The TGFβ signaling pathway is conserved from flies to humans and has been shown to regulate such diverse pro- cesses as cell proliferation, differentiation, motility, adhesion, organization, and programmed cell death...The TGFβ signaling pathway is conserved from flies to humans and has been shown to regulate such diverse pro- cesses as cell proliferation, differentiation, motility, adhesion, organization, and programmed cell death. Both in vitro and in vivo experiments suggest that TGF[~ can utilize these varied programs to promote cancer metastasis through its effects on the tumor microenvironment, enhanced invasive properties, and inhibition of immune cell function. Recent clinical evidence demonstrating a link between TGFβ signaling and cancer progression is fostering interest in this signaling pathway as a therapeutic target. Anti-TGFβ therapies are currently being developed and tested in pre- clinical studies. However, targeting TGFβ carries a substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. Additionally, clinical and experimental results show that TGFβ has diverse and often conflicting roles in tumor progression even within the same tumor types. The development of TGFβ inhibitors for clinical use will require a deeper understanding of TGFβ signaling, its consequences, and the contexts in which it acts.展开更多
The tumor suppressor p53 is one of the most frequently mutated genes in human cancers. MicroRNAs （miRNAs） are small non-protein coding RNAs that regulate gene expression on the post-transcriptional level. Recently, ...The tumor suppressor p53 is one of the most frequently mutated genes in human cancers. MicroRNAs （miRNAs） are small non-protein coding RNAs that regulate gene expression on the post-transcriptional level. Recently, it was shown that p53 regulates the expression of several miRNAs, thereby representing an important mechanism of p53 signaling. Several independent studies identified the members of the miR-34 family as the most prevalent p53-induced miRNAs, miR-34s are frequently silenced in variety of tumor entities, suggesting that they are important tumor suppressors. Indeed, ectopic expression of miR-34s inhibits proliferation, epithelial to mes- enchymat transition, migration, invasion, and metastasis of various cancer celt entities. Moreover, delivery or re-expression of miR-34 leads to notable repression of tumor growth and metastasis in cancer mouse models, and may therefore represent an efficient strategy for future cancer therapeutics. Besides their crucial functions in cancer, members of the miR-34 family also play important roles in spermatogenesis, stem cell differentiation, neuronal development, aging, and cardiovascular functions. Consequently, miR-34 has also been implicated in various non-cancerous diseases, such as brain disorders, osteoporosis, and cardiovascular complications.展开更多
Regulatory T cells （Tregs） expressing forkhead/winged-helix transcription factor Foxp3 represent a distinct lineage of lymphocytes which play a central role in protecting the host from autoimmune diseases. However, ...Regulatory T cells （Tregs） expressing forkhead/winged-helix transcription factor Foxp3 represent a distinct lineage of lymphocytes which play a central role in protecting the host from autoimmune diseases. However, Tregs also pose a major problem to anti-tumor immunity. Growing body of evidence from both laboratory and clinical investigations has demonstrated that expansion and accumulation of these immunosuppressive cells correlates with advanced tumor growth and predicts poor disease prognosis. How tumor development subverts normal self-tolerance function of Tregs thereby thwarts host anti-tumor immunity remains elusive. This review will discuss our current knowledge in understanding the dynamics and plasticity of Foxp3~ Treg activation and induction in tumor bearing hosts and their interaction with various antigen presenting cells （APCs） in tumor microenvironment leading to the establishment of active local and systemic immune suppression. Cellular ＆ Molecular Immunology.展开更多
