In this review, I describe our scientific journey to unearth the impact of RNA metabolism in cancer using the eukaryotic translation initiation factor eIF4E as an exemplar. This model allowed us to discover new structural, biochemical, and molecular features of RNA processing, and to reveal their substantial impact on cell physiology. This led us to develop proof-of-principle strategies to target these pathways in cancer patients leading to clinical benefit. I discuss the important role that the unexpected plays in research and the necessity of embracing the data even when it clashes with dogma. I also touch on the importance of equity, diversity and inclusion to the success of the scientific enterprise.
{"title":"The search for genetic dark matter and lessons learned from the journey.","authors":"K. Borden","doi":"10.1139/bcb-2022-0138","DOIUrl":"https://doi.org/10.1139/bcb-2022-0138","url":null,"abstract":"In this review, I describe our scientific journey to unearth the impact of RNA metabolism in cancer using the eukaryotic translation initiation factor eIF4E as an exemplar. This model allowed us to discover new structural, biochemical, and molecular features of RNA processing, and to reveal their substantial impact on cell physiology. This led us to develop proof-of-principle strategies to target these pathways in cancer patients leading to clinical benefit. I discuss the important role that the unexpected plays in research and the necessity of embracing the data even when it clashes with dogma. I also touch on the importance of equity, diversity and inclusion to the success of the scientific enterprise.","PeriodicalId":9524,"journal":{"name":"Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire","volume":"154 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74876222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Miao Pan, Q-F Sun, Chaowei Li, Ruiqing Tai, Xin’e Shi, Chao Sun
The highly regulated proliferation of adipocytes plays a momentous role in fat development and obesity. Hoxa5 is an important member of Hox family, its encoded protein is an important transcription factor related to development. And its differential expression in different adipose tissues seems to indicate that Hoxa5 may be involved in the regulation of adipocyte proliferation. In order to evaluate the regulation mechanism of Hoxa5 on adipocyte proliferation, we constructed a variety of Hoxa5 expression vectors in vivo and in vitro to explore its mechanism on adipocyte proliferation and its potential impact on obesity. We have observed that the overexpression of Hoxa5 strongly reduces cell counts, and Hoxa5 can inhibit cell proliferation and block cell cycle progression by regulating the expression of genes such as Cyclin E, Cycling D1 and p53. Most importantly, we demonstrated that Hoxa5 exerts its effect by regulating the signaling pathway of Janus kinase 2 (JAK2) signal transduction and transcription 3 (STAT3) activator, as well as binding to the promoter region of Ccne1 and inhibiting the transcription of Ccne1.This study provides an in-depth understanding of the potential molecular mechanism of Hoxa5 inhibiting adipocyte proliferation. Our results suggest the importance of Hoxa5 in the treatment of obesity.
{"title":"HOXA5 inhibits adipocytes proliferation through transcriptional regulation of Ccne1 and blocking JAK2/STAT3 signaling pathway in mice.","authors":"Miao Pan, Q-F Sun, Chaowei Li, Ruiqing Tai, Xin’e Shi, Chao Sun","doi":"10.1139/bcb-2021-0558","DOIUrl":"https://doi.org/10.1139/bcb-2021-0558","url":null,"abstract":"The highly regulated proliferation of adipocytes plays a momentous role in fat development and obesity. Hoxa5 is an important member of Hox family, its encoded protein is an important transcription factor related to development. And its differential expression in different adipose tissues seems to indicate that Hoxa5 may be involved in the regulation of adipocyte proliferation. In order to evaluate the regulation mechanism of Hoxa5 on adipocyte proliferation, we constructed a variety of Hoxa5 expression vectors in vivo and in vitro to explore its mechanism on adipocyte proliferation and its potential impact on obesity. We have observed that the overexpression of Hoxa5 strongly reduces cell counts, and Hoxa5 can inhibit cell proliferation and block cell cycle progression by regulating the expression of genes such as Cyclin E, Cycling D1 and p53. Most importantly, we demonstrated that Hoxa5 exerts its effect by regulating the signaling pathway of Janus kinase 2 (JAK2) signal transduction and transcription 3 (STAT3) activator, as well as binding to the promoter region of Ccne1 and inhibiting the transcription of Ccne1.This study provides an in-depth understanding of the potential molecular mechanism of Hoxa5 inhibiting adipocyte proliferation. Our results suggest the importance of Hoxa5 in the treatment of obesity.","PeriodicalId":9524,"journal":{"name":"Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82569128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wenjuan Zhou, Guanjun Dong, G. Gao, Zhangxu He, Jiale Xu, S. Aziz, Liying Ma, Wen-en Zhao
