Silencing of RIPK4 inhibits epithelial‑mesenchymal transition by inactivating the Wnt/β‑catenin signaling pathway in osteosarcoma

Yi, Zhigang; Pu, Yanchuan; Gou, Ruoyan; Chen, Yonggang; Ren, Xiaojun; Liu, Wenzhong; Dong, Ping

doi:10.3892/mmr.2020.10939

Cited by 16 publications

(19 citation statements)

References 30 publications

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“…RIPK4 has been implicated in the progression of numerous tumors [ 8 , 9 , 10 , 11 , 12 , 13 , 28 , 29 ]; however its role in melanoma remained unresolved. Our study fills this gap because it is the first to reveal the functional role of RIPK4 in melanoma.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the Functional Role of RIPK4 in Melanoma

Madej

Ryszawy

Brożyna

et al. 2021

IJMS

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The receptor-interacting protein kinase 4 (RIPK4) plays an important role in the development and maintenance of various tissues including skin, but its role in melanoma has not been reported. Using patient-derived cell lines and clinical samples, we show that RIPK4 is expressed in melanomas at different levels. This heterogenous expression, together with very low level of RIPK4 in melanocytes, indicates that the role of this kinase in melanoma is context-dependent. While the analysis of microarray data has revealed no straightforward correlation between the stage of melanoma progression and RIPK4 expression in vivo, relatively high levels of RIPK4 are in metastatic melanoma cell lines. RIPK4 down-regulation by siRNA resulted in the attenuation of invasive potential as assessed by time-lapse video microscopy, wound-healing and transmigration assays. These effects were accompanied by reduced level of pro-invasive proteins such as MMP9, MMP2, and N-cadherin. Incubation of melanoma cells with phorbol ester (PMA) increased PKC-1β level and hyperphosphorylation of RIPK4 resulting in degradation of RIPK4. Interestingly, incubation of cells with PMA for short and long durations revealed that cell migration is controlled by the NF-κB signaling in a RIPK4-dependent (RIPK4high) or independent (RIPK4low) manner depending on cell origin (distant or lymph node metastasis) or phenotype (mesenchymal or epithelial).

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Section: Discussionmentioning

confidence: 99%

Deciphering the Functional Role of RIPK4 in Melanoma

Madej

Ryszawy

Brożyna

et al. 2021

IJMS

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“…The Wnt signaling pathway is an important molecular signaling pathway with the ability to regulate biological processes such as apoptosis and differentiation [254][255][256][257]. A number of studies have shown that the Wnt signaling pathway contributes to increased invasion and malignancy of tumor cells via EMT induction [258][259][260]. The inhibition of Wnt by onco-suppressor factor Numb suppresses EMT in cancer cells, thereby illustrating the role of Wnt as an upstream mediator of EMT [261].…”

Section: Wnt Signaling Pathwaymentioning

confidence: 99%

Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

Ashrafizadeh

Zarrabi

Hushmandi

et al. 2020

IJMS

197

103

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Therapy resistance is a characteristic of cancer cells that significantly reduces the effectiveness of drugs. Despite the popularity of cisplatin (CP) as a chemotherapeutic agent, which is widely used in the treatment of various types of cancer, resistance of cancer cells to CP chemotherapy has been extensively observed. Among various reported mechanism(s), the epithelial–mesenchymal transition (EMT) process can significantly contribute to chemoresistance by converting the motionless epithelial cells into mobile mesenchymal cells and altering cell–cell adhesion as well as the cellular extracellular matrix, leading to invasion of tumor cells. By analyzing the impact of the different molecular pathways such as microRNAs, long non-coding RNAs, nuclear factor-κB (NF-ĸB), phosphoinositide 3-kinase-related protein kinase (PI3K)/Akt, mammalian target rapamycin (mTOR), and Wnt, which play an important role in resistance exhibited to CP therapy, we first give an introduction about the EMT mechanism and its role in drug resistance. We then focus specifically on the molecular pathways involved in drug resistance and the pharmacological strategies that can be used to mitigate this resistance. Overall, we highlight the various targeted signaling pathways that could be considered in future studies to pave the way for the inhibition of EMT-mediated resistance displayed by tumor cells in response to CP exposure.

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“…As mentioned above, RIPK4 expression is positively associated with favorable prognosis in tongue SCC and lung adenocarcinoma (49,56). By contrast, increased RIPK4 expression predicts a poor prognosis in cervical SCC, pancreatic cancer, bladder cancer, and osteosarcoma (21,46,58,60). RIPK4 is a novel and independent prognostic factor, which may be used to identify patients at risk and guide individualized treatment.…”

Section: Discussionmentioning

confidence: 95%

“…RIPK4 knockdown in A2780 and COV434 ovarian cancer cells could inhibit β-catenin accumulation and RIPK4 overexpression could promote ovarian cancer in a xenograft tumor model ( 20 ). In addition, RIPK4 was significantly upregulated in osteosarcoma and RIPK4 knockdown suppressed EMT by inactivating Wnt/β-catenin signaling ( 60 ). RIPK4 promoted Wnt signaling, implying that RIPK4 overexpression might be involved in the development of certain tumor types.…”

Section: The Role Of Ripk4 In Carcinogenesismentioning

confidence: 99%

Insight Into the Function of RIPK4 in Keratinocyte Differentiation and Carcinogenesis

Wei

2020

Front. Oncol.

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The receptor-interacting protein kinase 4 (RIPK4), a member of the RIPK family, was originally described as an interaction partner of protein kinase C (PKC) β and PKCδ. RIPK4 is identified as a key regulator of keratinocyte differentiation, cutaneous inflammation, and cutaneous wound repair. The mechanism by which RIPK4 integrates upstream signals to initiate specific responses remains elusive. Previous studies have indicated that RIPK4 can regulate several signaling pathways, including the NF-κB, Wnt/β-catenin, and RAF/MEK/ERK pathways. Furthermore, RIPK4-related biological signaling pathways interact with each other to form a complex network. Mounting evidence suggests that RIPK4 is aberrantly expressed in various kinds of cancers. In several types of squamous cell carcinoma (SCC), the mutations that drive aggressive SCC have been found in RIPK4. In addition, the function of RIPK4 in carcinogenesis is probably tissue-specific, since RIPK4 can play a dual role as both a tumor promoter and a tumor suppressor in different tumor types. Therefore, RIPK4 may represent as an independent prognostic factor and a promising novel therapeutic target, which can be used to identify the risks of patients and guide personalized treatments. In future, RIPK4-interacting pathways and precise molecular targets need to be investigated in order to further elucidate the mechanisms underlying epidermal differentiation and carcinogenesis.

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Silencing of RIPK4 inhibits epithelial‑mesenchymal transition by inactivating the Wnt/β‑catenin signaling pathway in osteosarcoma

Cited by 16 publications

References 30 publications

Deciphering the Functional Role of RIPK4 in Melanoma

Deciphering the Functional Role of RIPK4 in Melanoma

Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

Insight Into the Function of RIPK4 in Keratinocyte Differentiation and Carcinogenesis

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