Pub Date : 2024-10-01Epub Date: 2024-07-19DOI: 10.1002/mc.23788
Lili Dong, Nan Zhang, Jun Chen, Penghui Dong, Nan Mao, Huiling Li, Aiguo Wang
The effect of triiodothyronine (T3) on the phosphorylation of ERK and the occurrence and development of hepatocellular carcinoma (HCC) is controversial and remains to be clarified. In the present study, both in vitro (hepatoma cell lines) and in vivo (wild-type mice [WT] and mouse models of HCC [HrasG12Vand KrasG12Dtransgenic mice (Hras-Tg and Kras-Tg)]) systems were used to investigate the effect of T3 on p-ERK and hepatocarcinogenesis. The results showed that, in vitro, T3 treatment elevated the levels of p-ERK in hepatoma cells within 30 min. However, p-ERK levels returned to normal after 1 h with no significant effects on cellular proliferation or apoptosis. Interestingly, in vivo, T3 induced early rapid and transient activation of ERK and later persistent downregulation of p-ERK in liver tissues of WT. In Hras-Tg, liver weight, liver/body weight ratio, hepatic tumor numbers and sizes were significantly reduced withT3treatment compared with the untreated group. Furthermore, the levels of albumin, HrasG12V, and p-ERK in hepatic precancerous and tumor tissues were all significantly downregulated with T3 treatment; however, the levels of endogenous Hras were not affected. In WT, T3 also induced downregulation of Albumin in liver tissues, but without influence on the expression of endogenous Hras and p-MEK. Especially, the inhibitory effect of T3 on p-ERK and hepatic tumorigenesis and development without influence on the levels of KrasG12D and p-MEK was further confirmed in Kras-Tg. In conclusion, T3 suppresses hepatic tumorigenesis and development by independently and substantially inhibiting the phosphorylation of ERK in vivo.
{"title":"Triiodothyronine (T3) suppresses hepatic tumorigenesis and development by inhibiting the phosphorylation of ERK.","authors":"Lili Dong, Nan Zhang, Jun Chen, Penghui Dong, Nan Mao, Huiling Li, Aiguo Wang","doi":"10.1002/mc.23788","DOIUrl":"10.1002/mc.23788","url":null,"abstract":"<p><p>The effect of triiodothyronine (T3) on the phosphorylation of ERK and the occurrence and development of hepatocellular carcinoma (HCC) is controversial and remains to be clarified. In the present study, both in vitro (hepatoma cell lines) and in vivo (wild-type mice [WT] and mouse models of HCC [Hras<sup>G12V</sup>and Kras<sup>G12D</sup>transgenic mice (Hras-Tg and Kras-Tg)]) systems were used to investigate the effect of T3 on p-ERK and hepatocarcinogenesis. The results showed that, in vitro, T3 treatment elevated the levels of p-ERK in hepatoma cells within 30 min. However, p-ERK levels returned to normal after 1 h with no significant effects on cellular proliferation or apoptosis. Interestingly, in vivo, T3 induced early rapid and transient activation of ERK and later persistent downregulation of p-ERK in liver tissues of WT. In Hras-Tg, liver weight, liver/body weight ratio, hepatic tumor numbers and sizes were significantly reduced withT3treatment compared with the untreated group. Furthermore, the levels of albumin, Hras<sup>G12V</sup>, and p-ERK in hepatic precancerous and tumor tissues were all significantly downregulated with T3 treatment; however, the levels of endogenous Hras were not affected. In WT, T3 also induced downregulation of Albumin in liver tissues, but without influence on the expression of endogenous Hras and p-MEK. Especially, the inhibitory effect of T3 on p-ERK and hepatic tumorigenesis and development without influence on the levels of Kras<sup>G12D</sup> and p-MEK was further confirmed in Kras-Tg. In conclusion, T3 suppresses hepatic tumorigenesis and development by independently and substantially inhibiting the phosphorylation of ERK in vivo.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-07-11DOI: 10.1002/mc.23792
Yihong Chen, Jessica D Johnson, Sridharan Jayamohan, Yi He, Prabhakar P Venkata, Diksha Jamwal, Salvador Alejo, Yi Zou, Zhao Lai, Suryavathi Viswanadhapalli, Ratna K Vadlamudi, Edward Kost, Gangadhara R Sareddy
Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum-based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Recent studies have revealed that the epigenetic modifier lysine-specific histone demethylase 1A (KDM1A/LSD1) is highly overexpressed in OCa. However, the role of KDM1A in chemoresistance and whether its inhibition enhances chemotherapy response in OCa remains uncertain. Analysis of TCGA datasets revealed that KDM1A expression is high in patients who poorly respond to chemotherapy. Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient-derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin-resistant A2780-CP70 cells to carboplatin treatment and paclitaxel-resistant SKOV3-TR cells to paclitaxel. RNA-seq analysis revealed that a combination of KDM1A-KD and cisplatin treatment resulted in the downregulation of genes related to epithelial-mesenchymal transition (EMT). Interestingly, cisplatin treatment increased a subset of NF-κB pathway genes, and KDM1A-KD or KDM1A inhibition reversed this effect. Importantly, KDM1A-KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.