Liver fibrosis is a very common health problem and currently lacks effective treatments. Cullin ring E3 ligases (CRLs) regulate the turnover of ~20% of mammalian cell proteins. Neddylation, the process by which NEDD8 is covalently attached to cullin proteins through sequential enzymatic reactions, is critical for the activation of CRLs and was recently found to be elevated in liver fibrosis. NEDD8-activating enzyme E1-specific inhibition led to the reduced liver damage characterized by decreased apoptosis, inflammation and fibrosis. However, the relevance of a co-E3 ligase, DCN1, in liver fibrosis remains unclear. Here, a novel and potent DCN1-UBC12 interaction inhibitor HZX-960 was discovered with an IC50 value of 9.37nM, which could inhibit the neddylation of cullin3. Importantly, we identified that HZX-960 treatment could attenuate TGFβ-induced liver fibrotic responses by reducing the deposition of collagen I and α-SMA, and upregulating cellular NRF2, HO-1 and NQO1 level in two hepatic stellate cell lines. Additionally, DCN1 was shown to be unregulated in CCl4-induced mice liver tissue, and liver fibrotic signaling in mice was reduced by HZX-960. Therefore, our data demonstrated that HZX-960 possessed anti-liver fibrosis ability, and DCN1 may be a potential therapeutic target for liver fibrosis treatment.
{"title":"Evaluation of HZX-960, a novel DCN1-UBC12 interaction inhibitor, as a potential antifibrotic compound for liver fibrosis.","authors":"Wenjuan Zhou, Guanjun Dong, G. Gao, Zhangxu He, Jiale Xu, S. Aziz, Liying Ma, Wen-en Zhao","doi":"10.1139/bcb-2021-0585","DOIUrl":"https://doi.org/10.1139/bcb-2021-0585","url":null,"abstract":"Liver fibrosis is a very common health problem and currently lacks effective treatments. Cullin ring E3 ligases (CRLs) regulate the turnover of ~20% of mammalian cell proteins. Neddylation, the process by which NEDD8 is covalently attached to cullin proteins through sequential enzymatic reactions, is critical for the activation of CRLs and was recently found to be elevated in liver fibrosis. NEDD8-activating enzyme E1-specific inhibition led to the reduced liver damage characterized by decreased apoptosis, inflammation and fibrosis. However, the relevance of a co-E3 ligase, DCN1, in liver fibrosis remains unclear. Here, a novel and potent DCN1-UBC12 interaction inhibitor HZX-960 was discovered with an IC50 value of 9.37nM, which could inhibit the neddylation of cullin3. Importantly, we identified that HZX-960 treatment could attenuate TGFβ-induced liver fibrotic responses by reducing the deposition of collagen I and α-SMA, and upregulating cellular NRF2, HO-1 and NQO1 level in two hepatic stellate cell lines. Additionally, DCN1 was shown to be unregulated in CCl4-induced mice liver tissue, and liver fibrotic signaling in mice was reduced by HZX-960. Therefore, our data demonstrated that HZX-960 possessed anti-liver fibrosis ability, and DCN1 may be a potential therapeutic target for liver fibrosis treatment.","PeriodicalId":9524,"journal":{"name":"Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87519502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To date, there is no effective treatment strategy for Intracerebral hemorrhage (ICH). Curcumin, a major active ingredient of curcuma longa L, possesses a potential anti-inflammatory activity in many types of disease. In the current study, the mechanism underlying curcumin attenuates ICH-induced neuronal apoptosis and neuroinflammation was explored. Herein, we studied curcumin decreased brain edema and improved neurological function by using brain edema measurement, assessment of neurological-deficient score, immunofluorescence, and western blotting analyses after ICH. The results showed that curcumin improved ICH-induced neuronal apoptosis and neuroinflammation. Functionally, the polarization of microglia was assessed by immunofluorescence and western blotting analyses after ICH in the absence or presence of curcumin. The results suggested that the M1-type microglia were activated after ICH, while the effect was blocked by curcumin treatment, suggesting that curcumin alleviates the neuroinflammation and apoptosis of neurons by suppressing the M1-type polarization of microglia. Mechanically, M1 polarization of microglia was regulated by JAK1/STAT1 and the activation of JAK1/STAT1 was blocked by curcumin. Meanwhile, the protective function of curcumin can be blocked by RO8191, an activator of JAK1. Taken together our study suggests that curcumin improved the ICH-induced brain injury through alleviating M1 polarization of microglia/macrophage and neuroinflammation via suppressing JAK1/STAT1 pathway.
