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Article ; Online: Twist1 as a target for prevention of cutaneous squamous cell carcinoma.

Wang, Tingzeng / Rho, Okkyung / Eguiarte-Solomon, Fernando / DiGiovanni, John

2022 Volume 62, Issue 1, Page(s) 62–76

Abstract: Cutaneous squamous cell carcinoma (cSCC) represents an important clinical problem requiring novel approaches for both prevention and treatment. The transcription factor, Twist-related protein 1 (Twist1), has been identified as having a key mechanistic ... ...

Abstract	Cutaneous squamous cell carcinoma (cSCC) represents an important clinical problem requiring novel approaches for both prevention and treatment. The transcription factor, Twist-related protein 1 (Twist1), has been identified as having a key mechanistic role in the development and progression of cSCC. Studies in relevant mouse models of cSCC have shown that Twist1 regulates epithelial-mesenchymal transition (EMT) and stemness driving progression and metastasis of cSCC. In addition, further research has shown that Twist1 regulates the balance between keratinocyte proliferation and differentiation and therefore impacts earlier stages of cSCC development. Through use of keratinocyte specific Twist1 knockout models, a role for this gene in keratinocyte stem cell homeostasis has been revealed. As a transcription factor, Twist1 regulates a large number of genes both in a positive, as well as a negative manner across several interdependent pathways. Studies in keratinocyte specific knockout models have shown that Twist1 upregulates the expression of genes involved in proliferation, stemness, and EMT while downregulating the expression of genes associated with differentiation. Furthermore, a number of compounds, including naturally occurring compounds, have been identified that target Twist1 and can block its effects in cancer cells and in keratinocytes in vivo. Collectively, the current understanding of Twist1 function in cSCC development and progression suggests that it represents a potential target for prevention and treatment of cSCC.
MeSH term(s)	Animals ; Mice ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/prevention & control ; Carcinoma, Squamous Cell/metabolism ; Cell Line, Tumor ; Cell Proliferation/genetics ; Epithelial-Mesenchymal Transition/genetics ; Gene Expression Regulation, Neoplastic ; Skin Neoplasms/genetics ; Skin Neoplasms/prevention & control ; Skin Neoplasms/pathology ; Twist-Related Protein 1/genetics ; Twist-Related Protein 1/metabolism
Chemical Substances	Twist-Related Protein 1 ; Twist1 protein, mouse (136253-27-5)
Language	English
Publishing date	2022-11-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1004029-8
ISSN	1098-2744 ; 0899-1987
ISSN (online)	1098-2744
ISSN	0899-1987
DOI	10.1002/mc.23482
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Article ; Online: Inducible Keratinocyte Specific FGFR2 Deficiency Inhibits UVB-Induced Signaling, Proliferation, Inflammation, and Skin Carcinogenesis.

Thakur, Megha / Rho, Okkyung / Khandelwal, Alok / Nathan, Cherie-Ann O / DiGiovanni, John

The Journal of investigative dermatology

2023 Volume 144, Issue 2, Page(s) 341–350.e7

Abstract: A potential role for fibroblast growth factor receptor 2 (FGFR2) in cutaneous squamous cell carcinoma (cSCC) has been reported. To demonstrate the specific role of FGFR2 in UVB-induced skin carcinogenesis and development of cSCC, we generated a ... ...