{"title":"KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer.","authors":"Yihong Chen, Jessica D Johnson, Sridharan Jayamohan, Yi He, Prabhakar P Venkata, Diksha Jamwal, Salvador Alejo, Yi Zou, Zhao Lai, Suryavathi Viswanadhapalli, Ratna K Vadlamudi, Edward Kost, Gangadhara R Sareddy","doi":"10.1002/mc.23792","DOIUrl":"10.1002/mc.23792","url":null,"abstract":"<p><p>Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum-based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Recent studies have revealed that the epigenetic modifier lysine-specific histone demethylase 1A (KDM1A/LSD1) is highly overexpressed in OCa. However, the role of KDM1A in chemoresistance and whether its inhibition enhances chemotherapy response in OCa remains uncertain. Analysis of TCGA datasets revealed that KDM1A expression is high in patients who poorly respond to chemotherapy. Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient-derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin-resistant A2780-CP70 cells to carboplatin treatment and paclitaxel-resistant SKOV3-TR cells to paclitaxel. RNA-seq analysis revealed that a combination of KDM1A-KD and cisplatin treatment resulted in the downregulation of genes related to epithelial-mesenchymal transition (EMT). Interestingly, cisplatin treatment increased a subset of NF-κB pathway genes, and KDM1A-KD or KDM1A inhibition reversed this effect. Importantly, KDM1A-KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11421967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The tumorigenesis of intrahepatic cholangiocarcinoma (ICC) has been identified to be exceptionally involved in dysregulated Hippo/Yes-associated protein (YAP) signaling pathway (Hippo/YAP). Hippo/YAP functions as a master regulator engaged in a plethora of physiological and oncogenic processes as well. Therefore, the aberrant Hippo/YAP could serve as an Achilles' heel regarding the molecular therapeutic avenues for ICC patients. Herein, we comprehensively review the recent studies about the underlying mechanism of disrupted Hippo/YAP in ICC, how diagnostic values could be utilized upon the critical genes in this pathway, and what opportunities could be given upon this target pathway.
{"title":"Targeting Hippo/YAP in intrahepatic cholangiocarcinoma: Promising molecules in cancer therapy.","authors":"Xing Ma, Yangyang Zhou, Ruping Li, Xianmin Ding, Deyu Li, Tingting Pan, Fuqiang Zhang, Wenliang Li","doi":"10.1002/mc.23791","DOIUrl":"10.1002/mc.23791","url":null,"abstract":"<p><p>The tumorigenesis of intrahepatic cholangiocarcinoma (ICC) has been identified to be exceptionally involved in dysregulated Hippo/Yes-associated protein (YAP) signaling pathway (Hippo/YAP). Hippo/YAP functions as a master regulator engaged in a plethora of physiological and oncogenic processes as well. Therefore, the aberrant Hippo/YAP could serve as an Achilles' heel regarding the molecular therapeutic avenues for ICC patients. Herein, we comprehensively review the recent studies about the underlying mechanism of disrupted Hippo/YAP in ICC, how diagnostic values could be utilized upon the critical genes in this pathway, and what opportunities could be given upon this target pathway.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-06-18DOI: 10.1002/mc.23779
Qiang Luo, Xiaojia Li, Keping Xie
Plakophilin 1 (PKP1) belongs to the desmosome family as an anchoring junction protein in cellular junctions. It localizes at the interface of the cell membrane and cytoplasm. Although PKP1 is a non-transmembrane protein, it may become associated with the cell membrane via transmembrane proteins such as desmocollins and desmogleins. Homozygous deletion of PKP1 results in ectodermal dysplasia-skin fragility syndrome (EDSF) and complete knockout of PKP1 in mice produces comparable symptoms to EDSF in humans, although mice do not survive more than 24 h. PKP1 is not limited to expression in desmosomal structures, but is rather widely expressed in cytoplasm and nucleus, where it assumes important cellular functions. This review will summarize distinct roles of PKP1 in the cell membrane, cytoplasm, and nucleus with an overview of relevant studies on its function in diverse types of cancer.