{"title":"Curcumin attenuates intracerebral hemorrhage-induced neuronal apoptosis and neuroinflammation by suppressing the JAK1/STAT1 pathway.","authors":"Fei Wang, Jian-jun Xia, Lijuan Shen, Ting Jiang, Wu-Lin Li, Da-li You, Qing Chang, Shan-you Hu, Li Wang, Xiao Wu","doi":"10.1139/bcb-2021-0423","DOIUrl":"https://doi.org/10.1139/bcb-2021-0423","url":null,"abstract":"To date, there is no effective treatment strategy for Intracerebral hemorrhage (ICH). Curcumin, a major active ingredient of curcuma longa L, possesses a potential anti-inflammatory activity in many types of disease. In the current study, the mechanism underlying curcumin attenuates ICH-induced neuronal apoptosis and neuroinflammation was explored. Herein, we studied curcumin decreased brain edema and improved neurological function by using brain edema measurement, assessment of neurological-deficient score, immunofluorescence, and western blotting analyses after ICH. The results showed that curcumin improved ICH-induced neuronal apoptosis and neuroinflammation. Functionally, the polarization of microglia was assessed by immunofluorescence and western blotting analyses after ICH in the absence or presence of curcumin. The results suggested that the M1-type microglia were activated after ICH, while the effect was blocked by curcumin treatment, suggesting that curcumin alleviates the neuroinflammation and apoptosis of neurons by suppressing the M1-type polarization of microglia. Mechanically, M1 polarization of microglia was regulated by JAK1/STAT1 and the activation of JAK1/STAT1 was blocked by curcumin. Meanwhile, the protective function of curcumin can be blocked by RO8191, an activator of JAK1. Taken together our study suggests that curcumin improved the ICH-induced brain injury through alleviating M1 polarization of microglia/macrophage and neuroinflammation via suppressing JAK1/STAT1 pathway.","PeriodicalId":9524,"journal":{"name":"Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire","volume":"187 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85094751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fast, accessible, and high-quality DNA is fundamental to advancement in the life sciences that will drive forward fields like agriculture, energy, and medicine. Despite their importance in accelerating global progress, bioscience research and biotechnologies can also be misused, endangering humans, animals, and the environment. The ability to accidentally or deliberately endow or enhance pathogenicity of biological systems is of particular concern. Access to DNA sequences with a clear potential for Dual Use should be limited to responsible and identifiable groups with legitimate uses. Yet, none of the 195 countries party to the International Health Regulations have national laws that mandate this type of screening. Many DNA providers voluntarily screen orders and absorb increased costs, but this practice is not universally adopted for a variety of reasons. This article explores the incentives and regulatory structures that can bring the screening coverage of DNA orders towards 100%, which may include: expedited orders for approved customers, better tools and technology for more efficient screening, funding requirements that grantees use screened DNA, and early education in biosecurity aimed at researchers and students. Ultimately, an incentive-based multi-stakeholder approach to DNA screening can benefit researchers, industry, and global health security.