Abstract	A potential role for fibroblast growth factor receptor 2 (FGFR2) in cutaneous squamous cell carcinoma (cSCC) has been reported. To demonstrate the specific role of FGFR2 in UVB-induced skin carcinogenesis and development of cSCC, we generated a keratinocyte specific, tamoxifen inducible mouse model of FGFR2 deficiency. In this mouse model, topical application of 4-hydroxy tamoxifen led to the induction of Cre recombinase to delete FGFR2 in epidermal keratinocytes of both male and female transgenic mice. Analysis of epidermal protein lysates isolated from FGFR2 deficient mice exposed to UVB showed significant reductions of phospho-FGFR (pFGFR; Y653/654) and phospho-fibroblast growth factor receptor substrate 2α as well as downstream effectors of mTORC1 signaling. Phosphorylation of signal transducer and activators of transcription 1/3 was significantly reduced as well as levels of IRF-1, DUSP6, early growth response 1, and PD-L1 compared to the control groups. Keratinocyte-specific ablation of FGFR2 also significantly inhibited epidermal hyperproliferation, hyperplasia, and inflammation after exposure to UVB. Finally, keratinocyte-specific deletion of FGFR2 significantly inhibited UVB-induced cSCC formation. Collectively, the current data demonstrate an important role of FGFR2 in UVB-induced oncogenic signaling as well as development of cSCC. In addition, the current preclinical findings suggest that inhibition of FGFR2 signaling may provide a previously unreported strategy to prevent and/or treat UVB-induced cSCC.
MeSH term(s)	Animals ; Female ; Male ; Mice ; Carcinogenesis/genetics ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/metabolism ; Cell Proliferation ; Inflammation/metabolism ; Keratinocytes/metabolism ; Mice, Transgenic ; Receptor, Fibroblast Growth Factor, Type 2/genetics ; Receptor, Fibroblast Growth Factor, Type 2/metabolism ; Skin Neoplasms/genetics ; Skin Neoplasms/prevention & control ; Tamoxifen ; Ultraviolet Rays/adverse effects
Chemical Substances	Receptor, Fibroblast Growth Factor, Type 2 (EC 2.7.10.1) ; Tamoxifen (094ZI81Y45) ; Fgfr2 protein, mouse (EC 2.7.10.1)
Language	English
Publishing date	2023-09-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2023.08.013
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Article ; Online: Inhibition of Fibroblast Growth Factor Receptor Attenuates UVB-Induced Skin Carcinogenesis.

Thakur, Megha A / Khandelwal, Alok R / Gu, Xin / Rho, Okkyung / Carbajal, Steve / Kandula, Rima A / DiGiovanni, John / Nathan, Cherie-Ann O

The Journal of investigative dermatology

2022 Volume 142, Issue 11, Page(s) 2873–2884.e7

Abstract: Altered fibroblast GF receptor (FGFR) signaling has been shown to play a role in a number of cancers. However, the role of FGFR signaling in the development and progression of UVB-induced cutaneous squamous cell carcinoma remains unclear. In this study, ... ...

Abstract	Altered fibroblast GF receptor (FGFR) signaling has been shown to play a role in a number of cancers. However, the role of FGFR signaling in the development and progression of UVB-induced cutaneous squamous cell carcinoma remains unclear. In this study, the effect of UVB radiation on FGFR activation and its downstream signaling in mouse skin epidermis was examined. In addition, the impact of FGFR inhibition on UVB-induced signaling and skin carcinogenesis was also investigated. Exposure of mouse dorsal skin to UVB significantly increased the phosphorylation of FGFRs in the epidermis as well as the activation of downstream signaling pathways, including protein kinase B/mTOR, signal transducers and activators of transcription, and MAPK. Topical application of the pan-FGFR inhibitor AZD4547 to mouse skin before exposure to UVB significantly inhibited FGFR phosphorylation as well as mTORC1, signal transducer and activator of transcription 3, and MAPK activation (i.e., phosphorylation). Moreover, AZD4547 pretreatment significantly inhibited UVB-induced epidermal hyperplasia and hyperproliferation and reduced the infiltration of mast cells and macrophages into the dermis. AZD4547 treatment also significantly inhibited mRNA expression of inflammatory genes in the epidermis. Finally, mice treated topically with AZD4547 before UVB exposure showed decreased cutaneous squamous cell carcinoma incidence and increased survival rate. Collectively, the current data support the hypothesis that inhibition of FGFR in the epidermis may provide a new strategy to prevent and/or treat UVB-induced cutaneous squamous cell carcinoma.
MeSH term(s)	Mice ; Animals ; Receptors, Fibroblast Growth Factor/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; STAT3 Transcription Factor/metabolism ; Carcinoma, Squamous Cell/genetics ; Skin Neoplasms/etiology ; Skin Neoplasms/prevention & control ; Skin Neoplasms/pathology ; Ultraviolet Rays/adverse effects ; TOR Serine-Threonine Kinases/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Carcinogenesis ; RNA, Messenger
Chemical Substances	AZD4547 ; Receptors, Fibroblast Growth Factor ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; STAT3 Transcription Factor ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; RNA, Messenger
Language	English
Publishing date	2022-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2022.03.036
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Article ; Online: Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin.