目的探讨华蟾素注射液对结肠癌移植瘤血管新生的影响。方法皮下注射CT26细胞,建立结肠癌移植瘤模型。造模成功后采用随机数字表法将20只荷瘤小鼠随机分成五组,即华蟾素注射液高剂量组(CINO-H组)、华蟾素注射液中剂量组(CINO-M组)、华蟾...目的探讨华蟾素注射液对结肠癌移植瘤血管新生的影响。方法皮下注射CT26细胞,建立结肠癌移植瘤模型。造模成功后采用随机数字表法将20只荷瘤小鼠随机分成五组,即华蟾素注射液高剂量组(CINO-H组)、华蟾素注射液中剂量组(CINO-M组)、华蟾素注射液低剂量组(CINO-L组)、5-氟尿嘧啶(5-FU)组及生理盐水组,每组4只。CINO-H组给予华蟾素注射液0.5 m L,CINO-M组给予华蟾素注射液0.25 m L+生理盐水0.25 m L,CINO-L组给予华蟾素注射液0.125 m L+生理盐水0.375 m L,5-FU组给予5-FU注射液(20 mg/kg),用生理盐水配制成0.5 m L,生理盐水组给予生理盐水0.5 m L。每天腹腔内注射给药1次,连续给药7 d。观察小鼠一般状态、移植瘤大小、组织病理学及微血管密度(MVD)。结果 5-FU组瘤体积明显小于生理盐水组,差异有统计学意义(P<0.05),但华蟾素注射液各剂量组与生理盐水组比较差异无统计学意义(P>0.05)。从组织病理学观察可得,华蟾素注射液可使瘤体呈现不同程度的坏死,但坏死程度不如5-FU。华蟾素注射液各剂量组MVD均较生理盐水组明显降低,差异有高度统计学意义(P<0.01),而5-FU组MVD与生理盐水组比较差异无统计学意义(P>0.05)。结论华蟾素注射液能抑制肿瘤组织血管新生,减少瘤体内MVD,抑制肿瘤的生长。展开更多
Pancreatic cancer is estimated to be the fourth most common cancer in men and fifth in women in the world and has poor prognosis.In recent years,more and more effort has been put on the relationship between pancreatic...Pancreatic cancer is estimated to be the fourth most common cancer in men and fifth in women in the world and has poor prognosis.In recent years,more and more effort has been put on the relationship between pancreatic cancer and apoptosis.As a newly discovered inhibitor of apoptosis,survivin has drawn more attention.Strong evidence has shown that survivin is expressed in pancreatic cancer cells on frozen sections.Survivin increases in the development of pancreatic ductal adenocarcinoma and its expression can be a marker in evaluating the prognosis of pancreatic cancer patients.Survivin itself may be a new target in the treatment of pancreatic cancer and a survivin DNA vaccine could generate specific antitumor effects in pancreatic carcinoma models.展开更多
Parkin,an E3 ubiquitin ligase,plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy.Accumulating evidence suggests that the acetylation modification of the key mito...Parkin,an E3 ubiquitin ligase,plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy.Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level,but the underlying mechanism is poorly understood.Here,our study demonstrated that inhibition of histone deacetylase(HDAC)by treatment of HDACis activates mitophagy through mediating Parkin acetylation,leading to inhibition of cervical cancer cell proliferation.Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer,indicating the low acetylation level of Parkin.Using mass spectrometry,Parkin is identified to interact with two upstream molecules,acetylase acetyl-Co A acetyltransferase 1(ACAT1)and deacetylase HDAC2.Under treatment of suberoylanilide hydroxamic acid(SAHA),Parkin is acetylated at lysine residues 129,220 and 349,located in different domains of Parkin protein.In in vitro experiments,combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1(PINK1)and the function of Parkin in mitophagy induction and tumor suppression.In tumor xenografts,the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA.Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis,which offers a new mitophagy modulation strategy for cancer therapy.展开更多
Ovarian cancer accounts for only 3% of all cancers in women, but it causes more deaths than any other gynecologic cancer. Treatment with chemotherapy and cytoreductive surgery shows a good response to the therapy. How...Ovarian cancer accounts for only 3% of all cancers in women, but it causes more deaths than any other gynecologic cancer. Treatment with chemotherapy and cytoreductive surgery shows a good response to the therapy. However, in a large proportion of the patients the tumor grows back within a few years. Cancer stem cells, that are less responsive to these treatments, are blamed for this recurrence of disease. Immune therapy either cellular or humoral is a novel concept to treat cancer. It is based on the notice that immune cells invade the tumor. However, the tumor invest heavily to escape from immune elimination by recruiting several immune suppressive mechanisms. These processes are normally in place to limit excessive immune activation and prevent autoimmune phenomena. Here, we discuss current knowledge about the immune(suppressive)status in ovarian cancer. Moreover, we discuss the immunological targets of ovarian cancer stem cells.展开更多
