SLPI: a new target for stopping metastasis

Munn, Lance L.; Garkavtsev, Igor

doi:10.18632/aging.101372

Cited by 10 publications

(11 citation statements)

References 5 publications

(6 reference statements)

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“…Secretory leukocyte protease inhibitor (SLPI) promotes cell proliferation, invasion, metastasis, and drug resistance. 51,52 In patients with HR HPV positive low or high grade squamous intraepithelial lesions, SLPI concentrations in the cervical mucus were increased compared to controls. 53 These results, combined with our finding that SLPI was significantly upregulated in cervical cancers (Figures 3 and 4), merit further investigation of the role of SLPI in cervical cancers.…”

Section: Discussionmentioning

confidence: 99%

<p>Genes Regulated by HPV 16 E6 and High Expression of NFX1-123 in Cervical Cancers</p>

Chintala¹,

Levan²,

Robinson³

et al. 2020

OTT

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High-risk human papillomaviruses (HR HPV) cause cervical cancer, and in these cancers, HPV type 16 is the most common HR type. The HR viral oncogenes E6 and E7 partner with cellular proteins to drive cancer and modulate immune pathways; previously, we demonstrated in keratinocytes that HPV 16 E6 and high expression of the endogenous host protein partner NFX1-123 led to the increased expression of multiple genes, including Notch1, secretory leukocyte peptidase inhibitor (SLPI), and retinoic acid early transcript 1G (RAET1G). The present study was conducted to determine if NFX1-123 was highly expressed in cervical cancer and if genes increased by NFX1-123 and 16E6 in keratinocytes were also increased in cervical cancers. Materials and Methods: The Cancer Genome Atlas (TCGA) database and The Human Protein Atlas database were used to compare relative mRNA and protein gene expression, respectively, in the normal cervix and cervical cancers. Formalin-fixed paraffin-embedded (FFPE) normal cervix and HPV 16 positive cervical cancer samples were analyzed for relative protein expression by immunohistochemical staining. Protein expression of a subset of regulated genes was quantified by Western blot of HPV positive and negative cell lines. Results: Immunohistochemical staining of HPV 16 positive cervical dysplasias and cancers revealed high NFX1-123, Ki67, and Notch1 expression. NFX1 and NFX1L1 mRNA levels were increased in cervical cancers compared to normal cervix in the TCGA database. Fourteen genes previously identified as upregulated in keratinocytes with 16E6 and overexpressed NFX1-123 also had high mRNA expression and selected genes had high protein expression in cervical cancers and cell lines. Conclusion: In cervical cancer, NFX1-123 is highly expressed, and 16E6 and NFX1-123 together alter the expression of a wide set of genes. The involvement of these genes in cell proliferation, differentiation, invasion, and metastasis provides further insight into potential ways that HR HPVs promote cancer initiation and maintenance.

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Section: Discussionmentioning

confidence: 99%

<p>Genes Regulated by HPV 16 E6 and High Expression of NFX1-123 in Cervical Cancers</p>