Tremmel, Lisa / Rho, Okkyung / Slaga, Thomas J / DiGiovanni, John

Molecular carcinogenesis

2018 Volume 58, Issue 2, Page(s) 185–195

Abstract: Prevention remains an important strategy to reduce the burden of cancer. One approach to prevent cancer is the use of phytochemicals in various combinations as safe and effective cancer preventative agents. The purpose of this study was to examine the ... ...

Abstract	Prevention remains an important strategy to reduce the burden of cancer. One approach to prevent cancer is the use of phytochemicals in various combinations as safe and effective cancer preventative agents. The purpose of this study was to examine the effects of the combination of ursolic acid (UA) and curcumin (Curc) for potential combinatorial inhibition of skin tumor promotion using the mouse two-stage skin carcinogenesis model. In short-term experiments, the combination of UA + Curc given topically prior to 12-O-tetradecanoylphorbol-13-acetate (TPA) significantly inhibited activation of epidermal EGFR, p70S6K, NF-κB p50, Src, c-Jun, Rb, and IκBα. Levels of c-Fos, c-Jun, and Cox-2 were also significantly reduced by the combination compared to the TPA treated group. The alterations in these signaling pathways by the combination of UA + Curc were associated with decreased epidermal proliferation as assessed by measuring BrdU incorporation. Significant effects were also seen with the combination on epidermal inflammatory gene expression and dermal inflammation, with the greatest effects on expression of IL-1β, IL-6, IL-22, and CXCL2. Furthermore, results from skin tumor experiments demonstrated that the combination of UA + Curc given topically significantly inhibited mouse skin tumor promotion by TPA to a greater extent than the individual compounds given alone. The greatest effects were seen on tumor free survival, tumor size, and tumor weight, although tumor incidence and multiplicity were also further reduced by the combination. These results demonstrate the potential cancer chemopreventive activity and mechanism(s) for the combination of UA + Curc.
MeSH term(s)	Administration, Topical ; Animals ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Chemokine CXCL2/genetics ; Chemokine CXCL2/metabolism ; Curcumin/administration & dosage ; Curcumin/pharmacology ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Interleukin-1beta/genetics ; Interleukin-1beta/metabolism ; Interleukin-6/genetics ; Interleukin-6/metabolism ; Interleukins/genetics ; Interleukins/metabolism ; Mice ; Signal Transduction/drug effects ; Skin Neoplasms/chemically induced ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics ; Skin Neoplasms/metabolism ; Tetradecanoylphorbol Acetate/adverse effects ; Treatment Outcome ; Triterpenes/administration & dosage ; Triterpenes/pharmacology ; Xenograft Model Antitumor Assays ; Interleukin-22 ; Ursolic Acid
Chemical Substances	CXCL2 protein, human ; Chemokine CXCL2 ; IL1B protein, human ; IL6 protein, human ; Interleukin-1beta ; Interleukin-6 ; Interleukins ; Triterpenes ; Curcumin (IT942ZTH98) ; Tetradecanoylphorbol Acetate (NI40JAQ945)
Language	English
Publishing date	2018-10-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1004029-8
ISSN	1098-2744 ; 0899-1987
ISSN (online)	1098-2744
ISSN	0899-1987
DOI	10.1002/mc.22918
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Article ; Online: Twist1 is required for the development of UVB-induced squamous cell carcinoma.