{"title":"Plakophilin 1 in carcinogenesis.","authors":"Qiang Luo, Xiaojia Li, Keping Xie","doi":"10.1002/mc.23779","DOIUrl":"10.1002/mc.23779","url":null,"abstract":"<p><p>Plakophilin 1 (PKP1) belongs to the desmosome family as an anchoring junction protein in cellular junctions. It localizes at the interface of the cell membrane and cytoplasm. Although PKP1 is a non-transmembrane protein, it may become associated with the cell membrane via transmembrane proteins such as desmocollins and desmogleins. Homozygous deletion of PKP1 results in ectodermal dysplasia-skin fragility syndrome (EDSF) and complete knockout of PKP1 in mice produces comparable symptoms to EDSF in humans, although mice do not survive more than 24 h. PKP1 is not limited to expression in desmosomal structures, but is rather widely expressed in cytoplasm and nucleus, where it assumes important cellular functions. This review will summarize distinct roles of PKP1 in the cell membrane, cytoplasm, and nucleus with an overview of relevant studies on its function in diverse types of cancer.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-06-24DOI: 10.1002/mc.23778
Kewei Song, Chenhui Ma, Ewetse Paul Maswikiti, Baohong Gu, Bofang Wang, Na Wang, Pei Jiang, Hao Chen
This study explores the specific role and underlying mechanisms of ALDH5A1 in the chemoresistance of esophageal squamous cell carcinoma (ESCC). The levels of cleaved caspase-3, 4-hydroxynonenal (4-HNE), intracellular Fe2+, and lipid reactive oxygen species (ROS) were evaluated via immunofluorescence. Cell viability and migration were quantified using cell counting kit-8 assays and wound healing assays, respectively. Flow cytometry was utilized to analyze cell apoptosis and ROS production. The concentrations of malondialdehyde (MDA) and reduced glutathione were determined by enzyme-linked immunosorbent assay. Proteome profiling was performed using data-independent acquisition. Additionally, a xenograft mouse model of ESCC was established to investigate the relationship between ALDH5A1 expression and the cisplatin (DDP)-resistance mechanism in vivo. ALDH5A1 is overexpressed in both ESCC patients and ESCC/DDP cells. Silencing of ALDH5A1 significantly enhances the inhibitory effects of DDP treatment on the viability and migration of KYSE30/DDP and KYSE150/DDP cells and promotes apoptosis. Furthermore, it intensifies DDP's suppressive effects on tumor volume and weight in nude mice. Gene ontology biological process analysis has shown that ferroptosis plays a crucial role in both KYSE30/DDP cells and KYSE30/DDP cells transfected with si-ALDH5A1. Our in vitro and in vivo experiments demonstrate that DDP treatment promotes the accumulation of ROS, lipid ROS, MDA, LPO, and intracellular Fe2+ content, increases the levels of proteins that promote ferroptosis (ACSL4 and FTH1), and decreases the expression of anti-ferroptosis proteins (SLC7A11, FTL, and GPX4). Silencing of ALDH5A1 further amplifies the regulatory effects of DDP both in vitro and in vivo. ALDH5A1 potentially acts as an oncogene in ESCC chemoresistance. Silencing of ALDH5A1 can reduce DDP resistance in ESCC through promoting ferroptosis signaling pathways. These findings suggest a promising strategy for the treatment of ESCC in clinical practice.