文摘The TGFβ signaling pathway is conserved from flies to humans and has been shown to regulate such diverse pro- cesses as cell proliferation, differentiation, motility, adhesion, organization, and programmed cell death. Both in vitro and in vivo experiments suggest that TGF[~ can utilize these varied programs to promote cancer metastasis through its effects on the tumor microenvironment, enhanced invasive properties, and inhibition of immune cell function. Recent clinical evidence demonstrating a link between TGFβ signaling and cancer progression is fostering interest in this signaling pathway as a therapeutic target. Anti-TGFβ therapies are currently being developed and tested in pre- clinical studies. However, targeting TGFβ carries a substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. Additionally, clinical and experimental results show that TGFβ has diverse and often conflicting roles in tumor progression even within the same tumor types. The development of TGFβ inhibitors for clinical use will require a deeper understanding of TGFβ signaling, its consequences, and the contexts in which it acts.
文摘The tumor suppressor p53 is one of the most frequently mutated genes in human cancers. MicroRNAs （miRNAs） are small non-protein coding RNAs that regulate gene expression on the post-transcriptional level. Recently, it was shown that p53 regulates the expression of several miRNAs, thereby representing an important mechanism of p53 signaling. Several independent studies identified the members of the miR-34 family as the most prevalent p53-induced miRNAs, miR-34s are frequently silenced in variety of tumor entities, suggesting that they are important tumor suppressors. Indeed, ectopic expression of miR-34s inhibits proliferation, epithelial to mes- enchymat transition, migration, invasion, and metastasis of various cancer celt entities. Moreover, delivery or re-expression of miR-34 leads to notable repression of tumor growth and metastasis in cancer mouse models, and may therefore represent an efficient strategy for future cancer therapeutics. Besides their crucial functions in cancer, members of the miR-34 family also play important roles in spermatogenesis, stem cell differentiation, neuronal development, aging, and cardiovascular functions. Consequently, miR-34 has also been implicated in various non-cancerous diseases, such as brain disorders, osteoporosis, and cardiovascular complications.
基金This study was in part supported by cancer endowment fund of MDACC and grants from NIH.
文摘Regulatory T cells （Tregs） expressing forkhead/winged-helix transcription factor Foxp3 represent a distinct lineage of lymphocytes which play a central role in protecting the host from autoimmune diseases. However, Tregs also pose a major problem to anti-tumor immunity. Growing body of evidence from both laboratory and clinical investigations has demonstrated that expansion and accumulation of these immunosuppressive cells correlates with advanced tumor growth and predicts poor disease prognosis. How tumor development subverts normal self-tolerance function of Tregs thereby thwarts host anti-tumor immunity remains elusive. This review will discuss our current knowledge in understanding the dynamics and plasticity of Foxp3~ Treg activation and induction in tumor bearing hosts and their interaction with various antigen presenting cells （APCs） in tumor microenvironment leading to the establishment of active local and systemic immune suppression. Cellular ＆ Molecular Immunology.