Eguiarte-Solomon, Fernando / Blazanin, Nicholas / Rho, Okkyung / Carbajal, Steve / Felsher, Dean W / Tran, Phuoc T / DiGiovanni, John

Molecular carcinogenesis

2021 Volume 60, Issue 5, Page(s) 342–353

Abstract: The transcription factor Twist1 has been reported to be essential for the formation and invasiveness of chemically induced tumors in mouse skin. However, the impact of keratinocyte-specific Twist1 deletion on skin carcinogenesis caused by UVB radiation ... ...

Abstract	The transcription factor Twist1 has been reported to be essential for the formation and invasiveness of chemically induced tumors in mouse skin. However, the impact of keratinocyte-specific Twist1 deletion on skin carcinogenesis caused by UVB radiation has not been reported. Deletion of Twist1 in basal keratinocytes of mouse epidermis using K5.Cre × Twist1
MeSH term(s)	Administration, Topical ; Animals ; Carcinoma, Squamous Cell/drug therapy ; Carcinoma, Squamous Cell/etiology ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/metabolism ; Cell Differentiation ; Cells, Cultured ; Epithelial-Mesenchymal Transition/drug effects ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Knockout Techniques ; Harmine/administration & dosage ; Harmine/pharmacology ; Keratinocytes/cytology ; Keratinocytes/metabolism ; Keratinocytes/pathology ; Male ; Mice ; Skin Neoplasms/drug therapy ; Skin Neoplasms/etiology ; Skin Neoplasms/genetics ; Skin Neoplasms/metabolism ; Twist-Related Protein 1/genetics ; Ultraviolet Rays/adverse effects
Chemical Substances	Twist-Related Protein 1 ; Twist1 protein, mouse (136253-27-5) ; Harmine (4FHH5G48T7)
Language	English
Publishing date	2021-03-13
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1004029-8
ISSN	1098-2744 ; 0899-1987
ISSN (online)	1098-2744
ISSN	0899-1987
DOI	10.1002/mc.23296
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Article ; Online: Twist1 regulates keratinocyte proliferation and skin tumor promotion.

Srivastava, Jaya / Rho, Okkyung / Youssef, Ronnie M / DiGiovanni, John

Molecular carcinogenesis

2016 Volume 55, Issue 5, Page(s) 941–952

Abstract: In the present study, we evaluated the effect of deleting Twist1 on keratinocyte proliferation and on skin tumor development using the two-stage chemical carcinogenesis model. BK5.Cre × Twist1(flox/flox) mice, which have a keratinocyte-specific Twist1 ... ...

