p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells

Kang, Sumin; Elf, Shannon; Lythgoe, Katherine; Hitosugi, Taro; Taunton, Jack; Zhou, Wei; Xiong, Li; Wang, Dongsheng; Müller, Susan; Fan, Songqing; Sun, Shi-Yong; Marcus, Adam I.; Gu, Ting‐Lei; Polakiewicz, Roberto D.; Chen, Zhuo Georgia; Khuri, Fadlo R.; Shin, Dong M.; Chen, Jing

doi:10.1172/jci40582

Cited by 134 publications

(121 citation statements)

References 52 publications

(47 reference statements)

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“…Recently, there is an intense interest in applying proteomics to foster an improved understanding of cancer pathogenesis [42]. For example, Kang et al [27] performed a phospho-proteomics-based study using a phospho-antibody microarray to comprehensively provide mechanistic insight into the role of RSK2 in HNSCC metastasis. To further explore the underlying mechanisms by which MPZL1 stimulates cell migration and tumor metastasis, we used a phospho-antibody microarray-based proteomics approach [27], which has the unique capability of quantitative profiling of protein phosphorylation levels through the use of paired unphospho-and phospho-antibodies for each protein.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Kang et al [27] performed a phospho-proteomics-based study using a phospho-antibody microarray to comprehensively provide mechanistic insight into the role of RSK2 in HNSCC metastasis. To further explore the underlying mechanisms by which MPZL1 stimulates cell migration and tumor metastasis, we used a phospho-antibody microarray-based proteomics approach [27], which has the unique capability of quantitative profiling of protein phosphorylation levels through the use of paired unphospho-and phospho-antibodies for each protein. We identified multiple pro-metastatic proteins of which the phosphorylation and activation levels were regulated by MPZL1 in HCC cells, including ERK-1/2, AKT and cortactin.…”

Section: Discussionmentioning

confidence: 99%

“…We performed a phospho-proteomics-based study using a phospho-antibody microarray to explore the molecular mechanisms underlying MPZL1-mediated cell migration and tumor metastasis [27]. The microarray provides a high-throughput platform for an efficient protein phosphorylation status profiling, with detection and analysis of phosphorylation events at specific sites to identify MPZL1 downstream effectors that can regulate metastasis.…”

Section: Ectopic Expression Of Mpzl1 Leads To Increased Phosphorylatimentioning

confidence: 99%

“…The experiment was performed as described previously [27]. Cell lysates obtained from HUH-7 VECTOR and HUH-7 MPZL1 cells were applied to the Phospho Explorer Antibody Array (PEX100), which was designed and manufactured by Full Moon Biosystems Inc.…”

Section: Phosphory-antibody Arraymentioning

confidence: 99%

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Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

et al. 2013

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We have previously identified 1 241 regions of somatic copy number alterations (CNAs) in hepatocellular carcinoma (HCC). In the present study, we found that a novel recurrent focal amplicon, 1q24.1-24.2, targets the MPZL1 gene in HCC. Notably, there is a positive correlation between the expression levels of MPZL1 and intrahepatic metastasis of the HCC specimens. MPZL1 can significantly enhance the migratory and metastatic potential of the HCC cells. Moreover, we found that one of the mechanisms by which MPZL1 promotes HCC cell migration is by inducing the phosphorylation and activation of the pro-metastatic protein, cortactin. Additionally, we found that Src kinase mediates the phosphorylation and activation of cortactin induced by MPZL1 overexpression. Taken together, these findings suggest that MPZL1 is a novel pro-metastatic gene targeted by a recurrent region of copy number amplification at 1q24.1-24.2 in HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ectopic Expression Of Mpzl1 Leads To Increased Phosphorylatimentioning

confidence: 99%

Section: Phosphory-antibody Arraymentioning

confidence: 99%

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Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

et al. 2013

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“…In part, this is because RSK2 has been linked to numerous cancer types [50] such as head and neck squamous cell carcinoma [50] and those of hematopoietic origin [20]. More recently, a study to determine therapeutic targets for specific breast cancer subtypes by a siRNA screen identified RSK2 as one of three genes with potential for the TNBC subtype [31].…”

Section: Discussionmentioning

confidence: 99%

Targeting p90 Ribosomal S6 Kinase Eliminates Tumor-Initiating Cells by Inactivating Y-Box Binding Protein-1 in Triple-Negative Breast Cancers

