Kindlin-2, an integrin-interacting protein, regulates breast cancer progression. However, currently, no animal model to study the role of Kindlin-2 in the carcinogenesis of mammary gland is available. We established a...Kindlin-2, an integrin-interacting protein, regulates breast cancer progression. However, currently, no animal model to study the role of Kindlin-2 in the carcinogenesis of mammary gland is available. We established a Kindlin-2 transgenic mouse model using a mammary gland-specific promoter, mammary tumor virus(MMTV) long terminal repeat(LTR). Kindlin-2 was overexpressed in the epithelial cells of the transgenic mice. The mammary gland ductal trees were found to grow faster in MMTV-Kindlin-2 transgenic mice than in control mice during puberty. Kindlin-2 promoted mammary gland growth as indicated by more numerous duct branches and larger lumens, and more alveoli were formed in the mammary glands during pregnancy under Kindlin-2 overexpression. Importantly, mammary gland-specific expression of Kindlin-2 induced tumor formation at the age of 55 weeks on average. Additionally, the levels of estrogen receptor and progesterone receptor were decreased, whereas human epidermal growth factor receptor 2 and β-catenin were upregulated in the Kindlin-2-induced mammary tumors. These findings demonstrated that Kindlin-2 induces mammary tumor formation via activation of the Wnt signaling pathway.展开更多
PH20 is a member of the human hyaluronidase family that degrades hyaluronan in the extracellular matrix and controls tumor progression.Inhibition of DNA methyltransferases(DNMTs)leads to elevated hyaluronan levels;how...PH20 is a member of the human hyaluronidase family that degrades hyaluronan in the extracellular matrix and controls tumor progression.Inhibition of DNA methyltransferases(DNMTs)leads to elevated hyaluronan levels;however,whether DNMT inhibitors control PH20 remains unclear.Here,we report that the DNMT1 inhibitor,decitabine,suppresses PH20 expression by activating the long non-coding RNA PHACTR2-AS1(PAS1).PAS1 forms a tripartite complex with the RNA-binding protein vigilin and histone methyltransferase SUV39H1.The interaction between PAS1 and vigilin maintains the stability of PAS1.Meanwhile,PAS1 recruits SUV39H1 to trigger the H3K9 methylation of PH20,resulting in its silencing.Functionally,PAS1 inhibits breast cancer growth and metastasis,at least partially,by suppressing PH20.Combination therapy of decitabine and PAS1-30nt-RNA,which directly binds to SUV39H1,effectively blocked breast cancer growth and metastasis in mice.Taken together,DNMT1,PAS1,and PH20 comprise a regulatory axis to control breast cancer growth and metastasis.These findings reveal that the DNMT1-PAS1-PH20 axis is a potential therapeutic target for breast cancer.展开更多
Esophageal cancer （EC） is one of the most lethal malignancies in China, but the etiology and risk factors remain unclear. The integrin-interacting proteins Kindlin-1 and Kindlin-2 are focal adhesion molecules that a...Esophageal cancer （EC） is one of the most lethal malignancies in China, but the etiology and risk factors remain unclear. The integrin-interacting proteins Kindlin-1 and Kindlin-2 are focal adhesion molecules that activate transmembrane receptor integrins and regulate tumor cell growth, invasion, and metastasis. Here, we report that Kindlin-1 and Kindlin-2 are differentially expressed among Chinese EC patients. For this, Kindlin-1 and Kindlin-2 expression was evaluated in 220 EC patients by immunohistochemistry （IHC） and found to be correlated with the EC progression, along with a variety of epidemiologic parameters, including smoking, family EC history, and EC invasion status. Moreover, data downloaded from the Oncomine database revealed that both Kindlin- 1 and Kindlin-2 were upregulated in ECs compared with normal esophageal tissues; although Kindlin-1 was highly expressed in well-differentiated tumors, whereas Kindlin-2 was more prevalent in poorly differentiated tumors. Collectively, these data suggest that Kindlin-1 may inhibit, while Kindlin-2 may promote, EC progression. This study, for the first time, linked the expression of Kindlin-1 and Kindlin-2 with EC family genetic background and living habits, which may help further our understanding of the various causes of EC.展开更多
基金supported by grants from the Ministry of Science and Technology of China (2016YFC1302103, 2015CB553906, and 2013CB910501)the National Natural Science Foundation of China (81730071, 81230051, 81472734, and 31170711)+3 种基金the Beijing Natural Science Foundation (7120002 and 7171005)the 111 Project of the Ministry of Education, grants from Peking University (BMU20120314 and BMU20130364)a Leading Academic Discipline Project of Beijing Education Bureau to H.Z.supported by a grant from the National Natural Science Foundation of China (81773199) to J.Z
文摘Kindlin-2, an integrin-interacting protein, regulates breast cancer progression. However, currently, no animal model to study the role of Kindlin-2 in the carcinogenesis of mammary gland is available. We established a Kindlin-2 transgenic mouse model using a mammary gland-specific promoter, mammary tumor virus(MMTV) long terminal repeat(LTR). Kindlin-2 was overexpressed in the epithelial cells of the transgenic mice. The mammary gland ductal trees were found to grow faster in MMTV-Kindlin-2 transgenic mice than in control mice during puberty. Kindlin-2 promoted mammary gland growth as indicated by more numerous duct branches and larger lumens, and more alveoli were formed in the mammary glands during pregnancy under Kindlin-2 overexpression. Importantly, mammary gland-specific expression of Kindlin-2 induced tumor formation at the age of 55 weeks on average. Additionally, the levels of estrogen receptor and progesterone receptor were decreased, whereas human epidermal growth factor receptor 2 and β-catenin were upregulated in the Kindlin-2-induced mammary tumors. These findings demonstrated that Kindlin-2 induces mammary tumor formation via activation of the Wnt signaling pathway.