Abstract	In the present study, we evaluated the effect of deleting Twist1 on keratinocyte proliferation and on skin tumor development using the two-stage chemical carcinogenesis model. BK5.Cre × Twist1(flox/flox) mice, which have a keratinocyte-specific Twist1 knockout (Twist1 KO), developed significantly reduced numbers of papilloma (70% reduction) and squamous cell carcinoma (75% reduction) as well as delayed tumor latency compared to wild-type (WT) mice. Interestingly, knockdown of Twist1 in primary keratinocytes impeded cell cycle progression at the G1/S transition that coincided with reduced levels of the cell cycle proteins c-Myc, Cyclin E1, and E2F1 and increased levels of p53 and p21. Furthermore, ChIP analyses revealed that Twist1 bound to the promoter regions of Cyclin E1, E2F1, and c-Myc at the canonical E-box binding motif suggesting a direct transcriptional regulation. Further analyses of Twist1 KO mice revealed a significant reduction in the number of label-retaining cells as well as the number of α6-integrin(+) /CD34(+) cells in the hair follicles of untreated mice compared to WT mice. These mice also exhibited significantly reduced epidermal proliferation in response to TPA treatment that again correlated with reduced levels of cell cycle regulators and increased levels of p53 and p21. Finally, Twist1 deficiency in keratinocytes led to an upregulation of p53 via its stabilization and nuclear localization, which is responsible for the increased expression of p21 in these cells. Collectively, these findings indicate that Twist1 has a novel role in epithelial carcinogenesis by regulating proliferation of keratinocytes, including keratinocyte stem cells during tumor promotion.
MeSH term(s)	9,10-Dimethyl-1,2-benzanthracene/toxicity ; Animals ; Cell Cycle/drug effects ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Gene Knockout Techniques ; Keratinocytes/cytology ; Keratinocytes/metabolism ; Mice ; Mice, Transgenic ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Promoter Regions, Genetic ; Skin Neoplasms/chemically induced ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Tetradecanoylphorbol Acetate/toxicity ; Twist-Related Protein 1/genetics ; Twist-Related Protein 1/metabolism
Chemical Substances	Nuclear Proteins ; Twist-Related Protein 1 ; Twist1 protein, mouse (136253-27-5) ; 9,10-Dimethyl-1,2-benzanthracene (57-97-6) ; Tetradecanoylphorbol Acetate (NI40JAQ945)
Language	English
Publishing date	2016-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1004029-8
ISSN	1098-2744 ; 0899-1987
ISSN (online)	1098-2744
ISSN	0899-1987
DOI	10.1002/mc.22335
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Article ; Online: Overexpression of PRAS40(T246A) in the Proliferative Compartment Suppresses mTORC1 Signaling, Keratinocyte Migration, and Skin Tumor Development.

Rho, Okkyung / Srivastava, Jaya / Cho, Jiyoon / DiGiovanni, John

The Journal of investigative dermatology

2016 Volume 136, Issue 10, Page(s) 2070–2079

Abstract: The proline-rich Akt (v-akt murine thymoma viral oncogene homolog 1) substrate of 40 kDa (PRAS40), an inhibitory component of the mTORC1 complex, was identified as an Akt substrate through phosphorylation at Thr246. Phosphorylation at this site releases ... ...

Abstract	The proline-rich Akt (v-akt murine thymoma viral oncogene homolog 1) substrate of 40 kDa (PRAS40), an inhibitory component of the mTORC1 complex, was identified as an Akt substrate through phosphorylation at Thr246. Phosphorylation at this site releases PRAS40 from the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) complex allowing increased activity. Targeted expression of a mutant form of PRAS40 (PRAS40(T246A)) in basal keratinocytes of mouse epidermis (BK5.PRAS40(T246A) mice) has allowed further examination of mTORC1-specific signaling in epithelial carcinogenesis. BK5.PRAS40(T246A) mice were resistant to 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal hyperproliferation and skin tumor development. In transgenic mice, PRAS40(T246A) remained bound to raptor in keratinocytes even after treatment with TPA, consistent with reduced mTORC1 signaling and altered levels of cell cycle proteins. BK5.PRAS40(T246A) mice also displayed attenuated skin inflammation in response to TPA. Inhibition of mTORC1 in keratinocytes significantly inhibited their migration in vitro and, in addition, inhibited 12-O-tetradecanoylphorbol-13-acetate-induced proliferation and migration of bulge-region stem cells in vivo. Furthermore, targeted inhibition of mTORC1 in BK5.PRAS40(T246A) mice resulted in delayed wound healing. Decreased keratinocyte migration and impaired wound healing correlated with altered expression of epithelial-mesenchymal transition (EMT) markers and reduced smad signaling. Collectively, the current data using this unique mouse model provide further evidence that mTORC1 signaling in keratinocytes regulates key events in keratinocyte function and epithelial cancer development.
MeSH term(s)	Animals ; Cell Movement/genetics ; Cell Proliferation ; Epithelial-Mesenchymal Transition/genetics ; Female ; Keratinocytes/metabolism ; Male ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Mice, Transgenic ; Multiprotein Complexes/metabolism ; Phosphoproteins/genetics ; Signal Transduction/genetics ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Smad Proteins/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Tetradecanoylphorbol Acetate/toxicity ; Wound Healing/genetics
Chemical Substances	Multiprotein Complexes ; Phosphoproteins ; Smad Proteins ; proline-rich Akt substrate, 40 kDa protein, mouse ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Tetradecanoylphorbol Acetate (NI40JAQ945)
Language	English
Publishing date	2016-06-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2016.06.013
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Article ; Online: Impact of mTORC1 inhibition on keratinocyte proliferation during skin tumor promotion in wild-type and BK5.AktWT mice.

