| Part ?.The Correlation Between Kat5 Expression in Thyroid Carcinoma and Clinical PrognosisPurpose/Objective(s):Papillary thyroid carcinoma accounts for the majority of thyroid carcinoma,and the prognosis of most patients is excellent.However,some patients may develop more aggressive forms with frequent recurrence of the disease after primary treatment,and distant metastases that unresponsive to treatment,and their prognosis remains poor.Although anaplastic thyroid carcinoma is a rare disease which only accounts for 1% to 5% of all thyroid carcinoma,it is one of the most lethal human malignancies with a poor median survival of 5 months after diagnosis,and is responsible for the majority of thyroid carcinoma-related deaths.Therefore,to change this dismal condition it is vital to investigate the underlying mechanism of highly aggressive forms of PTC and ATC.Increasing evidence has proved that DNA damage response could promote the progression and treatment resistance of human malignancies.The present study aims to detect the expression level of DNA damage response key protein Kat5 in clinical papillary thyroid carcinoma and anaplastic thyroid carcinoma samples,and to further investigate the correlation between Kat5 expression in tumor tissue and prognosis of patients.Materials/methods : We plan to detect the expression level of Kat5 protein in clinical papillary thyroid carcinoma and anaplastic thyroid carcinoma samples by immunohistochemistry staining,and to investigate the correlation between Kat5 expression and risk factors including capsular invasion,metastasis by Chi Square test.We further plan to investigate the correlation between Kat5 expression and survival by survival analysis.Results:In our own enrolled 317 cases of papillary thyroid carcinoma patients,we found a positive correlation between Kat5 expression and adverse prognostic factors including capsular invasion(P value<0.001)and lymph node metastasis(P value<0.001).Similarly,in our enrolled 60 cases of anaplastic thyroid carcinoma patients,we also found Kat5 expression positively correlates with lymphatic,distant metastasis and poorer survival(P value<0.001).Conclusions : Kat5 expression positively correlates with capsular invasion,lympho metastasis,distant metastasis and poorer prognosis of thyroid carcinoma.However,the role of Kat5 in the progression and treatment resistance of thyroid carcinoma needs to be further explored.Part ? The Function of Kat5 on Progression and Radio/chemo-resistance in Human Thyroid CarcinomaPurpose/Objective(s):Based on our result above,we hypothesized that in human papillary thyroid carcinoma and anasplastic thyroid carcinoma,the up-regulated Kat5 may promote progression and treatment resistance,and result in poorer prognosis.We aim to investigate the function of Kat5 on proliferation,migration,invasion,metastasis,angiogenesis and treatment resistance in human thyroid carcinoma cells.Materials/methods: We overexpress Kat5 by plasmid in papillary thyroid carcinoma cell line Tpc1 and anasplastic thyroid carcinoma cell line 8505 c,while knockdown Kat5 expression by si RNA in 8505 c cells.Then,we conduct in vitro study to investigate the effects of Kat5 on proliferation,migration,invasion,angiogenesis and radio/chemo sensitivity by MTT assay,crystal violet staining assay,colony formation assay,wound healing assay,transwell migration assay,transwell invasion assay and in vitro tube formation assay,respectively.Next,we generate Kat5 stable knockdown and Kat5 stable overexpression thyroid carcinoma cells,recpectively.Then we conduct in vivo study to investigate the effect of Kat5 on metastasis ability of human thyroid carcinoma cells in nude mice.Results:MTT assay,crystal violet staining assay and colony formation assay showed that overexpression of Kat5 promote proliferation in both cells,while knockdown of Kat5 inhibits proliferation of 8505 c cells.In transwell invasion assay,the result indicated that overexpression of Kat5 promote invasion in both cells,while knockdown of Kat5 inhibits invasion of 8505 c cells.In in vitro tube formation assay,overexpression of Kat5 increases the length of tubes in 8505 c cells,while knockdown of Kat5 decreases that,however,Tpc-1 cells failed to form tubes.MTT and colony formation assay also showed that overexpression of Kat5 promotes radio/chemo resistance of both cells,while knockdown of Kat5 sensitizes 8505 c cells to radio/chemo-therapy.In our in vivo study,overexpression of Kat5 in Tpc-1 cells significantly increased the number of lung nodules,while knockdown of Kat5 in 8505 c cells remarkably decreased the number of lung nodules.Conclusions: Kat5 could promote proliferation,invasion,distant metastasis,angiogenesis,radio-resistance and chemo-resistance of thyroid carcinoma cells,and may be a novel target in clinical thyroid carcinoma treatment.Part ? Study the Underlying Mechanism of Kat5-mediated Progression and Radio/chemo-resistance in Human Thyroid CarcinomaPurpose/Objective(s): Based on our result above and literature search,we further hypothesized that in human papillary thyroid carcinoma and anasplastic thyroid carcinoma,Kat5 may promote progression and treatment resistance via c-myc signal.Materials/methods: We overexpress Kat5 by plasmid in papillary thyroid carcinoma cell line Tpc1 and anasplastic thyroid carcinoma cell line 8505 c,while knockdown Kat5 expression by si RNA in 8505 c cells.Then,we investigate the effect of Kat5 on c-myc expression,stability and ubiquitination degradation by western blotting and immunoprecipitation.Results : In this mechanism study,western blotting data showed a positive correlation between Kat5 expression and c-myc protein expression in both Tpc1 and 8505 c cells.Then immunoprecipitation study showed that overexpression of Kat5 extends the half-life and inhibits ubiquitination dependent degradation of c-myc protein in both cells,while knockdown of Kat5 has the opposite effect on 8505 c cells.Conclusions : Kat5 increases c-myc protein level in papillary thyroid carcinoma and anasplastic thyroid carcinoma cells by enhancing the stability and inhibiting ubiquitination dependent degradation of c-myc.Therefore,Kat5 may promote progression and treatment resistance of thyroid carcinoma cells via c-myc signal. |
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