European Review for Medical and Pharmacological Sciences 2018; 22: 7819-7825 DUSP22 promotes senescence of HS-1 skin cancer cells through triggering MAPK signaling pathway

X.-D. ZHAO1, C. HUANG2, R.-X. WANG3, S.-A. WANG1

1Department of Dermatology, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, Heilongjiang, China 2Department of Plastic Surgery, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, Heilongjiang, China 3Department of Dermatology, Daqing City Hospital, Daqing, Heilongjiang, China X.-D. Zhao and C. Huang contributed equally to this article

Abstract. – OBJECTIVE: Skin cancer severe- Introduction ly threatens the public health. Dual-specificity 22 (DUSP22) characterizes Skin cancer is one major death reason in with multiple roles regulating cell growth, prolif- dermatology, with 0.07% incidence and can eration and gaining. This study aims to investi- severely affect public health. Skin cancer has a gate the regulatory role of DUSP22 on aging of complicated pathogenesis mechanism1,2. Recent skin cancer cells and clarify molecular mecha- studies3,4 showed that abnormal cell proliferation nisms, along with potential application value. PATIENTS AND METHODS: and decreased number of aging cells are one HS-1 skin cancer major determinant factor for skin cancer. Early cells were transfected with DUSP22 by liposome transfection approach. Western blot assay was treatment is critical for skin cancer. Classical used to evaluate the effects of DUSP22 on aging treatments have satisfactory, but with various protein of HS-1 cells, and activation of mito- weakness and flaw. For example, there are various gen-activated protein kinase cascade (MAPK) complications such as lower appetite, mental signal pathway. Real-time PCR (RT-PCR) and refractory, body fatigue, nausea and vomiting, Western blot assay were used to examine the skin vessel bleeding may occur after chemo- or DUSP22 expression in HS-1 cancer cells. Mean- radio-therapy5,6. The strategy to improve precision while, the correlation between P53 protein and of skin cancer treatment and successful rate is aging was also investigated. major challenge. In clinical, precise medication RESULTS: Transfection of DUSP22 plasmid significantly elevated DUSP22 expression in HS- is important for skin cancer treatment, although 1 skin cancer cells compared to un-transfected the selection of target is the major challenge. cells (p<0.05), and activated MAPK to induce cell Therefore, more effective molecular drug targets aging. Transfection of small interfere RNA (siR- are required in clinics for skin cancer7,8. Recently NA) DUSP22 significantly suppressed DUSP22 dual-specificity protein phosphatase 22 (DUSP22) expression in HS-1 cancer cells, inhibited MAPK has become the potential treatment target for signal pathway, and decreased aging proteins multiple tumors. DUSP22 is one member P53 and P21 compared to the untreated group of non-receptor protein tyrosine phosphatase (p<0.05). DUSP22 was downregulated in HS-1 family sharing similar amino acid sequence. skin cancer cells, with MAPK signal pathway DUSP22 protein has phosphatase activity, inhibition, and lower aging protein P53 expres- especially for facilitating activation of mitogen sion. DUSP22 expression was positively cor- 9,10 related with aging protein P53 (p<0.05). activating protein (MAP) . Therefore, DUSP22 CONCLUSIONS: DUSP22 facilitated HS-1 may exert important response of cells targeting skin cancer cell aging via activating MAPK sig- environmental threaten via negative regulation, nal pathway, possibly providing novel strategy to maintain its normal function11. DUSP22 has against skin cancer. pluripotent functions, such as the inhibition of esophageal cancer cell growth or relation with Key Words 12-14 DUSP22, MAPK, Skin cancer cells, Cell aging. tumor metastasis . These studies suggested the possible involvement of DUSP22 in tumor