{"title":"Downregulation of ALDH5A1 suppresses cisplatin resistance in esophageal squamous cell carcinoma by regulating ferroptosis signaling pathways.","authors":"Kewei Song, Chenhui Ma, Ewetse Paul Maswikiti, Baohong Gu, Bofang Wang, Na Wang, Pei Jiang, Hao Chen","doi":"10.1002/mc.23778","DOIUrl":"10.1002/mc.23778","url":null,"abstract":"<p><p>This study explores the specific role and underlying mechanisms of ALDH5A1 in the chemoresistance of esophageal squamous cell carcinoma (ESCC). The levels of cleaved caspase-3, 4-hydroxynonenal (4-HNE), intracellular Fe<sup>2+</sup>, and lipid reactive oxygen species (ROS) were evaluated via immunofluorescence. Cell viability and migration were quantified using cell counting kit-8 assays and wound healing assays, respectively. Flow cytometry was utilized to analyze cell apoptosis and ROS production. The concentrations of malondialdehyde (MDA) and reduced glutathione were determined by enzyme-linked immunosorbent assay. Proteome profiling was performed using data-independent acquisition. Additionally, a xenograft mouse model of ESCC was established to investigate the relationship between ALDH5A1 expression and the cisplatin (DDP)-resistance mechanism in vivo. ALDH5A1 is overexpressed in both ESCC patients and ESCC/DDP cells. Silencing of ALDH5A1 significantly enhances the inhibitory effects of DDP treatment on the viability and migration of KYSE30/DDP and KYSE150/DDP cells and promotes apoptosis. Furthermore, it intensifies DDP's suppressive effects on tumor volume and weight in nude mice. Gene ontology biological process analysis has shown that ferroptosis plays a crucial role in both KYSE30/DDP cells and KYSE30/DDP cells transfected with si-ALDH5A1. Our in vitro and in vivo experiments demonstrate that DDP treatment promotes the accumulation of ROS, lipid ROS, MDA, LPO, and intracellular Fe<sup>2+</sup> content, increases the levels of proteins that promote ferroptosis (ACSL4 and FTH1), and decreases the expression of anti-ferroptosis proteins (SLC7A11, FTL, and GPX4). Silencing of ALDH5A1 further amplifies the regulatory effects of DDP both in vitro and in vivo. ALDH5A1 potentially acts as an oncogene in ESCC chemoresistance. Silencing of ALDH5A1 can reduce DDP resistance in ESCC through promoting ferroptosis signaling pathways. These findings suggest a promising strategy for the treatment of ESCC in clinical practice.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-06-27DOI: 10.1002/mc.23782
Xilei Zhou, Yusuo Tong, Changhua Yu, Juan Pu, Weiguo Zhu, Yun Zhou, Yuandong Wang, Yaozu Xiong, Xinchen Sun
Cancer-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in the tumor microenvironment, which play important roles in regulating tumor progression and therapy resistance by transferring exosomes to cancer cells. However, how CAFs modulate esophageal squamous cell carcinoma (ESCC) progression and radioresistance remains incompletely understood. The expression of fibroblast activation protein (FAP) in CAFs was evaluated by immunohistochemistry in 174 ESCC patients who underwent surgery and 78 pretreatment biopsy specimens of ESCC patients who underwent definitive chemoradiotherapy. We sorted CAFs according to FAP expression, and the conditioned medium (CM) was collected to culture ESCC cells. The expression levels of several lncRNAs that were considered to regulate ESCC progression and/or radioresistance were measured in exosomes derived from FAP+ CAFs and FAP- CAFs. Subsequently, cell counting kit-8, 5-ethynyl-2'-deoxyuridine, transwell, colony formation, and xenograft assays were performed to investigate the functional differences between FAP+ CAFs and FAP- CAFs. Finally, a series of in vitro and in vivo assays were used to evaluate the effect of AFAP1-AS1 on radiosensitivity of ESCC cells. FAP expression in stromal CAFs was positively correlated with nerve invasion, vascular invasion, depth of invasion, lymph node metastasis, lack of clinical complete response and poor survival. Culture of ESCC cells with CM/FAP+ CAFs significantly increased cancer proliferation, migration, invasion and radioresistance, compared with culture with CM/FAP- CAFs. Importantly, FAP+ CAFs exert their roles by directly transferring the functional lncRNA AFAP1-AS1 to ESCC cells via exosomes. Functional studies showed that AFAP1-AS1 promoted radioresistance by enhancing DNA damage repair in ESCC cells. Clinically, high levels of plasma AFAP1-AS1 correlated with poor responses to dCRT in ESCC patients. Our findings demonstrated that FAP+ CAFs promoted radioresistance in ESCC cells through transferring exosomal lncRNA AFAP1-AS1; and may be a potential therapeutic target for ESCC treatment.