{"title":"Establishing an incentive-based multi-stakeholder approach to Dual Use DNA screening.","authors":"Christopher R Isaac","doi":"10.1139/bcb-2021-0504","DOIUrl":"https://doi.org/10.1139/bcb-2021-0504","url":null,"abstract":"Fast, accessible, and high-quality DNA is fundamental to advancement in the life sciences that will drive forward fields like agriculture, energy, and medicine. Despite their importance in accelerating global progress, bioscience research and biotechnologies can also be misused, endangering humans, animals, and the environment. The ability to accidentally or deliberately endow or enhance pathogenicity of biological systems is of particular concern. Access to DNA sequences with a clear potential for Dual Use should be limited to responsible and identifiable groups with legitimate uses. Yet, none of the 195 countries party to the International Health Regulations have national laws that mandate this type of screening. Many DNA providers voluntarily screen orders and absorb increased costs, but this practice is not universally adopted for a variety of reasons. This article explores the incentives and regulatory structures that can bring the screening coverage of DNA orders towards 100%, which may include: expedited orders for approved customers, better tools and technology for more efficient screening, funding requirements that grantees use screened DNA, and early education in biosecurity aimed at researchers and students. Ultimately, an incentive-based multi-stakeholder approach to DNA screening can benefit researchers, industry, and global health security.","PeriodicalId":9524,"journal":{"name":"Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82075385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Proprotein Convertase Subtilisin/Kexin-type 9 (PCSK9) is a circulating negative regulator of hepatic low-density lipoprotein receptor (LDLR) which clears cholesterol from blood. Gain-of-function genetic mutations which amplify PCSK9 activity have been found to cause potentially lethal familial hypercholesterolemia. Inversely, reduction of its activity through loss-of-function genetics or with pharmaceuticals was shown to increase hepatic LDLR, to lower blood cholesterol, and to protect against cardiovascular diseases. New epidemiological and experimental evidence suggests that this reduction could also attenuate inflammation, reinforce cancer immunity, provide resistance to infections, and protect against liver pathologies. In this review, we question the relevance of this protein under normal physiology. We propose that PCSK9 is an important, but non-essential, modulator of cholesterol metabolism and immunity, and that its pathogenicity results from its chronic overexpression.
{"title":"The Biological Relevance of PCSK9: When Less Is Better….","authors":"M. Mbikay, M. Chrétien","doi":"10.1139/bcb-2021-0540","DOIUrl":"https://doi.org/10.1139/bcb-2021-0540","url":null,"abstract":"Proprotein Convertase Subtilisin/Kexin-type 9 (PCSK9) is a circulating negative regulator of hepatic low-density lipoprotein receptor (LDLR) which clears cholesterol from blood. Gain-of-function genetic mutations which amplify PCSK9 activity have been found to cause potentially lethal familial hypercholesterolemia. Inversely, reduction of its activity through loss-of-function genetics or with pharmaceuticals was shown to increase hepatic LDLR, to lower blood cholesterol, and to protect against cardiovascular diseases. New epidemiological and experimental evidence suggests that this reduction could also attenuate inflammation, reinforce cancer immunity, provide resistance to infections, and protect against liver pathologies. In this review, we question the relevance of this protein under normal physiology. We propose that PCSK9 is an important, but non-essential, modulator of cholesterol metabolism and immunity, and that its pathogenicity results from its chronic overexpression.","PeriodicalId":9524,"journal":{"name":"Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87846422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jing Zhang, Runfang Gao, Jie Li, Keren Yu, Kaixin Bi
Breast cancer is the most common malignant tumour in women. Our research on alloimperatorin from Angelica dahurica showed that alloimperatorin inhibited breast cancer cell viability in a concentration- and time-dependent manner; it also showed that apoptosis and ferroptosis inhibitors significantly weakened the anti-survival effect of alloimperatorin. Alloimperatorin clearly induced breast cancer cell apoptosis and increased the activities of Caspase-3, Caspase-8, Caspase-9 and PARP; it also caused significant mitochondrial shrinkage, promoted the accumulation of Fe2+, ROS and MDA, and significantly reduced mRNA and protein expression levels of SLC7A11 and GPX4, indicating that alloimperatorin induces ferroptosis. In addition, alloimperatorin significantly promoted Keap1 expression; although it did not affect the expression of PGAM5 and AIFM1, it significantly reduced the phosphorylation level of AIFM1. After downregulating the expression of Keap1, PGAM5 or AIFM1, the inhibitory effect of alloimperatorin on cell viability was significantly weakened, indicating that alloimperatorin regulates the Keap1/PGAM5/AIFM1 pathway to promote oxeiptosis. Alloimperatorin significantly inhibited the invasion of breast cancer cells, while Keap1 siRNA or GPX4 overexpression vectors significantly enhanced cell invasion and effectively reversed the anti-invasive effect of alloimperatorin. Therefore, alloimperatorin induces breast cancer cell apoptosis, ferroptosis and oxeiptosis, thereby inhibiting cell growth and invasion.
