NRAGE confers poor prognosis and promotes proliferation, invasion, and chemoresistance in gastric cancer

Jiang, Xiaodi; Jiang, Xiaofeng; Yang, Zhi

doi:10.1016/j.gene.2018.05.060

Cited by 10 publications

(9 citation statements)

References 29 publications

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“…In endometrial [16], gastric [17], colon [18], and breast cancers [19], MEK/ERK1/2 causes a multi-drug resistant phenotype by up-regulating anti-apoptotic proteins of the Bcl-2 family. In breast tumors, the mechanism can be reversed by miR-27b, which down-regulates Casitas B-lineage lymphoma proto-oncogene-b ( CBLB ) and GRB2 genes, two up-stream controllers of ERK [19].…”

Section: Erks Mediate the Resistance To Chemotherapymentioning

confidence: 99%

“…The ability of cancer cells to adapt to unfavorable environmental conditions confers a selective advantage in terms of survival and proliferation over normal cells [14,15]. ERK1/2 has been reported to mediate resistance to chemotherapy in endometrial [16], gastric [17], colon [18], breast [19], ovarian [20], liver [21], oesophageal [22], prostate [23], non small [24] and small cell lung [25] cancers, osteosarcomas [26], neuroblastomas [27], gliomas [28], and T-cell acute lymphoblastic leukemias [29]. ERK1/2 also promotes an immune-evasive phenotype in colon [30], breast [31], prostate [32], liver [33], non small cell lung [34] cancers, pleural malignant mesotheliomas [35], gastrointestinal sarcomas [36], Lewis lung carcinomas and melanomas [37], and glioblastomas [38].…”

Section: Introductionmentioning

confidence: 99%

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ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer

Salaroglio

Mungo

Gazzano

et al. 2019

IJMS

102

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The extracellular signal-related kinases (ERKs) act as pleiotropic molecules in tumors, where they activate pro-survival pathways leading to cell proliferation and migration, as well as modulate apoptosis, differentiation, and senescence. Given its central role as sensor of extracellular signals, ERK transduction system is widely exploited by cancer cells subjected to environmental stresses, such as chemotherapy and anti-tumor activity of the host immune system. Aggressive tumors have a tremendous ability to adapt and survive in stressing and unfavorable conditions. The simultaneous resistance to chemotherapy and immune system responses is common, and ERK signaling plays a key role in both types of resistance. In this review, we dissect the main ERK-dependent mechanisms and feedback circuitries that simultaneously determine chemoresistance and immune-resistance/immune-escape in cancer cells. We discuss the pros and cons of targeting ERK signaling to induce chemo-immune-sensitization in refractory tumors.

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Section: Erks Mediate the Resistance To Chemotherapymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer

Salaroglio

Mungo

Gazzano

et al. 2019

IJMS

102

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“…25 Interestingly, previous studies have reported that the ERK/MAPK signaling pathways mediate chemoresistance with various mechanisms, including increased cell proliferation and reduced cell apoptosis. In breast, 29 gastric, 30 colon and endometrial cancers, 31,32 ERK1/2 induces a multi-drug resistant phenotype by increasing anti-apoptotic proteins belonging to the Bcl-2 family. Moreover, increased cell growth and decreased apoptosis induced by ERK1/2 also causes resistance to various chemotherapeutic drugs in ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have reported that the ERK/MAPK signaling pathways mediate chemoresistance with various mechanisms, including increased cell proliferation, and reduced cell apoptosis. [29][30][31][32][33] To discover the molecular mechanism of GRHL2-regulated chemoresistance in SOC, we conducted Western blot assays to confirm the effects of GRHL2 on ERK/MAPK signaling pathways.…”

Section: Grhl2 Expression Activates Erk/mapk Signaling Pathways In Vitromentioning

confidence: 99%

<p>GRHL2 Upregulation Predicts a Poor Prognosis and Promotes the Resistance of Serous Ovarian Cancer to Cisplatin</p>