基金grants from Ministry of Science and Technology of the People’s Republic of China 2021YFC2501000National Natural Science Foundation of China 82073076,81972616,81730071,81621063,81572839Natural Science Foundation of Beijing Municipality 7192092,7171005,PKU2021LCXQ015.
文摘PH20 is a member of the human hyaluronidase family that degrades hyaluronan in the extracellular matrix and controls tumor progression.Inhibition of DNA methyltransferases(DNMTs)leads to elevated hyaluronan levels;however,whether DNMT inhibitors control PH20 remains unclear.Here,we report that the DNMT1 inhibitor,decitabine,suppresses PH20 expression by activating the long non-coding RNA PHACTR2-AS1(PAS1).PAS1 forms a tripartite complex with the RNA-binding protein vigilin and histone methyltransferase SUV39H1.The interaction between PAS1 and vigilin maintains the stability of PAS1.Meanwhile,PAS1 recruits SUV39H1 to trigger the H3K9 methylation of PH20,resulting in its silencing.Functionally,PAS1 inhibits breast cancer growth and metastasis,at least partially,by suppressing PH20.Combination therapy of decitabine and PAS1-30nt-RNA,which directly binds to SUV39H1,effectively blocked breast cancer growth and metastasis in mice.Taken together,DNMT1,PAS1,and PH20 comprise a regulatory axis to control breast cancer growth and metastasis.These findings reveal that the DNMT1-PAS1-PH20 axis is a potential therapeutic target for breast cancer.
基金supported by the Ministry of Science and Technology of China (2016YFC1302103, 2015CB553906. 2013CB910501)the National Natural Science Foundation of China (81230051, 81472734, 31170711, 81321003, 81301802, 30830048)+2 种基金Beijing Natural Science Foundation (7120002)the 111 Project of the Ministry of Education, Peking University (BMU20120314, BMU20130364)a Leading Academic Discipline Project of Beijing Education Bureau to Hongquan Zhang
文摘Esophageal cancer （EC） is one of the most lethal malignancies in China, but the etiology and risk factors remain unclear. The integrin-interacting proteins Kindlin-1 and Kindlin-2 are focal adhesion molecules that activate transmembrane receptor integrins and regulate tumor cell growth, invasion, and metastasis. Here, we report that Kindlin-1 and Kindlin-2 are differentially expressed among Chinese EC patients. For this, Kindlin-1 and Kindlin-2 expression was evaluated in 220 EC patients by immunohistochemistry （IHC） and found to be correlated with the EC progression, along with a variety of epidemiologic parameters, including smoking, family EC history, and EC invasion status. Moreover, data downloaded from the Oncomine database revealed that both Kindlin- 1 and Kindlin-2 were upregulated in ECs compared with normal esophageal tissues; although Kindlin-1 was highly expressed in well-differentiated tumors, whereas Kindlin-2 was more prevalent in poorly differentiated tumors. Collectively, these data suggest that Kindlin-1 may inhibit, while Kindlin-2 may promote, EC progression. This study, for the first time, linked the expression of Kindlin-1 and Kindlin-2 with EC family genetic background and living habits, which may help further our understanding of the various causes of EC.
