Overexpression of RIPK4 Predicts Poor Prognosis and Promotes Metastasis in Ovarian Cancer

Liu, Shaoqiu; He, Lenian; Sheng, Chenchen; Su, Rongjia; Wu, Xiaomei; Sun, Yunyan; Xi, Xiaowei

doi:10.1155/2021/6622439

Cited by 6 publications

(7 citation statements)

References 26 publications

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“…RIPK4 is involved in many processes related to skin development and epidermal homeostasis, as it is required for keratinocyte differentiation. Recent studies have shown that RIPK4 plays an important role in various cancers, exhibiting both oncogenic (Gong et al 2018 ; Liu et al 2015 , 2018 , 2021 ; Qi et al 2018 ; Yi et al 2020 ) and tumor suppressive (Kopparam et al 2017 ; Li et al 2021 ; Poligone et al 2015 ; Wang et al 2014 ) functions, depending on the cellular context. In our prior study, we demonstrated heterogeneous expression of RIPK4 in melanoma samples, where it acts as an oncogene, in contrast to cutaneous squamous cell carcinoma, where it functions as a tumor suppressor (Madej et al 2021 ).…”

Section: Discussionmentioning

confidence: 99%

The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells

Madej,

Lisek,

Brożyna

et al. 2024

J Cancer Res Clin Oncol

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Purpose The receptor-interacting protein kinase (RIPK4) has an oncogenic function in melanoma, regulates NF-κB and Wnt/β-catenin pathways, and is sensitive to the BRAF inhibitors: vemurafenib and dabrafenib which lead to its decreased level. As its role in melanoma remains not fully understood, we examined the effects of its downregulation on the transcriptomic profile of melanoma. Methods Applying RNA-seq, we revealed global alterations in the transcriptome of WM266.4 cells with RIPK4 silencing. Functional partners of RIPK4 were evaluated using STRING and GeneMANIA databases. Cells with transient knockdown (via siRNA) and stable knockout (via CRISPR/Cas9) of RIPK4 were stimulated with TNF-α. The expression levels of selected proteins were assessed using Western blot, ELISA, and qPCR. Results Global analysis of gene expression changes indicates a complex role for RIPK4 in regulating adhesion, migration, proliferation, and inflammatory processes in melanoma cells. Our study highlights potential functional partners of RIPK4 such as BIRC3, TNF-α receptors, and MAP2K6. Data from RIPK4 knockout cells suggest a putative role for RIPK4 in modulating TNF-α-induced production of IL-8 and IL-6 through two distinct signaling pathways—BIRC3/NF-κB and p38/MAPK. Furthermore, increased serum TNF-α levels and the correlation of RIPK4 with NF-κB were revealed in melanoma patients. Conclusion These data reveal a complex role for RIPK4 in regulating the immune signaling network in melanoma cells and suggest that this kinase may represent an alternative target for melanoma-targeted adjuvant therapy.

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Section: Discussionmentioning

confidence: 99%

The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells

Madej,

Lisek,

Brożyna

et al. 2024

J Cancer Res Clin Oncol

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“…As stated above, RIPK4 expression is confirmed to be positively associated with favorable prognosis in tongue SCC, lung adenocarcinoma, and hepatocellular carcinoma ( Wang et al, 2014 ; Kopparam et al, 2017 ; Li et al, 2021 ). By contrast, RIPK4 overexpression predicts poor prognosis in patients with ovarian cancer, cervical SCC, pancreatic cancer, bladder cancer, and osteosarcoma ( Qi et al, 2018 ; Liu et al, 2015 ; Liu et al, 2018 ; Yi et al, 2020 ; Liu et al, 2021 ). We then used public data set OncoLnc ( ) ( Anaya, 2016 ) to perform survival analyses of other tumor types.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, RIPK4 may have a context-specific function in different cancer progression and signal transduction ( Xu, Wei & He, 2020 ). RIPK4 expression is up-regulated and relates with a poor prognosis in ovarian cancer, cervical SCC, pancreatic cancer, bladder cancer and osteosarcoma ( Qi et al, 2018 ; Liu et al, 2015 ; Liu et al, 2018 ; Yi et al, 2020 ; Liu et al, 2021 ). However, the expression of RIPK4 is down-regulated and positively correlates with favorable prognosis in tongue SCC, hepatocellular carcinoma (HCC) and lung adenocarcinoma ( Wang et al, 2014 ; Kopparam et al, 2017 ; Li et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Depletion of RIPK4 parallels higher malignancy potential in cutaneous squamous cell carcinoma

