RON and PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with poor prognosis. In vitro , BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in colorectal cancer cells. Conclusions: RON, PD-L1 and the crosstalk between these proteins plays an important role in predicting the prognostic value of colorectal cancer. Moreover, phosphorylation of RON upregulates the expression of PD-L1, which provides a novel approach to immunotherapy in colorectal cancer.

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Oncogenes in immune cells as potential therapeutic targets

Cited by 16 publications

References 86 publications

Abnormal Expression of c-Myc Oncogene in NK Cells in Patients with Cancer

Abnormal Expression of c-Myc Oncogene in NK Cells in Patients with Cancer

5-aza-2′-deoxycitidine inhibits cell proliferation, extracellular matrix formation and Wnt/β-catenin pathway in human uterine leiomyomas

The pathological significance of abnormal RON and PD-L1 expression in colorectal cancer

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