Rho, Okkyung / Kiguchi, Kaoru / Jiang, Guiyu / DiGiovanni, John

Molecular carcinogenesis

2013 Volume 53, Issue 11, Page(s) 871–882

Abstract: In this study, we examined the impact of rapamycin on mTORC1 signaling during 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced keratinocyte proliferation and skin tumor promotion in both wild-type (FVB/N) and BK5.Akt(WT) mice. TPA activated mTORC1 ... ...

Abstract	In this study, we examined the impact of rapamycin on mTORC1 signaling during 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced keratinocyte proliferation and skin tumor promotion in both wild-type (FVB/N) and BK5.Akt(WT) mice. TPA activated mTORC1 signaling in a time-dependent manner in cultured primary mouse keratinocytes and a mouse keratinocyte cell line. Early activation (15-30 min) of mTORC1 signaling induced by TPA was mediated in part by PKC activation, whereas later activation (2-4 h) was mediated by activation of EGFR and Akt. BK5.Akt(WT) transgenic mice, where Akt1 is overexpressed in basal epidermis, are highly sensitive to TPA-induced epidermal proliferation and two-stage skin carcinogenesis. Targeting mTORC1 with rapamycin effectively inhibited TPA-induced epidermal hyperplasia and hyperproliferation as well as tumor promotion in a dose-dependent manner in both wild-type and BK5.Akt(WT) mice. A significant expansion (∼threefold) of the label retaining cell (LRC) population per hair follicle was observed in BK5.Akt(WT) mice compared to FVB/N mice. There was also a significant increase in K15 expressing cells in the hair follicle of transgenic mice that coincided with expression of phospho-Akt, phospho-S6K, and phospho-PRAS40, suggesting an important role of mTORC1 signaling in bulge-region keratinocyte stem cell (KSC) homeostasis. After 2 weeks of TPA treatment, LRCs had moved upward into the interfollicular epidermis from the bulge region of both wild-type and BK5.Akt(WT) mice. TPA-mediated LRC proliferation and migration was significantly inhibited by rapamycin. Collectively, the current data indicate that signaling through mTORC1 contributes significantly to the process of skin tumor promotion through effects on proliferation of the target cells for tumor development.
MeSH term(s)	Animals ; Antibiotics, Antineoplastic/pharmacology ; Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors ; Cell Line ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic/chemically induced ; Chromones/pharmacology ; ErbB Receptors/biosynthesis ; Female ; Flavonoids/pharmacology ; Hair Follicle/metabolism ; Hyperplasia/chemically induced ; Hyperplasia/prevention & control ; Keratinocytes/cytology ; Male ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Mice, Inbred ICR ; Mice, Transgenic ; Morpholines/pharmacology ; Multiprotein Complexes/antagonists & inhibitors ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase C/biosynthesis ; Proto-Oncogene Proteins c-akt/biosynthesis ; Signal Transduction/drug effects ; Sirolimus/pharmacology ; Skin Neoplasms/chemically induced ; Skin Neoplasms/pathology ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; Tetradecanoylphorbol Acetate/analogs & derivatives ; Tetradecanoylphorbol Acetate/pharmacology
Chemical Substances	12-O-tetradecanoylphorbol-1,3-acetate ; Antibiotics, Antineoplastic ; Chromones ; Flavonoids ; Morpholines ; Multiprotein Complexes ; Phosphoinositide-3 Kinase Inhibitors ; 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (31M2U1DVID) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; EGFR protein, mouse (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Protein Kinase C (EC 2.7.11.13) ; Calcium-Calmodulin-Dependent Protein Kinases (EC 2.7.11.17) ; Tetradecanoylphorbol Acetate (NI40JAQ945) ; 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (SJE1IO5E3I) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2013-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1004029-8
ISSN	1098-2744 ; 0899-1987
ISSN (online)	1098-2744
ISSN	0899-1987
DOI	10.1002/mc.22046
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Laser capture microdissection to examine transporter expression in specific cell regions.