{"title":"FAP positive cancer-associated fibroblasts promote tumor progression and radioresistance in esophageal squamous cell carcinoma by transferring exosomal lncRNA AFAP1-AS1.","authors":"Xilei Zhou, Yusuo Tong, Changhua Yu, Juan Pu, Weiguo Zhu, Yun Zhou, Yuandong Wang, Yaozu Xiong, Xinchen Sun","doi":"10.1002/mc.23782","DOIUrl":"10.1002/mc.23782","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in the tumor microenvironment, which play important roles in regulating tumor progression and therapy resistance by transferring exosomes to cancer cells. However, how CAFs modulate esophageal squamous cell carcinoma (ESCC) progression and radioresistance remains incompletely understood. The expression of fibroblast activation protein (FAP) in CAFs was evaluated by immunohistochemistry in 174 ESCC patients who underwent surgery and 78 pretreatment biopsy specimens of ESCC patients who underwent definitive chemoradiotherapy. We sorted CAFs according to FAP expression, and the conditioned medium (CM) was collected to culture ESCC cells. The expression levels of several lncRNAs that were considered to regulate ESCC progression and/or radioresistance were measured in exosomes derived from FAP<sup>+</sup> CAFs and FAP<sup>-</sup> CAFs. Subsequently, cell counting kit-8, 5-ethynyl-2'-deoxyuridine, transwell, colony formation, and xenograft assays were performed to investigate the functional differences between FAP<sup>+</sup> CAFs and FAP<sup>-</sup> CAFs. Finally, a series of in vitro and in vivo assays were used to evaluate the effect of AFAP1-AS1 on radiosensitivity of ESCC cells. FAP expression in stromal CAFs was positively correlated with nerve invasion, vascular invasion, depth of invasion, lymph node metastasis, lack of clinical complete response and poor survival. Culture of ESCC cells with CM/FAP<sup>+</sup> CAFs significantly increased cancer proliferation, migration, invasion and radioresistance, compared with culture with CM/FAP<sup>-</sup> CAFs. Importantly, FAP<sup>+</sup> CAFs exert their roles by directly transferring the functional lncRNA AFAP1-AS1 to ESCC cells via exosomes. Functional studies showed that AFAP1-AS1 promoted radioresistance by enhancing DNA damage repair in ESCC cells. Clinically, high levels of plasma AFAP1-AS1 correlated with poor responses to dCRT in ESCC patients. Our findings demonstrated that FAP<sup>+</sup> CAFs promoted radioresistance in ESCC cells through transferring exosomal lncRNA AFAP1-AS1; and may be a potential therapeutic target for ESCC treatment.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-07-09DOI: 10.1002/mc.23790
Hao Zhu, Fa-Lin Wang, Shuang Zhang, Li Xue, Guang-Qiang Gao, Hong-Wei Dong, Qi Wang, Wen-Guang Sun, Jia-Ren Liu
γ-Tocotrienol (γ-T3) is a major subtype of vitamin E, mainly extracted from palm trees, barley, walnuts, and other plants. γ-T3 has effects on anti-inflammation, anti-oxidation, and potential chemoprevention against malignancies. It is still uncompleted to understand the effect of γ-T3 on the inhibitory mechanism of cancer. This study aimed to investigate whether γ-T3 enhanced autophagy in gastric cancer and the underlying molecular mechanism. The results showed that γ-T3 (0-90 μmol/L) inhibited the proliferation of gastric cancer MKN45 cells and AGS cells, and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner. Autophagy was increased in MKN45 cells treated with γ-T3 (0-45 μmol/L), especially at a dose of 30 μmol/L for 24 h. These effects were reversed by 3-methyladenine pretreatment. Furthermore, γ-T3 (30 μmol/L) also significantly downregulated the expression of pGSK-3β (ser9) and β-catenin protein in MKN45 cells, and γ-T3 (20 mg/kg b.w.) effectively decreased the growth of MKN45 cell xenografts in BABL/c mice. GSK-3β inhibitor-CHIR-99021 reversed the negative regulation of GSK-3β/β-Catenin signaling and autophagy. Our findings indicated that γ-T3 enhances autophagy in gastric cancer cells mediated by GSK-3β/β-Catenin signaling, which provides new insights into the role of γ-T3 enhancing autophagy in gastric cancer.