Stratford

Reipas

et al. 2012

Stem Cells

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Y-box binding protein-1 (YB-1) is the first reported oncogenic transcription factor to induce the tumor-initiating cell (TIC) surface marker CD44 in triple-negative breast cancer (TNBC) cells. In order for CD44 to be induced, YB-1 must be phosphorylated at S102 by p90 ribosomal S6 kinase (RSK). We therefore questioned whether RSK might be a tractable molecular target to eliminate TICs. In support of this idea, injection of MDA-MB-231 cells expressing Flag-YB-1 into mice increased tumor growth as well as enhanced CD44 expression. Despite enrichment for TICs, these cells were sensitive to RSK inhibition when treated ex vivo with BI-D1870. Targeting RSK2 with small interfering RNA (siRNA) or small molecule RSK kinase inhibitors (SL0101 and BI-D1870) blocked TNBC monolayer cell growth by $100%. In a diverse panel of breast tumor cell line models RSK2 siRNA predominantly targeted models of TNBC. RSK2 inhibition decreased CD44 promoter activity, CD44 mRNA, protein expression, and mammosphere formation. CD44 1 cells had higher P-RSK S221/227 , P-YB-1 S102 , and mitotic activity relative to CD44 2 cells. Importantly, RSK2 inhibition specifically suppressed the growth of TICs and triggered cell death. Moreover, silencing RSK2 delayed tumor initiation in mice. In patients, RSK2 mRNA was associated with poor disease-free survival in a cohort of 244 women with breast cancer that had not received adjuvant treatment, and its expression was highest in the basal-like breast cancer subtype. Taking this further, we report that P-RSK S221/227 is present in primary TNBCs and correlates with P-YB-1 S102 as well as CD44. In conclusion, RSK2 inhibition provides a novel therapeutic avenue for TNBC and holds the promise of eliminating TICs.

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A novel intronic circular RNA, circGNG7, inhibits head and neck squamous cell carcinoma progression by blocking the phosphorylation of heat shock protein 27 at Ser78 and Ser82

Wei

et al. 2021

Cancer Communications

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Background There is increasing evidence that circular RNAs (circRNAs) play a significant role in pathological processes including tumorigenesis. In contrast to exonic circRNAs, which are the most frequently reported circRNAs in cancer so far, the studies of intronic circRNAs have been greatly lagged behind. Here, we aimed to investigate the regulatory role of intronic circRNAs in head and neck squamous cell carcinoma (HNSCC). Methods We conducted whole‐transcriptome sequencing with four pairs of primary tumor tissues and adjacent normal tissues from HNSCC patients. Then, we characterized circGNG7 expression in HNSCC tissues and cell lines and explored its association with the prognosis of HNSCC patients. We also identified interactions between circGNG7 and functional proteins, which alter downstream signaling that regulate HNSCC progression. Results In this study, we identified a new intronic circRNA, circGNG7, and validated its functional roles in HNSCC progression. CircGNG7 was predominately localized to the cytoplasm, and its expression was downregulated in both HNSCC tissues andCAL27, CAL33, SCC4, SCC9, HN6, and HN30 cells. Low expression of circGNG7 was significantly correlated with poor prognosis in HNSCC patients. Consistent with this finding, overexpression of circGNG7 strongly inhibited tumor cell proliferation, colony formation, in vitro migration, and in vivo tumor growth. Mechanistically, the expression of circGNG7 in HNSCC cells was regulated by the transcription factor SMAD family member 4 (SMAD4). Importantly, we discovered that circGNG7 could bind to serine residues 78 and 82 of the functional heat shock protein 27 (HSP27), occupying its phosphorylation sites and hindering its phosphorylation, which reduced HSP27‐JNK/P38 mitogen‐activated protein kinase (MAPK) oncogenic signaling. Downregulation of circGNG7 expression in HNSCC increased HSP27‐JNK/P38 MAPK signaling and promoted tumor progression. Conclusions Our results revealed that a new intronic circRNA, circGNG7, functions as a strong tumor suppressor and that circGNG7/HSP27‐JNK/P38 MAPK signaling is a novel mechanism by which HNSCC progression can be controlled.

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p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells

Cited by 134 publications

References 52 publications

Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

Targeting p90 Ribosomal S6 Kinase Eliminates Tumor-Initiating Cells by Inactivating Y-Box Binding Protein-1 in Triple-Negative Breast Cancers

A novel intronic circular RNA, circGNG7, inhibits head and neck squamous cell carcinoma progression by blocking the phosphorylation of heat shock protein 27 at Ser78 and Ser82

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