Current Status of Raf Kinase Inhibitor Protein (RKIP) in Lung Cancer: Behind RTK Signaling

Raquel-Cunha, Ana; Cardoso-Carneiro, Diana; Reis, Rui Manuel; Martinho, Olga

doi:10.3390/cells8050442

Cited by 28 publications

(22 citation statements)

References 121 publications

(200 reference statements)

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“…This suggested that RKIP may not have a fundamental role in the primary tumour, but instead has great importance as a metastasis suppressor. In accordance, loss or reduction of RKIP expression is associated with malignancy and poor prognosis in several tumour types, as reported by our [16][17][18][19][20][21][22] and other groups [4,5,18,[23][24][25][26]. Biologically, RKIP is a multifunctional protein in carcinogenesis, regulating cellular growth [27,28], motility [29,30], epithelial-to-mesenchymal transition (EMT) [31] and invasion [32].…”

Section: Introductionsupporting

confidence: 70%

RKIP as an Inflammatory and Immune System Modulator: Implications in Cancer

et al. 2019

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Raf kinase inhibitor protein (RKIP), an important modulator of intracellular signalling pathways, is commonly downregulated in multiple cancers. This reduction, or loss of expression, is correlated not only with the presence of metastasis, contributing to RKIP’s classification as a metastasis suppressor, but also with tumour aggressiveness and poor prognosis. Recent findings suggest a strong involvement of RKIP in the modulation of tumour microenvironment components, particularly by controlling the infiltration of specific immune cells and secretion of pro-metastatic factors. Additionally, RKIP interaction with multiple signalling molecules seems to potentiate its function as a regulator of inflammatory processes, mainly through stimulation of anti- or pro-inflammatory cytokines. Furthermore, RKIP is involved in the modulation of immunotherapeutic drugs response, through diverse mechanisms that sensitize cells to apoptosis. In the present review, we will provide updated information about the role of RKIP as an inflammatory and immune modulator and its potential implications in cancer will be addressed.

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Section: Introductionsupporting

confidence: 70%

RKIP as an Inflammatory and Immune System Modulator: Implications in Cancer

et al. 2019

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“…Raf kinase inhibitor protein (RKIP) is a well-known suppressor in carcinogenesis and malignant progression 18 . Downregulation of RKIP has been observed in various cancers such as prostate cancer 19 , breast cancer 20 , lung cancer 21 , gastric cancer 22 , esophageal squamous cell carcinoma 23 , and colorectal cancer 24 . Reduction of RKIP is almost involved in promotion of each malignant characteristics, especially for metastasis and therapy resistance, by activating oncogenic regulators or signaling axes like NF-κB 25 , YY1 26 , STAT3 27 , MAPK 28 , and AKT 29 .…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Downregulation of RKIP promotes radioresistance of nasopharyngeal carcinoma by activating NRF2/NQO1 axis via downregulating miR-450b-5p

et al. 2020

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Dysregulation of RKIP and NRF2 has been widely involved in the therapy resistance of multiple malignances, however, their relation and the corresponding mechanisms, especially in radiation response, have not been elucidated. In this study, we revealed that RKIP could negatively regulate the expression of NRF2 in nasopharyngeal carcinoma (NPC) cells. Depletion or ectopic expression of NRF2 countered the pro- or anti- radioresistant effects of RKIP knockdown or overexpression on NPC cells, respectively, both in vitro and in vivo. Furthermore, our results indicated that NQO1 was positively regulated by NRF2 and served as the downstream effector of RKIP/NRF2 axis in regulation of NPC radioresistance. Mechanistically, miR-450b-5p, being positively regulated by RKIP in NPC cells, could sensitize NPC cells to irradiation by directly targeting and suppressing the level of NRF2. Besides, we analyzed the level of aforementioned molecules in NPC tissues. The results indicated that RKIP was significantly downregulated, NRF2 and NQO1 were notably upregulated in NPC tissues compared with in normal nasopharyngeal mucosa (NNM) tissues. Furthermore, RKIP and miR-450b-5p were remarkably lower, yet NRF2 and NQO1 were notably higher, in radioresistant NPC tissues relative to in radiosensitive NPC tissues. Consistent with the pattern in NPC cells, the RKIP/miR-450b-5p/NRF2/NQO1 axis was significantly correlated in NPC tissues. Downregulation of RKIP and miR-450b-5p, and upregulation of NRF2 and NQO1, positively correlated to malignant pathological parameters such as primary T stage, Lymph node (N) metastasis, and TNM stage. Finally, RKIP and miR-450b-5p served as favorable prognostic indicators, and NRF2 and NQO1 acted as unfavorable prognostic biomarkers in patients with NPC. Collectively, our outcomes reveal that RKIP downregulation promotes radioresistance of NPC by downregulating miR-450b-5p and subsequently upregulating and activating NRF2 and NQO1, highlighting RKIP/miR-450b-5p/NRF2/NQO1 axis as a potential therapeutic target for improving the radiosensitivity of NPC.

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“…Since these proteins are closely related to senescence processes [ 26 , 27 , 28 ], we decided to evaluate them in appendiceal NENs, and complement the analysis with the evaluation of an anti-apoptotic protein Bcl-2. We also evaluated RKIP, a protein that has been associated with a metastasis suppressive role in various neoplasms, namely gastrointestinal stromal tumors, breast cancer, prostate, and many others [ 29 , 30 , 31 , 32 , 33 ]. Contrary to the GCA [ 16 ], in appendiceal NENs of our series, p16 was expressed in the majority of the cases with moderate or strong staining.…”

Section: Discussionmentioning

confidence: 99%

A 30-Year Long-Term Experience in Appendix Neuroendocrine Neoplasms—Granting a Positive Outcome

Vinagre

Pinheiro

Martinho

et al. 2020

Cancers

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Neuroendocrine neoplasms (NENs) are the most common tumor of the appendix and have an excellent prognosis. Appendiceal tumors diagnosed between 1989 and 2019 were reviewed, and clinical data were collected from patient files. Part of the series was immuno-profiled for markers related to cell cycle proliferation and/or senescence-type, apoptotic, and metastatic potential. Appendix NENs were detected in 74 patients, with 0.47% of incidence per appendectomy. The median age of the patients was 21.5 years, with two age peaks of incidence at 17.0 and 55.2 years. The median tumors size was 5.8 mm, and most were smaller than 10 mm. Lymphovascular and perineural invasion, as well as necrosis, was associated with larger tumor size. G1 tumors composed 96.0% of the cohort. The presence of moderate/strong p16 and the absent/low Bcl-2 expression was frequently observed and associated with a smaller size. This study represents one of the largest cohorts and with a long follow-up. For tumors smaller than 10 mm appendicectomy was sufficient as a curative procedure, as revealed by the good outcome. This series presented a 100% disease-free survival. The indolent phenotype of appendix NENs is supported by the expression of markers that point towards a strong inhibition of cell replication and growth inhibition.

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Current Status of Raf Kinase Inhibitor Protein (RKIP) in Lung Cancer: Behind RTK Signaling

Cited by 28 publications

References 121 publications

RKIP as an Inflammatory and Immune System Modulator: Implications in Cancer

RKIP as an Inflammatory and Immune System Modulator: Implications in Cancer

RETRACTED ARTICLE: Downregulation of RKIP promotes radioresistance of nasopharyngeal carcinoma by activating NRF2/NQO1 axis via downregulating miR-450b-5p

A 30-Year Long-Term Experience in Appendix Neuroendocrine Neoplasms—Granting a Positive Outcome

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