{"title":"γ-Tocotrienol enhances autophagy of gastric cancer cells by the regulation of GSK3β/β-Catenin pathway.","authors":"Hao Zhu, Fa-Lin Wang, Shuang Zhang, Li Xue, Guang-Qiang Gao, Hong-Wei Dong, Qi Wang, Wen-Guang Sun, Jia-Ren Liu","doi":"10.1002/mc.23790","DOIUrl":"10.1002/mc.23790","url":null,"abstract":"<p><p>γ-Tocotrienol (γ-T3) is a major subtype of vitamin E, mainly extracted from palm trees, barley, walnuts, and other plants. γ-T3 has effects on anti-inflammation, anti-oxidation, and potential chemoprevention against malignancies. It is still uncompleted to understand the effect of γ-T3 on the inhibitory mechanism of cancer. This study aimed to investigate whether γ-T3 enhanced autophagy in gastric cancer and the underlying molecular mechanism. The results showed that γ-T3 (0-90 μmol/L) inhibited the proliferation of gastric cancer MKN45 cells and AGS cells, and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner. Autophagy was increased in MKN45 cells treated with γ-T3 (0-45 μmol/L), especially at a dose of 30 μmol/L for 24 h. These effects were reversed by 3-methyladenine pretreatment. Furthermore, γ-T3 (30 μmol/L) also significantly downregulated the expression of pGSK-3β (ser9) and β-catenin protein in MKN45 cells, and γ-T3 (20 mg/kg b.w.) effectively decreased the growth of MKN45 cell xenografts in BABL/c mice. GSK-3β inhibitor-CHIR-99021 reversed the negative regulation of GSK-3β/β-Catenin signaling and autophagy. Our findings indicated that γ-T3 enhances autophagy in gastric cancer cells mediated by GSK-3β/β-Catenin signaling, which provides new insights into the role of γ-T3 enhancing autophagy in gastric cancer.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The study aimed to investigate the impact of synaptotagmin 7 (SYT7) on the metastasis of epithelial ovarian cancer (EOC) and its potential mechanisms. This was achieved through the analysis of SYT7 expression levels and clinical relevance in EOC using bioinformatics analysis from TCGA. Additionally, the study examined the influence of SYT7 on the migration and invasion of EOC cells, as well as explored its molecular mechanisms using in vitro EOC cell lines and in vivo mouse xenograft models. Our research revealed that human EOC tissues exhibit significantly elevated levels of SYT7 compared to normal ovarian tissues, and that SYT7 expression is inversely correlated with overall survival. Suppression of SYT7 effectively impeded the migratory and invasive capabilities of CAOV3 cells, whereas overexpression of SYT7 notably accelerated tumor progression in A2780 cells. Mechanistic investigations demonstrated that SYT7 upregulates p-STAT3 and MMP2 in EOC cells. Importantly, treatment with the STAT3 inhibitor niclosamide effectively counteracted the oncogenic effects of SYT7 in EOC. The inhibition of SYT7 was found to significantly reduce in vivo tumor metastasis in a nude mouse xenograft model. Our findings suggest that the upregulation of SYT7 in EOC is associated with a negative prognosis, as it enhances tumor migration and invasion by activating the STAT3 signaling pathway. Thus, SYT7 might be utilized as a EOC prognostic marker and treatment target.