{"title":"Alloimperatorin activates apoptosis, ferroptosis and oxeiptosis to inhibit the growth and invasion of breast cancer cells in vitro.","authors":"Jing Zhang, Runfang Gao, Jie Li, Keren Yu, Kaixin Bi","doi":"10.1139/bcb-2021-0399","DOIUrl":"https://doi.org/10.1139/bcb-2021-0399","url":null,"abstract":"Breast cancer is the most common malignant tumour in women. Our research on alloimperatorin from Angelica dahurica showed that alloimperatorin inhibited breast cancer cell viability in a concentration- and time-dependent manner; it also showed that apoptosis and ferroptosis inhibitors significantly weakened the anti-survival effect of alloimperatorin. Alloimperatorin clearly induced breast cancer cell apoptosis and increased the activities of Caspase-3, Caspase-8, Caspase-9 and PARP; it also caused significant mitochondrial shrinkage, promoted the accumulation of Fe2+, ROS and MDA, and significantly reduced mRNA and protein expression levels of SLC7A11 and GPX4, indicating that alloimperatorin induces ferroptosis. In addition, alloimperatorin significantly promoted Keap1 expression; although it did not affect the expression of PGAM5 and AIFM1, it significantly reduced the phosphorylation level of AIFM1. After downregulating the expression of Keap1, PGAM5 or AIFM1, the inhibitory effect of alloimperatorin on cell viability was significantly weakened, indicating that alloimperatorin regulates the Keap1/PGAM5/AIFM1 pathway to promote oxeiptosis. Alloimperatorin significantly inhibited the invasion of breast cancer cells, while Keap1 siRNA or GPX4 overexpression vectors significantly enhanced cell invasion and effectively reversed the anti-invasive effect of alloimperatorin. Therefore, alloimperatorin induces breast cancer cell apoptosis, ferroptosis and oxeiptosis, thereby inhibiting cell growth and invasion.","PeriodicalId":9524,"journal":{"name":"Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73284979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Small Proline Rich Protein 1A (SPRR1A) plays a critical role in regulating squamous cell differentiation. It has been reported that SPRR1A overexpression was closely related to the progression of some tumors such as gastric cancer and colon cancer. However, the function of SPRR1A in lung adenocarcinoma (LUAD) has not been elucidated. Here we firstly examined the expression pattern of SPRR1A in LUAD tissues, which indicated that SPRR1A expression level was significantly elevated in LUAD tissues compared to normal lung tissues. High expression of SPRR1A was closely related to the larger tumor size. LUAD patients with higher SPRR1A expression had poorer overall survival and SPRR1A was identified as an independent unfavorable prognosis factor. In addition, the effects of SPRR1A on lung cancer cells were tested through cellular experiments and the result demonstrated that knockdown of SPRR1A can suppress proliferation and invasion capacities of tumor cells, while overexpressing SPRR1A exerted opposite effects. Finally, our findings were substantiated by the data obtained from in vivo xenografts using mice model. In conclusion, LUAD patients with higher SPRR1A expression were more predisposed to poorer clinical outcomes and unfavorable prognosis, indicating the potential role of SPRR1A as a novel clinical biomarker and therapeutic target.
