Previous studies have shown that Meis1 plays an important role in the pathogenesis of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Meis1 belongs to the TALE family, the members of which are use...Previous studies have shown that Meis1 plays an important role in the pathogenesis of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Meis1 belongs to the TALE family, the members of which are used as biomarkers for AML. Meis1 has been shown to play a functional role in epithelial tissues, such as skin. However, its functions in skin carcinogenesis remain poorly understood. On the other hand, the c-Met inhibitor SU11274 has been identified through drug screening with HOXA9/Meis1-induced AML cell lines. SU11274 altered cell proliferation and the cell cycle status in human AML cell lines. Thus, we hypothesized that the effects of SU11274 are dependent on Meis1 and that its knockdown may diminish the effects of SU11274 not only in AML cell lines, but also in skin cancer cell lines. In order to test our hypothesis, we established Meis1 knockdown cell lines using two skin squamous cell carcinoma cell lines (B9 and D3) and treated these cell lines with SU11274. The results obtained showed that SU11274 suppressed cell proliferation by modulating cell cycle progression in the presence of Meis1, but not in its absence. Furthermore, an expression analysis showed that SU11274 activated the transcription of Meis1, which led to the transcription of Hif1α and Cdkn2a (p16Ink4a and p19Arf). These results suggest that Meis1 is required for the c-Met inhibitor SU11274 to suppress the proliferation of the skin squamous cell carcinoma cell lines.展开更多
The debate exists whether or not gonadotropin-releasing hormone（GnRH） analogs used in controlled ovarian hyperstimulation（COH） impair endometrial receptivity.Homeobox A11（Hoxa11）,Meis homeobox 1（Meis1）,cadheri...The debate exists whether or not gonadotropin-releasing hormone（GnRH） analogs used in controlled ovarian hyperstimulation（COH） impair endometrial receptivity.Homeobox A11（Hoxa11）,Meis homeobox 1（Meis1）,cadherin 1（Cdh1）,and catenin beta 1（Ctnnb1） are well known to be involved in successful implantation.In this study,the endometrial expression of Hoxa11,Meis1,Cdh1,and Ctnnb1 during the peri-implantation period was investigated in an in vitro fertilization（IVF） mouse model by real-time RT-PCR and Western blot to evaluate the relationship between Hoxa11,Meis1,Cdh1,and Ctnnb1 expression and the impact of the COH on endometrial receptivity.The mimic COH protocols included GnRH agonist plus human menopausal gonadotropin（HMG）（GnRH agonist group）,GnRH antagonist plus HMG（GnRH antagonist group）,and HMG alone（HMG group）.The expression levels of Hoxa11,Meis1,Cdh1,and Ctnnb1 mRNA and protein were decreased in all of the COH groups.The expression levels of Hoxa11 and Ctnnb1 were the lowest in the GnRH agonist group,and those of Meis1 and Cdh1 were lower in the GnRH analog groups than the HMG group.There were positive correlations between the expression of Hoxa11 and Ctnnb1,as well as the expression of Meis1 and Cdh1 among all the groups.In conclusion,the COH protocols,particularly with GnRH analogs,suppressed Hoxa11,Meis1,Ctnnb1 and Cdh1 expression,in mouse endometrium during the peri-implantation period.Our data reveal a novel molecular mechanism by which the COH protocols might impair endometrial receptivity.展开更多
The recent and exciting discovery of germline HOXB13 mutations in familial prostate cancer has brought HOX signaling to the forefront of prostate cancer research.An enhanced understanding of HOX signaling,and the co-f...The recent and exciting discovery of germline HOXB13 mutations in familial prostate cancer has brought HOX signaling to the forefront of prostate cancer research.An enhanced understanding of HOX signaling,and the co-factors regulating HOX protein specificity and transcriptional regulation,has the high potential to elucidate novel approaches to prevent,diagnose,stage,and treat prostate cancer.Toward our understanding of HOX biology in prostate development and prostate cancer,basic research in developmental model systems as well as other tumor sites provides a mechanistic framework to inform future studies in prostate biology.Here we describe our current understanding of HOX signaling in genitourinary development and cancer,current clinical data of HOXB13 mutations in multiple cancers including prostate cancer,and the role of HOX protein co-factors in development and cancer.These data highlight numerous gaps in our understanding of HOX function in the prostate,and present numerous potentially impactful mechanistic and clinical opportunities for future investigation.展开更多
文摘Previous studies have shown that Meis1 plays an important role in the pathogenesis of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Meis1 belongs to the TALE family, the members of which are used as biomarkers for AML. Meis1 has been shown to play a functional role in epithelial tissues, such as skin. However, its functions in skin carcinogenesis remain poorly understood. On the other hand, the c-Met inhibitor SU11274 has been identified through drug screening with HOXA9/Meis1-induced AML cell lines. SU11274 altered cell proliferation and the cell cycle status in human AML cell lines. Thus, we hypothesized that the effects of SU11274 are dependent on Meis1 and that its knockdown may diminish the effects of SU11274 not only in AML cell lines, but also in skin cancer cell lines. In order to test our hypothesis, we established Meis1 knockdown cell lines using two skin squamous cell carcinoma cell lines (B9 and D3) and treated these cell lines with SU11274. The results obtained showed that SU11274 suppressed cell proliferation by modulating cell cycle progression in the presence of Meis1, but not in its absence. Furthermore, an expression analysis showed that SU11274 activated the transcription of Meis1, which led to the transcription of Hif1α and Cdkn2a (p16Ink4a and p19Arf). These results suggest that Meis1 is required for the c-Met inhibitor SU11274 to suppress the proliferation of the skin squamous cell carcinoma cell lines.