Rho, Okkyung / Miller, Gary W

Methods in molecular biology (Clifton, N.J.)

2003 Volume 227, Page(s) 85–96

MeSH term(s)	Coloring Agents/pharmacology ; Dissection/methods ; Humans ; Immunohistochemistry ; Lasers ; Membrane Transport Proteins/biosynthesis ; Membrane Transport Proteins/genetics ; Micromanipulation/methods ; Neurons/metabolism ; Parkinson Disease/metabolism ; RNA/metabolism ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Tissue Distribution ; Tolonium Chloride/pharmacology
Chemical Substances	Coloring Agents ; Membrane Transport Proteins ; Tolonium Chloride (15XUH0X66N) ; RNA (63231-63-0)
Language	English
Publishing date	2003
Publishing country	United States
Document type	Journal Article
ISSN	1064-3745
ISSN	1064-3745
DOI	10.1385/1-59259-387-9:85
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Article ; Online: Growth factor signaling pathways as targets for prevention of epithelial carcinogenesis.

Rho, Okkyung / Kim, Dae Joon / Kiguchi, Karou / Digiovanni, John

Molecular carcinogenesis

2010 Volume 50, Issue 4, Page(s) 264–279

Abstract: Growth factor receptor (GFR) signaling controls epithelial cell growth by responding to various endogenous or exogenous stimuli and subsequently activating downstream signaling pathways including Stat3, PI3K/Akt/mTOR, MAPK, and c-Src. Environmental ... ...

Abstract	Growth factor receptor (GFR) signaling controls epithelial cell growth by responding to various endogenous or exogenous stimuli and subsequently activating downstream signaling pathways including Stat3, PI3K/Akt/mTOR, MAPK, and c-Src. Environmental chemical toxicants and UVB irradiation cause enhanced and prolonged activation of GFR signaling and downstream pathways that contributes to epithelial cancer development including skin cancer. Recent studies, especially those with tissue-specific transgenic mouse models, have demonstrated that GFRs and their downstream signaling pathways contribute to all three stages of epithelial carcinogenesis by regulating a wide variety of biological functions including proliferation, apoptosis, angiogenesis, cell adhesion, and migration. Inhibiting these signaling pathways early in the carcinogenic process results in reduced cell proliferation and survival, leading to decreased tumor formation. Collectively, these studies suggest that GFR signaling and subsequent downstream signaling pathways are potential targets for the prevention of epithelial cancers including skin cancer.
MeSH term(s)	Animals ; Antineoplastic Agents/therapeutic use ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic/drug effects ; Cell Transformation, Neoplastic/metabolism ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Humans ; Models, Biological ; Receptor, IGF Type 1/metabolism ; Receptors, Growth Factor/metabolism ; Signal Transduction/drug effects ; Signal Transduction/physiology
Chemical Substances	Antineoplastic Agents ; Receptors, Growth Factor ; Receptor, IGF Type 1 (EC 2.7.10.1)
Language	English
Publishing date	2010-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1004029-8
ISSN	1098-2744 ; 0899-1987
ISSN (online)	1098-2744
ISSN	0899-1987
DOI	10.1002/mc.20665
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