小脯氨酸富蛋白1A (Small Proline Rich Protein 1A, SPRR1A)在调节鳞状细胞分化中起关键作用。有报道称SPRR1A过表达与胃癌、结肠癌等肿瘤的进展密切相关。然而，SPRR1A在肺腺癌(LUAD)中的功能尚未阐明。我们首先检测了SPRR1A在LUAD组织中的表达模式，结果表明，与正常肺组织相比，SPRR1A在LUAD组织中的表达水平显著升高。SPRR1A的高表达与肿瘤大小密切相关。SPRR1A表达较高的LUAD患者总生存期较差，SPRR1A被认为是一个独立的不良预后因素。此外，通过细胞实验检测SPRR1A对肺癌细胞的作用，结果表明，敲低SPRR1A可以抑制肿瘤细胞的增殖和侵袭能力，而过表达SPRR1A则相反。最后，我们的研究结果得到了小鼠体内异种移植物模型数据的证实。综上所述，SPRR1A表达较高的LUAD患者更容易出现较差的临床结局和不良预后，提示SPRR1A作为一种新的临床生物标志物和治疗靶点的潜在作用。
{"title":"Small Proline Rich Protein 1A promotes lung adenocarcinoma progression and indicates unfavorable clinical outcomes.","authors":"Shenqiu Wang, Wenmei Zhang","doi":"10.1139/bcb-2021-0348","DOIUrl":"https://doi.org/10.1139/bcb-2021-0348","url":null,"abstract":"Small Proline Rich Protein 1A (SPRR1A) plays a critical role in regulating squamous cell differentiation. It has been reported that SPRR1A overexpression was closely related to the progression of some tumors such as gastric cancer and colon cancer. However, the function of SPRR1A in lung adenocarcinoma (LUAD) has not been elucidated. Here we firstly examined the expression pattern of SPRR1A in LUAD tissues, which indicated that SPRR1A expression level was significantly elevated in LUAD tissues compared to normal lung tissues. High expression of SPRR1A was closely related to the larger tumor size. LUAD patients with higher SPRR1A expression had poorer overall survival and SPRR1A was identified as an independent unfavorable prognosis factor. In addition, the effects of SPRR1A on lung cancer cells were tested through cellular experiments and the result demonstrated that knockdown of SPRR1A can suppress proliferation and invasion capacities of tumor cells, while overexpressing SPRR1A exerted opposite effects. Finally, our findings were substantiated by the data obtained from in vivo xenografts using mice model. In conclusion, LUAD patients with higher SPRR1A expression were more predisposed to poorer clinical outcomes and unfavorable prognosis, indicating the potential role of SPRR1A as a novel clinical biomarker and therapeutic target.","PeriodicalId":9524,"journal":{"name":"Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91304908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. A. Ross, B. Ahn, Jennifer C. King, Kamiko R. Bressler, D. Senger, N. Thakor
Glioblastoma multiforme (GBM) is among the deadliest cancers, owing in part to complex inter- and intra-tumor heterogeneity and the presence of a population of stem-like cells called brain tumor stem cells (BTSCs/BTICs). These cancer stem cells survive treatment and confer resistance to the current therapies-namely, radiation and the chemotherapeutic, temozolomide (TMZ). TMZ induces cell death by alkylating DNA, and BTSCs resist this mechanism via a robust DNA damage response. Hence, recent studies aimed to sensitize BTSCs to TMZ using combination therapy, such as inhibition of DNA repair machinery. We have previously demonstrated in established GBM cell lines that eukaryotic initiation factor 5B (eIF5B) promotes the translation of pro-survival and anti-apoptotic proteins. Consequently, silencing eIF5B sensitizes these cells to TRAIL-induced apoptosis. However, established cell lines do not always recapitulate the features of human glioma. Therefore, we investigated this mechanism in patient-derived BTSCs. We show that silencing eIF5B leads to increased TMZ sensitivity in two BTSC lines, BT25 and BT48. Depletion of eIF5B decreases levels of anti-apoptotic proteins in BT48 and sensitizes these cells to TMZ-induced activation of caspase-3, cleavage of PARP, and apoptosis. We suggest that eIF5B represents a rational target to sensitize GBM tumors to the current standard-of-care.