{"title":"SYT7 as a Potential Prognostic Marker Promotes the Metastasis of Epithelial Ovarian Cancer Cells by Activating the STAT3 Pathway.","authors":"Yinguang Li, Fengping Shao, Ying Huang, Qian Yin, Jun Liu, Yunhe Zhao, Linjing Yuan","doi":"10.1002/mc.23821","DOIUrl":"https://doi.org/10.1002/mc.23821","url":null,"abstract":"<p><p>The study aimed to investigate the impact of synaptotagmin 7 (SYT7) on the metastasis of epithelial ovarian cancer (EOC) and its potential mechanisms. This was achieved through the analysis of SYT7 expression levels and clinical relevance in EOC using bioinformatics analysis from TCGA. Additionally, the study examined the influence of SYT7 on the migration and invasion of EOC cells, as well as explored its molecular mechanisms using in vitro EOC cell lines and in vivo mouse xenograft models. Our research revealed that human EOC tissues exhibit significantly elevated levels of SYT7 compared to normal ovarian tissues, and that SYT7 expression is inversely correlated with overall survival. Suppression of SYT7 effectively impeded the migratory and invasive capabilities of CAOV3 cells, whereas overexpression of SYT7 notably accelerated tumor progression in A2780 cells. Mechanistic investigations demonstrated that SYT7 upregulates p-STAT3 and MMP2 in EOC cells. Importantly, treatment with the STAT3 inhibitor niclosamide effectively counteracted the oncogenic effects of SYT7 in EOC. The inhibition of SYT7 was found to significantly reduce in vivo tumor metastasis in a nude mouse xenograft model. Our findings suggest that the upregulation of SYT7 in EOC is associated with a negative prognosis, as it enhances tumor migration and invasion by activating the STAT3 signaling pathway. Thus, SYT7 might be utilized as a EOC prognostic marker and treatment target.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thyroid carcinoma (TC) is the most common malignant tumor of the endocrine system with increasing incidence. In this study, we found that BCL9 is markedly upregulated in human TC tumors and its expression is positively corrected with the process of TC. Functionally, we found that overexpression of BCL9 promoted the proliferation and migration of TC cells, while reduced the sensitivity of TC cells to ferroptosis, a form of cell death driven by iron‐dependent lipid peroxidation and implicated as a novel cancer therapeutic strategy. Mechanistically, the co‐immunoprecipitation assay determined that BCL9 could bind to Nrf2 which has been confirmed to play an important role in ferroptosis. Furthermore, we demonstrated that silence of BCL9 could decrease Nrf2 expression, and then affect the expression of the downstream genes of Nrf2, ultimately induce ferroptosis. Importantly, we confirmed the effects of BCL9 on TC tumors in vivo. Overall, this study unveils the functional role and clinical significance of BCL9 in TC progression, and highlights the potential of targeting BCL9/Nrf2 ferroptosis axis as a novel therapeutic strategy for TC treatment.
{"title":"Dysregulated BCL9 Controls Tumorigenicity and Ferroptosis Susceptibility by Binding With Nrf2 in Thyroid Carcinoma","authors":"Bin Wang, Zhihao Yao, Zhenhua Wang, Shenzhen Yao, Xiaoxia Cen, Wei Zhang","doi":"10.1002/mc.23816","DOIUrl":"https://doi.org/10.1002/mc.23816","url":null,"abstract":"Thyroid carcinoma (TC) is the most common malignant tumor of the endocrine system with increasing incidence. In this study, we found that BCL9 is markedly upregulated in human TC tumors and its expression is positively corrected with the process of TC. Functionally, we found that overexpression of BCL9 promoted the proliferation and migration of TC cells, while reduced the sensitivity of TC cells to ferroptosis, a form of cell death driven by iron‐dependent lipid peroxidation and implicated as a novel cancer therapeutic strategy. Mechanistically, the co‐immunoprecipitation assay determined that BCL9 could bind to Nrf2 which has been confirmed to play an important role in ferroptosis. Furthermore, we demonstrated that silence of BCL9 could decrease Nrf2 expression, and then affect the expression of the downstream genes of Nrf2, ultimately induce ferroptosis. Importantly, we confirmed the effects of BCL9 on TC tumors in vivo. Overall, this study unveils the functional role and clinical significance of BCL9 in TC progression, and highlights the potential of targeting BCL9/Nrf2 ferroptosis axis as a novel therapeutic strategy for TC treatment.","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142248412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Deyu Liao, Shiyu Yang, Ling Zhao, Wei Ren, Shiyan Liu, Huomei Yu, Yuanxiang Chen, Tao Yu, Tao Zeng, Lan Zhou, Yan Zhang
Inhibitor of β-catenin and T-cell factor (ICAT) is a classical inhibitor of the Wnt signaling pathway. Nonetheless, our previous work found that ICAT is overexpressed in cervical cancer (CC), resulting in the augmentation of migration and invasion capabilities of CC cells. It remains unclear what molecular mechanism underlies this phenomenon. The interaction between cancer cells and the tumor microenvironment (TME) promotes the outgrowth and metastasis of tumors. Tumor-associated macrophages (TAMs) are a major constituent of the TME and have a significant impact on the advancement of CC. Consequently, our inquiry pertains to the potential of ICAT to facilitate tumor development through its modulation of the cervical TME. In this study, we first verified that ICAT regulated the secretion of cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) in CC cells, leading to M2-like macrophage polarization and enhancement of the migration and invasion of CC cells. Furthermore, the system of co-culturing human umbilical vein endothelial cells (HUVECs) with macrophages revealed that depending on the CC cells' overexpression or inhibition of ICAT, the vascular tube formation by HUVECs can be either increased or decreased. Overall, our study indicates that ICAT stimulates M2-like polarization of TAMs via upregulating IL-10 and TGF-β, which results in increased neovascularization, tumor metastasis, and immunosuppression in CC. In upcoming times, inhibiting crosstalk between CC cells and TAMs may be a possible strategy for CC therapy.