Nie

Ding

Yang

2020

OTT

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Background: GRHL2 has been shown to function in ovarian carcinogenesis. However, the relationship between GRHL2 and cisplatin (DDP) resistance in serous ovarian cancer (SOC) is not clear. The purpose of this study was to elucidate the function and mechanism of GRHL2 in DDP resistance of SOC. Materials and Methods: Immunohistochemistry (IHC) was utilized to identify GRHL2 protein expression in DDP resistant and sensitive SOC tissues. GRHL2 mRNA and protein levels were identified using quantitative real-time PCR (qRT-PCR) and Western blotting in SKOV3/DDP and SKOV3 cell lines. We conducted loss-and gain-of-function experiments to uncover the consequence of GRHL2 knockdown or overexpression on the sensitivity of ovarian cancer cells to DDP in vitro and in vivo and the underlying mechanism. Results: It was observed that expression of GRHL2 was higher in DDP resistant SOC tissues relative to DDP sensitive SOC tissues. In addition, the increased expression of GRHL2 led to shorter progression-free survival (PFS) and overall survival (OS). Meanwhile, the GRHL2 transcript and protein levels in SKOV3/DDP were also higher than SKOV3. Small hairpin RNA (shRNA)-facilitated GRHL2 gene knockdown considerably heightened the sensitivity of SKOV3/DDP cells to DDP by inhibiting proliferation and promoting apoptosis, while upregulation of GRHL2 significantly reduced the sensitivity of SKOV3 cells to DDP by promoting proliferation and decreasing apoptosis. In addition, GRHL2 promotes DDP resistance of SOC through activation of ERK/MAPK signaling pathways. Conclusion: Our results suggest that GRHL2 up-regulation predicts a poor prognosis and promotes the resistance of SOC to DDP. Therefore, GRHL2 may be a possible treatment target for cisplatin-resistant serous ovarian cancer.

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“…It encodes an 86-KDa protein and is a member of the Type II MAGE family, comprising 778 amino acids (aa), of which the MAGE homology domain is common for MAGE family members and the interspersed repeat domain (IRD) is relatively unique to NRAGE for no homology to any public speci c protein. These features imply that there are both uniform and speci c characteristics of NRAGE compared with other members of the MAGE family [28][29][30]. Growing evidence con rmed that NRAGE functions as a transcriptional regulator mediating multiple signaling pathways from proptosis [13][14][15][16], cell differentiation [31][32][33], cell cycle distribution [22], cell adhesion [34], and angiogenesis [18].…”

Section: Discussionmentioning

confidence: 99%

NRAGE, a potential biomarker, induces radioresistance in two- and three-dimensional culture and confers poor prognosis in esophageal squamous cell carcinoma

Hong-bin¹,

Wang²,

Xiao³

et al. 2020

Preprint

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Background To explore the mechanism of NRAGE enhancing radioresistance of ESCC in 2D and 3D levels. Methods Stably NRAGE-overexpressed ESCC cells and 3D-printing models for ESCC cells were established. Then, cellular malignancy indexes, such as cell morphology, proliferation, radioresistance, motility, apoptosis, cell cycle, and proteins of the Wnt/β-catenin pathway, were compared between radioresistant and its parental cells in 2D and 3D levels. Additionally, 44 paraffin ESCC specimens with radical radiotherapy were selected to examine NRAGE and β-catenin protein expression and analyze the clinical correlation. Results Experiments in 2D culture showed that Eca109/NRAGE cells’ morphology was more irregular, elongated spindle-shaped and disappeared polarity. It obtained faster growth ability, stronger resistance to irradiation, enhanced motility, reduced apoptosis ratio and cell cycle rearrangement. Moreover, Western blot results showed β-catenin, p-Gsk-3β and CyclinD1 expressions were induced, while p-β-catenin and Gsk-3β expressions decreased in Eca109/NRAGE cells. Experiments in the 3D-printing model showed Eca109/NRAGE cell-laden 3D scaffolds had the advantage on growth and spheroiding according to the brigbtfield observation, scanning electron microscopy and Ki-67 IHC staining, and higher expression at the β-catenin protein. Clinical analysis showed that NRAGE expression was higher in tumor tissues than in control tissues of ESCC patients from the Public DataBase. Compared with radiotherapy effective group, both NRAGE total and nuclear and β-catenin nuclear expressions were significantly upregulated from ESCC specimens in invalid group. Further analysis showed a positive and linear correlation between NRAGE nuclear and β-catenin nuclear expressions. Additionally, results from univariate and multivariate analyses revealed NRAGE nuclear expression could serve as a risk factor for ESCC patients receiving radical radiotherapy. Conclusion ESCC cells with NRAGE nuclear accumulation demonstrated greater radioresistance, which may be related to the activation of the Wnt/β-catenin signaling pathway. It indicated that NRAGE nuclear expression was a potential biomarker for monitoring radiotherapeutic response.

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NRAGE confers poor prognosis and promotes proliferation, invasion, and chemoresistance in gastric cancer

Cited by 10 publications

References 29 publications

ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer

ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer

<p>GRHL2 Upregulation Predicts a Poor Prognosis and Promotes the Resistance of Serous Ovarian Cancer to Cisplatin</p>

NRAGE, a potential biomarker, induces radioresistance in two- and three-dimensional culture and confers poor prognosis in esophageal squamous cell carcinoma

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