Liver cancer is a prevalent malignant cancer,ranking third in terms of mortality rate.Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer.Hepatocellular carcinoma(HCC)has low expr...Liver cancer is a prevalent malignant cancer,ranking third in terms of mortality rate.Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer.Hepatocellular carcinoma(HCC)has low expression of focal adhesion kinase(FAK),which increases the risk of metastasis and recurrence.Nevertheless,the efficacy of FAK phosphorylation inhibitors is currently limited.Thus,investigating the mechanisms by which FAK affects HCC metastasis to develop targeted therapies for FAK may present a novel strategy to inhibit HCC metastasis.This study examined the correlation between FAK expression and the prognosis of HCC.Additionally,we explored the impact of FAK degradation on HCC metastasis through wound healing experiments,transwell invasion experiments,and a xenograft tumor model.The expression of proteins related to epithelial-mesenchymal transition(EMT)was measured to elucidate the underlying mechanisms.The results showed that FAK PROTAC can degrade FAK,inhibit the migration and invasion of HCC cells in vitro,and notably decrease the lung metastasis of HCC in vivo.Increased expression of E-cadherin and decreased expression of vimentin indicated that EMT was inhibited.Consequently,degradation of FAK through FAK PROTAC effectively suppressed liver cancer metastasis,holding significant clinical implications for treating liver cancer and developing innovative anti-neoplastic drugs.展开更多
BACKGROUND: Secondary lesions can occur in tissues surrounding the hematoma following intracerebral hemorrhage, with the presence of inflammatory reactions, cytokine expression and apoptosis These have been confirmed...BACKGROUND: Secondary lesions can occur in tissues surrounding the hematoma following intracerebral hemorrhage, with the presence of inflammatory reactions, cytokine expression and apoptosis These have been confirmed in animal studies. Our study sought to determine whether these could be detected in human tissues surrounding the hematoma following intracerebral hemorrhage. OBJECTIVE: To investigate expression of inflammatory cytokines, Bax and Bcl-x, and identify neural cell apoptosis in tissues surrounding the hematoma, and to analyze the correlation between them and pathological damage in intracerebral hemorrhage patients. DESIGN, TIME AND SETTING: This histopathology, controlled study was performed at the Department of Neurosurgery, Sichuan People's Hospital, China, from January 2003 to January 2005. PARTICIPANTS: Brain tissues 1 cm from the hematoma in 30 intracerebral hemorrhage patients served as the experimental group. Brain tissues located away from the hematoma in 7 patients served as the control group. METHODS: TUNEL was used to detect neural cell apoptosis. Immunohistochemistry (labeled dextran polymer) and RT-PCR were used to measure tumor necrosis factor- α, interleukin-1 β, interleukin-6, Bax and Bcl-x protein and mRNA expression. Pathological changes in brain tissues surrounding the hematoma were observed following HE staining. MAIN OUTCOME MEASURES: Neural cell apoptosis, inflammatory cytokines, Bax and Bcl-x protein and mRNA expression, pathological changes in brain tissues surrounding the hematoma. RESULTS: Brain tissues surrounding the hematoma were mildly damaged within 6 hours, severely damaged at 24-72 hours, and significantly improved 1 week following intracerebral hemorrhage. Expression of tumor necrosis factor- α protein and mRNA, interleukin-1β and interleukin-6 mRNA was not significant in tissues surrounding the hematoma, which was identical to the control group within 6 hours after intracerebral hemorrhage. This expression was significantly higher compared with the control group from 12-72 hours, and gradually decreased after 72 hours. The number of apoptotic neural cells reached a peak between 12- 72 hours. Tumor necrosis factor-α protein and mRNA, interleukin-1β and interleukin-6 mRNA levels were positively correlated with apoptosis, Bax protein and mRNA levels (P 〈 0.01 ). CONCLUSION: Tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels are highly correlated with apoptosis. With the decrease in tumor necrosis factor-α, interleukin-1β and interleukin-6 levels, the number of apoptotic cells gradually reduced.展开更多
基金supported by the National Natural Science Foundation of China Fund Project(82272956).