基金supported by a grant from the Major State Basic Research Development Program of China (973 Program)(No. 2007-CB948100)
文摘The debate exists whether or not gonadotropin-releasing hormone（GnRH） analogs used in controlled ovarian hyperstimulation（COH） impair endometrial receptivity.Homeobox A11（Hoxa11）,Meis homeobox 1（Meis1）,cadherin 1（Cdh1）,and catenin beta 1（Ctnnb1） are well known to be involved in successful implantation.In this study,the endometrial expression of Hoxa11,Meis1,Cdh1,and Ctnnb1 during the peri-implantation period was investigated in an in vitro fertilization（IVF） mouse model by real-time RT-PCR and Western blot to evaluate the relationship between Hoxa11,Meis1,Cdh1,and Ctnnb1 expression and the impact of the COH on endometrial receptivity.The mimic COH protocols included GnRH agonist plus human menopausal gonadotropin（HMG）（GnRH agonist group）,GnRH antagonist plus HMG（GnRH antagonist group）,and HMG alone（HMG group）.The expression levels of Hoxa11,Meis1,Cdh1,and Ctnnb1 mRNA and protein were decreased in all of the COH groups.The expression levels of Hoxa11 and Ctnnb1 were the lowest in the GnRH agonist group,and those of Meis1 and Cdh1 were lower in the GnRH analog groups than the HMG group.There were positive correlations between the expression of Hoxa11 and Ctnnb1,as well as the expression of Meis1 and Cdh1 among all the groups.In conclusion,the COH protocols,particularly with GnRH analogs,suppressed Hoxa11,Meis1,Ctnnb1 and Cdh1 expression,in mouse endometrium during the peri-implantation period.Our data reveal a novel molecular mechanism by which the COH protocols might impair endometrial receptivity.
基金DOD PCRP PC130587(Vander Griend)NWU/UC/NSUHS Prostate SPORE(P50 CA180995)the University of Chicago Comprehensive Cancer Center(UCCCC)+2 种基金especially the Cancer Center Support Grant(P30CA014599)H.Brechka and C.Van Opstall were supported by the Cancer Biology Training Grant(T32 CA009594)R.Bhanvadia is supported by a University of Chicago Pritzker School of Medicine Fellowship.
文摘The recent and exciting discovery of germline HOXB13 mutations in familial prostate cancer has brought HOX signaling to the forefront of prostate cancer research.An enhanced understanding of HOX signaling,and the co-factors regulating HOX protein specificity and transcriptional regulation,has the high potential to elucidate novel approaches to prevent,diagnose,stage,and treat prostate cancer.Toward our understanding of HOX biology in prostate development and prostate cancer,basic research in developmental model systems as well as other tumor sites provides a mechanistic framework to inform future studies in prostate biology.Here we describe our current understanding of HOX signaling in genitourinary development and cancer,current clinical data of HOXB13 mutations in multiple cancers including prostate cancer,and the role of HOX protein co-factors in development and cancer.These data highlight numerous gaps in our understanding of HOX function in the prostate,and present numerous potentially impactful mechanistic and clinical opportunities for future investigation.