文摘目的探讨华蟾素注射液对结肠癌移植瘤血管新生的影响。方法皮下注射CT26细胞,建立结肠癌移植瘤模型。造模成功后采用随机数字表法将20只荷瘤小鼠随机分成五组,即华蟾素注射液高剂量组(CINO-H组)、华蟾素注射液中剂量组(CINO-M组)、华蟾素注射液低剂量组(CINO-L组)、5-氟尿嘧啶(5-FU)组及生理盐水组,每组4只。CINO-H组给予华蟾素注射液0.5 m L,CINO-M组给予华蟾素注射液0.25 m L+生理盐水0.25 m L,CINO-L组给予华蟾素注射液0.125 m L+生理盐水0.375 m L,5-FU组给予5-FU注射液(20 mg/kg),用生理盐水配制成0.5 m L,生理盐水组给予生理盐水0.5 m L。每天腹腔内注射给药1次,连续给药7 d。观察小鼠一般状态、移植瘤大小、组织病理学及微血管密度(MVD)。结果 5-FU组瘤体积明显小于生理盐水组,差异有统计学意义(P<0.05),但华蟾素注射液各剂量组与生理盐水组比较差异无统计学意义(P>0.05)。从组织病理学观察可得,华蟾素注射液可使瘤体呈现不同程度的坏死,但坏死程度不如5-FU。华蟾素注射液各剂量组MVD均较生理盐水组明显降低,差异有高度统计学意义(P<0.01),而5-FU组MVD与生理盐水组比较差异无统计学意义(P>0.05)。结论华蟾素注射液能抑制肿瘤组织血管新生,减少瘤体内MVD,抑制肿瘤的生长。
文摘Pancreatic cancer is estimated to be the fourth most common cancer in men and fifth in women in the world and has poor prognosis.In recent years,more and more effort has been put on the relationship between pancreatic cancer and apoptosis.As a newly discovered inhibitor of apoptosis,survivin has drawn more attention.Strong evidence has shown that survivin is expressed in pancreatic cancer cells on frozen sections.Survivin increases in the development of pancreatic ductal adenocarcinoma and its expression can be a marker in evaluating the prognosis of pancreatic cancer patients.Survivin itself may be a new target in the treatment of pancreatic cancer and a survivin DNA vaccine could generate specific antitumor effects in pancreatic carcinoma models.
基金supported by research grants from Zhejiang Provincial Natural Science Foundation(LR18H160002,China)National Natural Science Foundation of China(32070740)+3 种基金Zhejiang Provincial Program in Medicine and Health Sciences and Technology(2018KY010)Zhejiang Provincial Outstanding Talent Project of Ten Thousand Talents ProgramZhejiang Provincial Qianjiang Talents ProgramZhejiang Provincial High-Level Innovative Health Talents Program to Dr.Jianbin Zhang。
文摘Parkin,an E3 ubiquitin ligase,plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy.Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level,but the underlying mechanism is poorly understood.Here,our study demonstrated that inhibition of histone deacetylase(HDAC)by treatment of HDACis activates mitophagy through mediating Parkin acetylation,leading to inhibition of cervical cancer cell proliferation.Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer,indicating the low acetylation level of Parkin.Using mass spectrometry,Parkin is identified to interact with two upstream molecules,acetylase acetyl-Co A acetyltransferase 1(ACAT1)and deacetylase HDAC2.Under treatment of suberoylanilide hydroxamic acid(SAHA),Parkin is acetylated at lysine residues 129,220 and 349,located in different domains of Parkin protein.In in vitro experiments,combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1(PINK1)and the function of Parkin in mitophagy induction and tumor suppression.In tumor xenografts,the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA.Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis,which offers a new mitophagy modulation strategy for cancer therapy.
基金Supported by The Dutch government to the Netherlands Institute for Regenerative Medicine,No.FES0908
文摘Ovarian cancer accounts for only 3% of all cancers in women, but it causes more deaths than any other gynecologic cancer. Treatment with chemotherapy and cytoreductive surgery shows a good response to the therapy. However, in a large proportion of the patients the tumor grows back within a few years. Cancer stem cells, that are less responsive to these treatments, are blamed for this recurrence of disease. Immune therapy either cellular or humoral is a novel concept to treat cancer. It is based on the notice that immune cells invade the tumor. However, the tumor invest heavily to escape from immune elimination by recruiting several immune suppressive mechanisms. These processes are normally in place to limit excessive immune activation and prevent autoimmune phenomena. Here, we discuss current knowledge about the immune(suppressive)status in ovarian cancer. Moreover, we discuss the immunological targets of ovarian cancer stem cells.