文摘Liver cancer is a prevalent malignant cancer,ranking third in terms of mortality rate.Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer.Hepatocellular carcinoma(HCC)has low expression of focal adhesion kinase(FAK),which increases the risk of metastasis and recurrence.Nevertheless,the efficacy of FAK phosphorylation inhibitors is currently limited.Thus,investigating the mechanisms by which FAK affects HCC metastasis to develop targeted therapies for FAK may present a novel strategy to inhibit HCC metastasis.This study examined the correlation between FAK expression and the prognosis of HCC.Additionally,we explored the impact of FAK degradation on HCC metastasis through wound healing experiments,transwell invasion experiments,and a xenograft tumor model.The expression of proteins related to epithelial-mesenchymal transition(EMT)was measured to elucidate the underlying mechanisms.The results showed that FAK PROTAC can degrade FAK,inhibit the migration and invasion of HCC cells in vitro,and notably decrease the lung metastasis of HCC in vivo.Increased expression of E-cadherin and decreased expression of vimentin indicated that EMT was inhibited.Consequently,degradation of FAK through FAK PROTAC effectively suppressed liver cancer metastasis,holding significant clinical implications for treating liver cancer and developing innovative anti-neoplastic drugs.
基金the Scientific Foundation Program of Health Department of Sichuan Province,No.05KJB180105the Scientific Research Foundation of Sichuan Province Administration Bureau of Traditional Chinese Medicine,No.CX07s_035z
文摘BACKGROUND: Secondary lesions can occur in tissues surrounding the hematoma following intracerebral hemorrhage, with the presence of inflammatory reactions, cytokine expression and apoptosis These have been confirmed in animal studies. Our study sought to determine whether these could be detected in human tissues surrounding the hematoma following intracerebral hemorrhage. OBJECTIVE: To investigate expression of inflammatory cytokines, Bax and Bcl-x, and identify neural cell apoptosis in tissues surrounding the hematoma, and to analyze the correlation between them and pathological damage in intracerebral hemorrhage patients. DESIGN, TIME AND SETTING: This histopathology, controlled study was performed at the Department of Neurosurgery, Sichuan People's Hospital, China, from January 2003 to January 2005. PARTICIPANTS: Brain tissues 1 cm from the hematoma in 30 intracerebral hemorrhage patients served as the experimental group. Brain tissues located away from the hematoma in 7 patients served as the control group. METHODS: TUNEL was used to detect neural cell apoptosis. Immunohistochemistry (labeled dextran polymer) and RT-PCR were used to measure tumor necrosis factor- α, interleukin-1 β, interleukin-6, Bax and Bcl-x protein and mRNA expression. Pathological changes in brain tissues surrounding the hematoma were observed following HE staining. MAIN OUTCOME MEASURES: Neural cell apoptosis, inflammatory cytokines, Bax and Bcl-x protein and mRNA expression, pathological changes in brain tissues surrounding the hematoma. RESULTS: Brain tissues surrounding the hematoma were mildly damaged within 6 hours, severely damaged at 24-72 hours, and significantly improved 1 week following intracerebral hemorrhage. Expression of tumor necrosis factor- α protein and mRNA, interleukin-1β and interleukin-6 mRNA was not significant in tissues surrounding the hematoma, which was identical to the control group within 6 hours after intracerebral hemorrhage. This expression was significantly higher compared with the control group from 12-72 hours, and gradually decreased after 72 hours. The number of apoptotic neural cells reached a peak between 12- 72 hours. Tumor necrosis factor-α protein and mRNA, interleukin-1β and interleukin-6 mRNA levels were positively correlated with apoptosis, Bax protein and mRNA levels (P 〈 0.01 ). CONCLUSION: Tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels are highly correlated with apoptosis. With the decrease in tumor necrosis factor-α, interleukin-1β and interleukin-6 levels, the number of apoptotic cells gradually reduced.