PKCη promotes a proliferation to differentiation switch in keratinocytes via upregulation of p27Kip1 mRNA through suppression of JNK/c-Jun signaling under stress conditions

Hara, Takeshi; Miyazaki, Makoto; Hakuno, Fumihiko; Takahashi, Satoru; Chida, Kazuhiro

doi:10.1038/cddis.2011.40

Cited by 26 publications

(29 citation statements)

References 37 publications

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“…We analyzed the expression of CLCA1 in these published microarray data sets with the GEO software. The identity of genes across microarray data sets was established with public annotations primarily based on Unigene …”

Section: Methodsmentioning

confidence: 99%

Low expression of chloride channel accessory 1 predicts a poor prognosis in colorectal cancer

Yang

Cao

Liu

et al. 2015

Cancer

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BACKGROUNDChloride channel accessory 1 (CLCA1) is a CLCA protein that plays a functional role in regulating the differentiation and proliferation of colorectal cancer (CRC) cells. Here we investigated the relationship between the level of CLCA1 and the prognosis of CRC.METHODSFirst, the level of CLCA1 was detected quantitatively in normal and cancerous colonic epithelial tissues with immunohistochemistry. Next, the correlations between CLCA1 expression, pathological tumor features, and the overall survival rate of patients was analyzed. Finally, 3 publicly available data sets from the Gene Expression Omnibus were examined: normal CRC versus early CRC (GSE4107), primary CRC versus metastatic lesions (GSE28702), and low chromosomal instability versus high chromosomal instability (GSE30540).RESULTSThe expression of CLCA1 was decreased markedly in tumor specimens. CLCA1 expression was correlated significantly with the histological grade (P < .01) and lymph node metastasis (P < .01). A significantly poorer overall survival rate was found in patients with low levels of CLCA1 expression versus those with high expression levels (P < .05). The results confirmed that the low expression of CLCA1 in CRC was highly associated with tumorigenesis, metastasis, and high chromosomal instability. In addition, the loss of CLCA1 disrupted the differentiation of human colon adenocarcinoma cells (Caco-2) in vitro.CONCLUSIONSThese findings suggest that CLCA1 levels may be a potential predictor of prognosis in primary human CRC. Low expression of CLCA1 predicts disease recurrence and lower survival, and this has implications for the selection of patients most likely to need and benefit from adjuvant chemotherapy. Cancer 2015;121:1570–1580. © 2015 American Cancer Society.

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Section: Methodsmentioning

confidence: 99%

Low expression of chloride channel accessory 1 predicts a poor prognosis in colorectal cancer

Yang

Cao

Liu

et al. 2015

Cancer

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“…We filtered the GDS2609 data set for the expression of chloride channel family members using the software on GEO. The identity of genes across microarray data sets was established using public annotations, primarily based on Unigene [71].…”

Section: Methodsmentioning

confidence: 99%

The Transition from Proliferation to Differentiation in Colorectal Cancer Is Regulated by the Calcium Activated Chloride Channel A1

et al. 2013

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Breaking the balance between proliferation and differentiation in animal cells can lead to cancer, but the mechanisms maintaining this balance remain largely undefined. The calcium activated chloride channel A1 (CLCA1) is a member of the calcium sensitive chloride conductance family of proteins and is expressed mainly in the colon, small intestine and appendix. We show that CLCA1 plays a functional role in differentiation and proliferation of Caco-2 cells and of intestinal tissue. Caco-2 cells spontaneously differentiate either in confluent culture or when treated with butyrate, a molecule present naturally in the diet. Here, we compared CLCA1 expressional levels between patients with and without colorectal cancer (CRC) and determined the functional role of CLCA1 in differentiation and proliferation of Caco-2 cells. We showed that: 1) CLCA1 and CLCA4 expression were down-regulated significantly in CRC patients; 2) CLCA1 expression was up-regulated in Caco-2 cells induced to differentiate by confluent culture or by treatment with sodium butyrate (NaBT); 3) Knockdown of CLCA1 with siRNA significantly inhibited cell differentiation and promoted cell proliferation in Caco-2 confluent cultures, and 4) In Caco-2 3D culture, suppression of CLCA1 significantly increased cell proliferation and compromised NaBT-induced inhibition of proliferation. In conclusion, CLCA1 may contribute to promoting spontaneous differentiation and reducing proliferation of Caco-2 cells and may be a target of NaBT-induced inhibition of proliferation and therefore a potential diagnostic marker for CRC prognosis.