Corresponding Author: Shu-An Wang, MD; e-mail: [email protected] 7819 X.-D. Zhao, C. Huang, R.-X. Wang, S.-A. Wang occurrence and progression. The participation of consents. Among 50 skin cancer patients, 11 of DUSP22 in skin cancer occurrence or progression, them received surgery. Tumor was resected 0.5 cm however, is still unclear. Current researches15,16 at basal carcinoma site from tumor edge based on showed that cell aging may exert important roles tumor size, infiltration degree. Skin graft was then in occurrence and progression of skin cancer. Cell performed at surgical site. This study was approved aging is one progressive aging process during by the Ethics Committee of The Fifth Affiliated cell cycle, which is frequently accompanied with Hospital of Harbin Medical University (Daqing, elevated expression of aging related proteins such Heilongjiang, China). as P21 and P53, and blue staining of cells in beta- galactosidase, which has become one major index Cell Culture detecting cell aging17,18. However, molecules HS-1 skin carcinoma cells were resuscitated of cell aging that directly affect skin cancer and re-suspended in Dulbecco’s modified eagle occurrence are still unclear. Therefore, this work medium (DMEM) high-glucose cult ure medium 21. used HS-1 skin cancer cell model, on which the possible regulatory function of DUSP22 on HS-1 Transfection skin cancer cells was investigated for clinical Liposome transfection kit (Huamei Bio, implication. Beijing, China) was used to transfect DUSP22 and controlled plasmid into HS-1 skin cancer cells following routine method22. Cells were cultured at Patients and Methods 75% density. In brief, 2 μl (1 μg/μl) DUSP22 and controlled plasmid were re-suspended in Lipo2000 Reagent, Cell Model and Clinical Samples liposome for transfection and cell culture. P53 and P21 test for cell aging was purchased from Beyotime Biotech. (Shanghai, Immune Blotting of Cell Aging China). Fetal bovine serum (FBS) and cell HS-1 skin cancer cells after transfecting culture medium were purchased from Hualan DUSP22 or siRNA were extracted for protein Biological Engineering Inc., (Xinxiang, China). following manual instruction of protein Liposome cell transfection reagent was produced extraction kit. Protein sample was prepared for by Invitrogen/Life Technologies (Carlsbad, CA, quantification by micro-plate reader to separate USA). 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl- proteins by centrifugation. Protein samples 2-H-tetrazolium bromide (MTT) kit for testing were analyzed by electrophoresis. After Tris- cell viability was purchased from Dingguo Tech. buffered saline and Tween-20 (TBST) rinsing, (Beijing, China). Other reagents were purchased primary antibody was added for 4°C overnight from Santa Cruz Biotechnology (Santa Cruz, CA, incubation at 1:1000 dilution. TBST was used to USA). Small interfere RNA (siRNA) DUSP22 rinse mouse originated primary antibody (1:2000 (5’-ATAAT CGCAG GTGTC CACTC AT-3’; and for actin, 1:1000 for DUSP22, 1:1000 for MAPK, 5’-AATAA GAAGG AAGAC GGTAC A-3’) 1:1000 for P53 and 1:1000 for P21, Santa Cruz and control siRNA (5’-CCATC TATGA GGACG Biotech., Santa Cruz, CA, USA). Secondary CTTGC-3’ and 5’-TTATG TCCTA GCACA GAT- antibody (1:2500, Santa Cruz Biotech., Santa 3’), and DUSP22 plasmids were purchased from Cruz, CA, USA) was added for 37°C for 3 h. Shanghai GenePharma Co. Ltd. (Shanghai, China) TBST was then used for rinsing, followed by to amplify target . Expression vectors were development in enhanced chemiluminescence used to amplify DUSP22 protein. Skin cancer cell (ECL) substrate. 5% defatted milk powder was model HS-1 was purchased from American Microbe used to block, anti-MAPK primary antibody Strain Bank (Manassas, VA, USA). Based on and anti-mouse IgG secondary antibody were inclusive and exclusive criteria of skin cancer19,20, we sequentially used for incubation. After three selected skin cancer patients from October 2016 to times of rinsing, horseradish peroxidase (HRP) September 2017 in The Fifth Affiliated Hospital of was added for staining. Gel imaging apparatus Harbin Medical University (Daqing, Heilongjiang, was used for protein quantification by grey value China). We selected 50 patients and 50 controlled analysis. Gel imaging system (Qinxinag, China) volunteers aging between 46 and 80 years (average was used for capturing pictures and to analyze age = 66.5±6.5 years). This study fitted Ethical protein expression level. MAPK expression level requirements and all subjects (including skin cancer of MAPK in HS-1 cells was compared among patients and healthy volunteers) signed informed groups23.