Zhang

et al. 2022

PeerJ

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Background The RIPK4 (receptor-interacting protein kinase 4), a member of the RIPK family, acts as an important regulator of epidermal differentiation, cutaneous inflammation, and cutaneous wound repair. However, Until now, the role of RIPK4 in tumorigenesis remains elusive. There have been no studies exploring the effects of RIPK4 on the signaling pathway in cutaneous squamous cell carcinoma (SCC). It remains unknown whether RIPK4 expression, which can affect the degree of epidermal differentiation can also influence the radiosensitivity of skin SCC. It is urgent to fully elucidate the biological mechanism by which RIPK4 promotes carcinogenesis in skin SCC and determine whether RIPK4 expression levels predicts the sensitivity to radiotherapy in skin SCC. Methods Human skin SCC cell line, A431, was transfected with either small interfering RNAs (siRNAs) targeting RIPK4 (siR-RIPK4) or negative control siRNA (siR-NC). Western blotting was used to detect the expression of RIPK4 and Raf/MEK/ERK pathway-related proteins. The cells were irradiated using an X-ray irradiator at 6 MV with different radiation doses (0, 2, 6, and 10 Gy). Cell proliferation analysis, colony formation assay, transwell cell migration and invasion assay, cell cycle and apoptosis analysis were conducted to investigate the effect of RIPK4 silencing on skin SCC malignancy and radiosensitivity. Results RIPK4 protein expression was significantly decreased in the A431 cells transfected with siR-RIPK4, compared with the A431 cells transfected with siR-NC. RIPK4 silencing facilitated the proliferation, colony formation, migration, and invasion ability of A431 cell line, while cell cycle progression or cell apoptosis were not significantly influenced. In contrast with the previous literature, Raf/MEK/ERK pathway was not effected by RIPK4 knockdown in skin SCC. RIPK4 knockdown could not reverse the radiation resistance of A431 cells to irradiation in vitro. Conclusions In general, although depletion of RIPK4 cannot reverse the radiation resistance of A431 cells in vitro, it parallels higher malignancy potential in cutaneous SCC. To our knowledge, this is the first report of the effects of RIPK4 expression on the Raf/MEK/ERK signaling pathway and radiosensitivity in cutaneous SCC. The better understanding of the molecular mechanism of RIPK4 in cutaneous SCC may provide a promising biomarker for skin SCC prognosis and treatment.

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“…However, there are a few of reports regarding the role of RIPK4 and potential mechanism in OC. Liu et al have reported that RIPK4 can act as a potential prognostic molecular marker for poor survival and promoted tumor metastasis in OC (S. Liu et al, 2021). In addition, another study also showed that miR‐330‐3p suppressed the progression of OC by targeting RIPK4.…”

Section: Discussionmentioning

confidence: 99%

“…there are a few of reports regarding the role of RIPK4 and potential mechanism in OC.Liu et al have reported that RIPK4 can act as a potential prognostic molecular marker for poor survival and promoted tumor metastasis in OC (S Liu et al, 2021)…”

mentioning

confidence: 99%

Receptor interacting protein kinase 4 promotes cell proliferation, migration, and invasion in ovarian cancer via targeting protein kinase C delta

Jin

Zhang

Fang

et al. 2021

Drug Development Research

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Receptor interacting protein kinase 4 (RIPK4) has been reported to function as an oncogenic role in several types of cancers. The aim of this study was to evaluate the role of RIPK4 in ovarian cancer (OC) cells and to elucidate the mechanism behind this effect. In this study, the GEPIA database was used to analyze the RIPK4 expressions in OC tissues and overall survival. qRT‐PCR and western blot assay were performed to detect the expressions of RIPK4 and protein kinase C delta (PRKCD) in OC cells. In addition, cell proliferation was assessed by CCK‐8 and colony formation assay while cell invasion and migration were evaluated by transwell, wound healing and western blot assay. The interaction of RIPK4 and PRKCD was analyzed by the STRING database and the bioGRID database, and verified with co‐immunoprecipitation. Herein, we describe that RIPK4 expression was upregulated in OC tissues and cells and was associated with poor overall survival. RIPK4 silencing repressed the proliferation, migration, and invasion of OC cells. Mechanistically, PRKCD was highly expressed in OC cells and was combined with RIPK4. PRKCD was highly positively associated with RIPK4 in OC and was regulated by RIPK4. Moreover, PRKCD overexpression reversed the inhibitory effects of RIPK4 silencing on OC cell proliferation, migration, and invasion. RIPK4 functions as an oncogene in OC cells via at least partially binding to PRKCD, which might represent a novel therapeutic strategy for improving survival for patients with OC.

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Overexpression of RIPK4 Predicts Poor Prognosis and Promotes Metastasis in Ovarian Cancer

Cited by 6 publications

References 26 publications

The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells

The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells

Depletion of RIPK4 parallels higher malignancy potential in cutaneous squamous cell carcinoma

Receptor interacting protein kinase 4 promotes cell proliferation, migration, and invasion in ovarian cancer via targeting protein kinase C delta

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