{"title":"Eukaryotic initiation factor 5B (eIF5B) regulates temozolomide-mediated apoptosis in brain tumor stem cells (BTSCs).","authors":"J. A. Ross, B. Ahn, Jennifer C. King, Kamiko R. Bressler, D. Senger, N. Thakor","doi":"10.1139/bcb-2019-0329","DOIUrl":"https://doi.org/10.1139/bcb-2019-0329","url":null,"abstract":"Glioblastoma multiforme (GBM) is among the deadliest cancers, owing in part to complex inter- and intra-tumor heterogeneity and the presence of a population of stem-like cells called brain tumor stem cells (BTSCs/BTICs). These cancer stem cells survive treatment and confer resistance to the current therapies-namely, radiation and the chemotherapeutic, temozolomide (TMZ). TMZ induces cell death by alkylating DNA, and BTSCs resist this mechanism via a robust DNA damage response. Hence, recent studies aimed to sensitize BTSCs to TMZ using combination therapy, such as inhibition of DNA repair machinery. We have previously demonstrated in established GBM cell lines that eukaryotic initiation factor 5B (eIF5B) promotes the translation of pro-survival and anti-apoptotic proteins. Consequently, silencing eIF5B sensitizes these cells to TRAIL-induced apoptosis. However, established cell lines do not always recapitulate the features of human glioma. Therefore, we investigated this mechanism in patient-derived BTSCs. We show that silencing eIF5B leads to increased TMZ sensitivity in two BTSC lines, BT25 and BT48. Depletion of eIF5B decreases levels of anti-apoptotic proteins in BT48 and sensitizes these cells to TMZ-induced activation of caspase-3, cleavage of PARP, and apoptosis. We suggest that eIF5B represents a rational target to sensitize GBM tumors to the current standard-of-care.","PeriodicalId":9524,"journal":{"name":"Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire","volume":"102 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80495958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Both tobacco smoking and nicotine have been reported to regulate the occurrence and progression of periodontitis. Many studies have demonstrated that nicotine destroys regeneration of periodontal tissues primarily by inhibiting the proliferation of human periodontal ligament (PDL) cells. However, the mechanism underlying this process is still unclear. Therefore, we investigated whether nicotine-upregulated miR-30a inhibited the proliferation of human PDL cells by downregulating cyclin E2 (CCNE2) in vitro. Quantitative real-time PCR analysis revealed that nicotine upregulated the expression of miR-30a in human PDL cells. In addition, nicotine could inhibit the proliferation of human PDL cells by inducing cell cycle arrest. To support this hypothesis, we showed that nicotine downregulated the expression of CCNE2 in human PDL cells, whereas inhibition of miR-30a restored CCNE2 expression that were downregulated by nicotine. Furthermore, we found that miR-30a directly interacts with the CCNE2 3'UTR through luciferase reporter assay. In conclusion, these findings indicate that nicotine-upregulated miR-30a inhibits the proliferation of human PDL cells by downregulating the expression of CCNE2.
{"title":"Nicotine-upregulated miR-30a arrests cell cycle in G1 phase by directly targeting CCNE2 in human periodontal ligament cells.","authors":"Lizheng Wu, Kuan Yang, Yajie Gui, Xiaojing Wang","doi":"10.1139/bcb-2019-0156","DOIUrl":"https://doi.org/10.1139/bcb-2019-0156","url":null,"abstract":"Both tobacco smoking and nicotine have been reported to regulate the occurrence and progression of periodontitis. Many studies have demonstrated that nicotine destroys regeneration of periodontal tissues primarily by inhibiting the proliferation of human periodontal ligament (PDL) cells. However, the mechanism underlying this process is still unclear. Therefore, we investigated whether nicotine-upregulated miR-30a inhibited the proliferation of human PDL cells by downregulating cyclin E2 (CCNE2) in vitro. Quantitative real-time PCR analysis revealed that nicotine upregulated the expression of miR-30a in human PDL cells. In addition, nicotine could inhibit the proliferation of human PDL cells by inducing cell cycle arrest. To support this hypothesis, we showed that nicotine downregulated the expression of CCNE2 in human PDL cells, whereas inhibition of miR-30a restored CCNE2 expression that were downregulated by nicotine. Furthermore, we found that miR-30a directly interacts with the CCNE2 3'UTR through luciferase reporter assay. In conclusion, these findings indicate that nicotine-upregulated miR-30a inhibits the proliferation of human PDL cells by downregulating the expression of CCNE2.","PeriodicalId":9524,"journal":{"name":"Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire","volume":"601 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77304891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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