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MAPK Activity Assay Aging of HS-1 cell cancer cells was described by MAPK activity kit (Beyotime Biotech., Shanghai, China) following routine method. In brief, HS-1 skin cancer cells were cultured and transfected with DUSP22 or controlled plasmid used methods abovementioned. HS-1 skin cancer cells after transfecting DUSP22 or controlled plasmid were lysed for chromogenic reaction using p protein as the substrate. Model 545 microplate reader was used for 20 min incubation in triplicates. Under room temperature, HS-1 skin cancer cells were place Figure 1. Effects of DUSP22 plasmid or siRNA-DUSP22 in 24-well plate, for measuring absorbent values plasmid transfection on expression levels of MAPK signal of each group on micro-plate reader24. MAPK pathway and aging proteins P53 or P21. relative activity was calculated as follows: using absorbent values of DUSP22 controlled plasmid transfected cells as the basal level, Results control values subtracted activity of DUSP22- transfected cells. Effects of DUSP22 Plasmid or siRNA-DUSP22 Plasmid Transfection on Effects of Interference or Over- Expression Levels of MAPK Signal Path Expression of DUSP22 on Aging of HS-1 way and Aging Proteins P53 or P21 Skin Cancer Cells As shown in Figure 1, transfection of DUSP22 To test the effect of interference or over- plasmid significantly elevated DUSP22 expression expression of DUSP22 on aging of HS-1 skin level in HS-1 skin cancer cells, activating MAPK cancer cells, Lipo2000 liposome transfection and inducing cell aging. Transfection of siRNA reagent was used to transfect HS-1 cells with DUSP22 significantly depressed DUSP22 DUSP22 siRNA or DUSP22 over-expression expression level in HS-1 skin cancer cells, plasmid following the manual instruction of inhibiting MAPK signal pathway and decreasing transfection kit. Cultured cells were transfected expression levels of aging proteins P53 and P21. using 2 μl (0.5 μg/μl) siRNA DUSP22 or DUSP22 plasmid suspension in Lipo2000 liposome, Real-Time PCR Results of DUSP22 followed by further culture. in Skin Cancer Patient’s Skin Tissues Figure 2 showed decreased DUSP22 level in Real-Time PCR Assay skin tissues of skin cancer patients compared Real-time PCR was performed to test DUSP22 to those in healthy volunteers (p<0.05). After level in skin tissues following routine method. treatment, DUSP22 level in skin tissues was Reaction system and conditions followed the elevated, indicating possible relationship between manual instruction of test kit. Primer sequences DUSP22 level and occurrence or prognosis of were: 5’-CTGAT GATCT GCGAC AGTGG-3’ skin cancer. and 5’-AGCGA GGAAT GGAAG AGTGC-3’; 5’-CTCAT GATTG AGACT GGTTC GGGTC Western Blot Results for DUSP22 GCACA GTTGA G-3’ and 5’-CTCAA CTGTC Protein in Skin Tissues of Skin Cancer GAGAG GTGTC GGCCG TGAAT GGATT C-3’. Patients The functional mechanism of DUSP22 in Statistical Analysis skin cancer remains to be further illustrated. As SPSS 14.0 software (SPSS Inc., Chicago, IL, shown in Figure 3, Western blot results showed USA) was used for analysis. Student’s t-test was lower DUSP22 level in skin cancer tissue (p<0.05 used to compare between two groups of HS-1 skin compared to skin of healthy volunteers). After cancer cells. Tukey’s post-hoc test was used to treatment, DUSP22 level in skin tissues was validate the ANOVA for comparing measurement elevated, indicating possible correlation between data among groups. A significance was defined DUSP22 level and occurrence or prognosis of when p<0.05 to confirm replicable results. skin cancer.

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Figure 3. Western blot results of DUSP22 in skin tissues from Figure 2. Real-time PCR results of DUSP22 in skin cancer skin cancer patients. **p<0.01 compared to control group. patient’s skin tissues. **p<0.01 compare to control group.