β-catenin和T细胞因子抑制剂(ICAT)是Wnt信号通路的经典抑制剂。然而,我们之前的研究发现,ICAT 在宫颈癌(CC)中过度表达,导致 CC 细胞的迁移和侵袭能力增强。目前仍不清楚这一现象的分子机制是什么。癌细胞与肿瘤微环境(TME)之间的相互作用促进了肿瘤的生长和转移。肿瘤相关巨噬细胞(TAMs)是肿瘤微环境的主要组成部分,对CC的发展有重要影响。因此,我们的研究涉及 ICAT 通过调节宫颈 TME 促进肿瘤发展的潜力。在这项研究中,我们首先验证了 ICAT 可调节 CC 细胞中白细胞介素-10(IL-10)和转化生长因子-β(TGF-β)的分泌,从而导致 M2 样巨噬细胞极化并增强 CC 细胞的迁移和侵袭。此外,人脐静脉内皮细胞(HUVECs)与巨噬细胞共培养的系统显示,根据 CC 细胞过表达或抑制 ICAT 的情况,HUVECs 的血管管形成会增加或减少。总之,我们的研究表明,ICAT通过上调IL-10和TGF-β刺激TAMs的M2样极化,从而导致CC中血管新生、肿瘤转移和免疫抑制的增加。今后,抑制CC细胞和TAMs之间的串联可能是治疗CC的一种可行策略。
{"title":"ICAT-Mediated Crosstalk Between Cervical Cancer Cells and Macrophages Promotes M2-Like Macrophage Polarization to Reinforce Tumor Malignant Behaviors.","authors":"Deyu Liao, Shiyu Yang, Ling Zhao, Wei Ren, Shiyan Liu, Huomei Yu, Yuanxiang Chen, Tao Yu, Tao Zeng, Lan Zhou, Yan Zhang","doi":"10.1002/mc.23820","DOIUrl":"https://doi.org/10.1002/mc.23820","url":null,"abstract":"<p><p>Inhibitor of β-catenin and T-cell factor (ICAT) is a classical inhibitor of the Wnt signaling pathway. Nonetheless, our previous work found that ICAT is overexpressed in cervical cancer (CC), resulting in the augmentation of migration and invasion capabilities of CC cells. It remains unclear what molecular mechanism underlies this phenomenon. The interaction between cancer cells and the tumor microenvironment (TME) promotes the outgrowth and metastasis of tumors. Tumor-associated macrophages (TAMs) are a major constituent of the TME and have a significant impact on the advancement of CC. Consequently, our inquiry pertains to the potential of ICAT to facilitate tumor development through its modulation of the cervical TME. In this study, we first verified that ICAT regulated the secretion of cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) in CC cells, leading to M2-like macrophage polarization and enhancement of the migration and invasion of CC cells. Furthermore, the system of co-culturing human umbilical vein endothelial cells (HUVECs) with macrophages revealed that depending on the CC cells' overexpression or inhibition of ICAT, the vascular tube formation by HUVECs can be either increased or decreased. Overall, our study indicates that ICAT stimulates M2-like polarization of TAMs via upregulating IL-10 and TGF-β, which results in increased neovascularization, tumor metastasis, and immunosuppression in CC. In upcoming times, inhibiting crosstalk between CC cells and TAMs may be a possible strategy for CC therapy.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}