Low expression of SerpinB2 is associated with reduced survival in lung adenocarcinomas

Ramnefjell, Maria; Aamelfot, Christina; Helgeland, Lars; Akslen, Lars A.

doi:10.18632/oncotarget.21456

Cited by 13 publications

(14 citation statements)

References 53 publications

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“…Increased SERPINB2 expression has been reported in various inflammatory or autoimmune diseases, including psoriasis, asthma, preeclampsia and lupus erythematosus . In addition, increased SERPINB2 has been previously shown to be a potential biomarker in discriminating non‐allergic asthma and its severity while reduced expression of SERPINB2 was an independent prognostic marker in lung adenocarcinomas associated with reduced survival . Our study suggests that increased SERPINB2 expression is associated with more severe psoriasis.…”

Section: Discussionsupporting

confidence: 59%

SERPINB2 and miR‐146a/b are coordinately regulated and act in the suppression of psoriasis‐associated inflammatory responses in keratinocytes

Vaher

Kivihall

Runnel

et al. 2019

Experimental Dermatology

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Psoriasis is a chronic inflammatory skin disease with numerous involved factors. miR‐146a and miR‐146b (miR‐146a/b) are anti‐inflammatory miRNAs that are increased in psoriatic skin. SERPINB2 has been shown to be upregulated in the inflammation and infections. Here we aimed to study the relationship between miR‐146a/b and SERPINB2 and to delineate the role of SERPINB2 in association of plaque psoriasis. We report increased SERPINB2 expression in the skin of psoriasis patients, which was in a positive relationship with psoriasis severity and in a negative relationship with miR‐146a/b in psoriatic lesions. In cultured keratinocytes, both cellular and secreted SERPINB2 levels were strongly induced in response to IFN‐γ and TNF‐α. Interestingly, SERPINB2 mRNA was downregulated by IL‐17A and the combination of TNF‐α and IL‐17A at time points when miR‐146a was increased. The predicted binding site for miR‐146a/b in 3’ untranslated region of SERPINB2 revealed no activity in luciferase assay, while siRNA silencing of miR‐146a/b direct targets IRAK1 and CARD10 resulted in reduced expression of SERPINB2, suggesting that miR‐146a/b indirectly control SERPINB2 expression in the skin. The siRNA silencing of SERPINB2 increased the expression of IL‐8, CXCL5 and CCL5 and migration of neutrophils revealing its anti‐inflammatory role in keratinocytes. Our data together suggest that SERPINB2 and miR‐146a/b are part of disease‐related network of molecules that are coordinately regulated and act in controlling the inflammatory responses in psoriatic skin.

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Section: Discussionsupporting

confidence: 59%

SERPINB2 and miR‐146a/b are coordinately regulated and act in the suppression of psoriasis‐associated inflammatory responses in keratinocytes

Vaher

Kivihall

Runnel

et al. 2019

Experimental Dermatology

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“…Loss of expression of SerpinB2 was, however, shown to be associated with the activation of tumor growth and metastasis in several cancer types, including BC 32–34 . Expression levels of SerpinB2 was also shown to correlate negatively with survival of patients with lung carcinomas 35 . Also, downregulation of SerpinB2 was found to contribute to chemoresistance in head and neck carcinomas 36 .…”

Section: Discussionmentioning

confidence: 94%

The Kindlin2-p53-SerpinB2 signaling axis is required for cellular senescence in breast cancer

et al. 2019

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In cancer, cellular senescence is a complex process that leads to inhibition of proliferation of cells that may develop a neoplastic phenotype. A plethora of signaling pathways, when dysregulated, have been shown to elicit a senescence response. Two well-known tumor suppressor pathways, controlled by the p53 and retinoblastoma proteins, have been implicated in maintaining the cellular senescence phenotype. Kindlin-2, a member of an actin cytoskeleton organizing and integrin activator proteins, has been shown to play a key role in the regulation of several hallmarks of several cancers, including breast cancer (BC). The molecular mechanisms whereby Kindlin-2 regulates cellular senescence in BC tumors remains largely unknown. Here we show that Kindlin-2 regulates cellular senescence in part through its interaction with p53, whereby it regulates the expression of the p53-responsive genes; i.e., SerpinB2 and p21, during the induction of senescence. Our data show that knockout of Kindlin-2 via CRISPR/Cas9 in several BC cell lines significantly increases expression levels of both SerpinB2 and p21 resulting in the activation of hallmarks of cellular senescence. Mechanistically, interaction between Kindlin-2 and p53 at the promotor level is critical for the regulated expression of SerpinB2 and p21. These findings identify a previously unknown Kindlin-2/p53/SerpinB2 signaling axis that regulates cellular senescence and intervention in this axis may serve as a new therapeutic window for BCs treatment.

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“…It was reported that the elevated expression of SPB2 resulted in a poor survival of bladder cancer patients 27 , or patients diagnosed with esophageal squamous cell carcinoma 28 . However, reduced expression of SPB2 also leads to reduced survival rate of patients suffering from breast 29–31 or pancreatic cancer 32 . In this study we demonstrate that upon UV irradiation SPB2 mRNA level is highly increased in cell types originated from skin tissue.…”

Section: Resultsmentioning

confidence: 99%

SerpinB2 is involved in cellular response upon UV irradiation

Majoros

Újfaludi

Borsos

et al. 2019

Sci Rep

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Ultraviolet light induced pyrimidine dimer is a helix distortion DNA damage type, which recruits repair complexes. However, proteins of these complexes that take part in both DNA damage recognition and repair have been well-described, the regulation of the downstream steps of nucleotide excision repair (NER) have not been clearly clarified yet. In a high-throughput screen, we identified SerpinB2 (SPB2) as one of the most dramatically upregulated gene in keratinocytes following UV irradiation. We found that both the mRNA and the protein levels of SPB2 were increased upon UV irradiation in various cell lines. Additionally, UV damage induced translocation of SPB2 from the cytoplasm to the nucleus as well as the damage induced foci formation of it. Here we show that SPB2 co-localizes with XPB involved in the NER pathway at UV-induced repair foci. Finally, we demonstrated that UV irradiation promoted the association of SPB2 with ubiquitylated proteins. In basal cell carcinoma tumour cells, we identified changes in the subcellular localization of SPB2. Based on our results, we conclude that SPB2 protein has a novel role in UV-induced NER pathway, since it regulates the removal of the repair complex from the damaged site leading to cancerous malformation.

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Low expression of SerpinB2 is associated with reduced survival in lung adenocarcinomas

Abstract: In summary, low expression of SerpinB2 in lung adenocarcinomas was an independent prognostic factor. In contrast to findings by others, we found no impact of L1CAM on survival.

Cited by 13 publications

References 53 publications

SERPINB2 and miR‐146a/b are coordinately regulated and act in the suppression of psoriasis‐associated inflammatory responses in keratinocytes

SERPINB2 and miR‐146a/b are coordinately regulated and act in the suppression of psoriasis‐associated inflammatory responses in keratinocytes

The Kindlin2-p53-SerpinB2 signaling axis is required for cellular senescence in breast cancer

SerpinB2 is involved in cellular response upon UV irradiation

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