Western Blot Results for Skin Tissue DUSP22 and skin cancer, hoping to provide Aging of Skin Cancer valuable information for disease test. DUSP22 has Cell aging is accompanied with alternation of dual roles of mediating cell growth, proliferation aging proteins, especially P21 and P53 proteins and aging. This study indicated that DUSP22 with elevated expression. To further investigate could facilitate cell aging. the role of cell aging in skin cancer, we explored Currently important molecules for skin expression level of aged proteins in skin cancer cancer diagnosis include CD44, ECM protein tissues. As shown in Figure 4, Western blot results showed inhibited cell aging in skin cancer tissues compared to those from healthy volunteers, in addition to lower level of aging proteins P21 and P53.

Results of DUSP22 Level and P53 Aging Protein Level in Skin Cancer Tissues To further explore the correlation between DUSP22 level and aging protein P53 in skin cancer tissues, Pearson correlation analysis was used to analyze the correlation between skin cancer tissue DUSP22 level and aging protein P53/P21 levels. As shown in Figure 5 and Figure 6, Pearson correlation analysis revealed close correlation between DUSP22 level in skin cancer tissues and aging proteins P53 and P21 levels.

Discussion

Skin cancer severely threatens public health, making the early diagnosis and assay as one major 25 challenge for both clinicians and researchers . Figure 4. Western blot results of tissues aging in skin can- We investigated the possible correlation between cer patients.

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Figure 5. Test results of DUSP22 level in skin cancer tis- Figure 6. Test results of skin cancer tissue DUSP22 level sues and aging protein P53 level. and aging protein P21 expression.

laminin α5 and proteoglycan. DUSP22 is these facts: (1) transfection of DUSP22 plasmid closely correlated with various physio- significantly elevated DUSP22 expression in pathological processes in clinics26,27. For HS-1 skin cancer cells, and also activated MAPK example, DUSP22 is closely correlated with for cell aging. (2) Transfection of DUSP22 siRNA occurrence and progression of digestive tract significantly decreased DUSP22 expression in cancer, whilst DUSP14 and DUSP3 are related HS-1 skin cancer cells, thus suppressing MAPK with inflammatory response and prognosis of signal pathway for decreasing expression level of multiple tumors including esophageal carcinoma aging proteins P53 and P21. (3) DUSP22 is down- and lung cancer. These researches13,14,16 indicate regulated in HS-skin cancer cells, accompanied certain relationship between DUSP22 and by suppression of MAPK signal pathway and lower disease onset or progression, making it one P53 expression level. (4) DUSP22 is positively potential molecular marker reflecting disease correlated with expression level of aging protein onset and progression. The role and mechanism P53. This study has certain weakness. Firstly, of DUSP22 in skin cancer remain to be further relatively smaller sample size (including tissue elucidated. This work utilized HS-1 skin cancer number of skin cancer) may bias the conclusion. cell as the model, on which regulatory role of Further analyses should thus expand samples size DUSP22 on HS-1 skin cancer cells and possible including both cancer tissues and control tissues mechanism were investigated from molecular for further substantiation26. Secondarily, although and protein levels. Data showed that transfection skin DUSP22 level is correlated with cell aging of DUSP22 caused aging of HS-1 skin cancer protein P53 expression, no direct evidence has cells, as consistent with previous studies, which been shown at animal or individual levels. Thirdly, also suggested the participation of DUSP22 in this work did not classify skin cancer patients cell aging4. MAPK protein can facilitate cell based on tumor severity for further investigating aging23. In current study, whether MAPK is under correlation between DUSP22 level and cell aging DUSP22 regulation for further mediation of HS-1 protein P53 expression level. skin cancer cell growth remains unclear24,28. We showed that transfection of DUSP22 elevated MAPK level. After transfecting DUSP22 and Conclusions enhancing MAPK expression, HS-1 skin cancer cell aging rate was elevated. On the other hands, We showed that DUSP22 could facilitate HS-1 transfection of siRNA DUSP22 inhibited MAPK skin cancer cell aging via activating MAPK activity, suppressing HS-1 skin cancer cell signal pathway, possibly providing novel strategy aging. This study for the first time demonstrated for anti-skin cancer.

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