Chintala¹,

Levan²,

Robinson³

et al. 2020

OTT

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“…We found that aldo-keto reductase family 1 member B10 ( AKR1B10 ), NAD(P)H quinone dehydrogenase 1 ( NQO1 ), and aldo-keto reductase family 1 member C3 ( AKR1C3 ) are highly expressed in HLRCC-associated kidney cancer relative to the other cancer types, all of which have been reported to be highly expressed in HLRCC-associated kidney cancer in association with a dysregulated Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (NRF2) axis ( Figure 3 A) ( Ooi et al., 2011 ). In addition, we found that carboxypeptidase D ( CPD ), growth Differentiation Factor 15 ( GDF15 ), S100 calcium binding protein A6 ( S100A6 ), secretory leukocyte peptidase inhibitor ( SLP1 ), paired box 2 ( PAX2 ), KCNQ1 opposite strand/antisense transcript 1 ( KCNQ1OT1 ), metastasis associated in lung adenocarcinoma transcript-1 ( MALAT1 ), and insulin like growth factor 2 mRNA binding protein 2 ( IGF2BP2 ) are highly expressed in HLRCC-associated kidney cancer relative to the other cancer types, all of which have been reported to be expressed in highly aggressive cancers with poor prognosis ( Chen et al., 2015 ; Feng et al., 2020 ; Gao et al., 2021 ; Han et al., 2020 ; Miyazaki et al., 2019 ; Munn and Garkavtsev, 2018 ; Shi et al., 2019 ; Wang et al., 2020 ; Ye et al., 2021 ; Yi et al., 2021 ; Zhang et al., 2021a ). Using Gene Set Enrichment Analysis (GSEA), we compared three types of hereditary kidney cancers and found that gene sets related to cell migration and metastasis were enriched in HLRCC-associated kidney cancer, consistent with the fact that this highly aggressive kidney cancer subtype has a propensity to metastasize from a small primary lesion ( Figure 3 B).…”

Section: Resultsmentioning

confidence: 99%

Single-cell transcriptomes underscore genetically distinct tumor characteristics and microenvironment for hereditary kidney cancers

et al. 2022

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“…SLPI, a known immunomodulator that functions to downregulate the immune system [ 30 ], and KRT16, a stress keratin with a role in innate immunity [ 31 ], were also highly upregulated in response to 16E6E7 expression in HFKs. HFK2 E6E7 exhibited a stark increase of 10–20-fold for both of these genes; HFK1 and HFK3 E6E7 returned less pronounced, yet still statistically significant increases of 2–3-fold ( Figure 5 A, colored bars).…”

Section: Resultsmentioning

confidence: 99%

Cervical Cancer Development: Implications of HPV16 E6E7-NFX1-123 Regulated Genes

Quist

Solorzano

Wendel

et al. 2021

Cancers

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High-risk human papillomavirus (HR HPV) causes nearly all cervical cancers, half of which are due to HPV type 16 (HPV16). HPV16 oncoprotein E6 (16E6) binds to NFX1-123, and dysregulates gene expression, but their clinical implications are unknown. Additionally, HPV16 E7’s role has not been studied in concert with NFX1-123 and 16E6. HR HPVs express both oncogenes, and transformation requires their expression, so we sought to investigate the effect of E7 on gene expression. This study’s goal was to define gene expression profiles across cervical precancer and cancer stages, identify genes correlating with disease progression, assess patient survival, and validate findings in cell models. We analyzed NCBI GEO datasets containing transcriptomic data linked with cervical cancer stage and utilized LASSO analysis to identify cancer-driving genes. Keratinocytes expressing 16E6 and 16E7 (16E6E7) and exogenous NFX1-123 were tested for LASSO-identified gene expression. Ten out of nineteen genes correlated with disease progression, including CEBPD, NOTCH1, and KRT16, and affected survival. 16E6E7 in keratinocytes increased CEBPD, KRT16, and SLPI, and decreased NOTCH1. Exogenous NFX1-123 in 16E6E7 keratinocytes resulted in significantly increased CEBPD and NOTCH1, and reduced SLPI. This work demonstrates the clinical relevance of CEBPD, NOTCH1, KRT16, and SLPI, and shows the regulatory effects of 16E6E7 and NFX1-123.

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SLPI: a new target for stopping metastasis

Cited by 10 publications

References 5 publications

<p>Genes Regulated by HPV 16 E6 and High Expression of NFX1-123 in Cervical Cancers</p>

<p>Genes Regulated by HPV 16 E6 and High Expression of NFX1-123 in Cervical Cancers</p>

Single-cell transcriptomes underscore genetically distinct tumor characteristics and microenvironment for hereditary kidney cancers

Cervical Cancer Development: Implications of HPV16 E6E7-NFX1-123 Regulated Genes

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