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“…A large body of evidence supports a central regulatory role of particularly PKCη and PKCδ in the transition of keratinocytes from a proliferative to a differentiated phenotype. This is evidenced by the introduction of PKCη-null keratinocytes in 3D organotypic cultures resulting in increased epidermal thickness and delayed terminal differentiation that can be normalized by re-expression of wild-type PKCη [32]. In another study, overexpression of PKCη and PKCδ blocked proliferation of primary human keratinocytes and increased expression and activation of transglutaminase 1, which is involved in covalent crosslinking of protein components, such as INVL, FLG, LOR, necessary for forming the cornified envelope in terminally differentiated keratinocytes [33].…”

Section: Discussionmentioning

confidence: 99%

Ingenol Disoxate: A Novel 4-Isoxazolecarboxylate Ester of Ingenol with Improved Properties for Treatment of Actinic Keratosis and Other Non-Melanoma Skin Cancers

Bertelsen

Stahlhut

Grue-Sørensen

et al. 2016

Dermatol Ther (Heidelb)

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IntroductionIngenol mebutate gel (Picato®, LEO Pharma A/S) is approved for the field treatment of actinic keratosis and is characterized by high sustained clearance of actinic lesions. The inherent propensity of ingenol mebutate towards chemical rearrangement necessitates refrigeration of the final product. We sought to identify novel ingenol derivatives with enhanced chemical stability and similar or improved in vitro potency and in vivo efficacy.MethodsA number of ingenol esters were synthesized with full regiocontrol from ingenol. Chemical stability was determined in aqueous buffer at physiological pH and hydroalcoholic gel at lower pH. Acute cytotoxicity was determined in HeLa or HSC-5 cells. Keratinocyte proliferation, viability and caspase 3/7 activation was measured in primary epidermal keratinocytes. Relative gene expression levels were determined by real-time quantitative PCR. Evaluation of in vivo tumor ablating potential was performed in the murine B16 melanoma mouse model and in the UV-induced skin carcinogenesis model in hairless SKH-1 mice following topical treatment for two consecutive days with test compounds formulated at 0.1% in a hydroalcoholic gel.ResultsThis work resulted in the identification of ingenol disoxate (LEO 43204) displaying increased stability in a clinically relevant formulation and in aqueous buffer with minimal pH-dependent acyl migration degradation. Ingenol disoxate exhibited a significantly higher cytotoxic potency relative to ingenol mebutate. Likewise, cell growth arrest in normal human keratinocyte was more potently induced by ingenol disoxate, which was accompanied by protein kinase C dependent transcription of markers of keratinocyte differentiation. Most notably, ingenol disoxate possessed a superior antitumor effect in a B16 mouse melanoma model and significantly increased median survival time relative to ingenol mebutate. A significant effect on tumor ablation was also observed in a murine model of ultraviolet irradiation-induced skin carcinogenesis.ConclusionThese data illustrate that the favorable in vitro and in vivo pharmacological properties driving ingenol mebutate efficacy are either preserved or improved in ingenol disoxate. In combination with improved chemical stability to potentially facilitate storage of the final product at ambient temperatures, these features support further development of ingenol disoxate as a convenient and efficacious treatment modality of non-melanoma skin cancers.FundingLEO Pharma A/S.Electronic supplementary materialThe online version of this article (doi:10.1007/s13555-016-0137-2) contains supplementary material, which is available to authorized users.

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PKCη promotes a proliferation to differentiation switch in keratinocytes via upregulation of p27Kip1 mRNA through suppression of JNK/c-Jun signaling under stress conditions

Cited by 26 publications

References 37 publications

Low expression of chloride channel accessory 1 predicts a poor prognosis in colorectal cancer

Low expression of chloride channel accessory 1 predicts a poor prognosis in colorectal cancer

The Transition from Proliferation to Differentiation in Colorectal Cancer Is Regulated by the Calcium Activated Chloride Channel A1

Ingenol Disoxate: A Novel 4-Isoxazolecarboxylate Ester of Ingenol with Improved Properties for Treatment of Actinic Keratosis and Other Non-Melanoma Skin Cancers

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