Kieun Bae, Dong Eon Kim, Jin Hee Kim, Ja Young Lee, Kyong-Ah Yoon
{"title":"Oncogenic fusion of CD63-BCAR4 contributes cancer stem cell-like properties via ALDH1 activity.","authors":"Kieun Bae, Dong Eon Kim, Jin Hee Kim, Ja Young Lee, Kyong-Ah Yoon","doi":"10.1002/mc.23808","DOIUrl":"10.1002/mc.23808","url":null,"abstract":"<p><p>Gene fusions are common somatic alterations in cancers, and fusions with tumorigenic features have been identified as novel drivers of cancer and therapeutic targets. Few studies have determined whether the oncogenic ability of fusion genes is related to the induction of stemness in cells. Cancer stem cells (CSCs) are a subset of cells that contribute to cancer progression, metastasis, and recurrence, and are critical components of the aggressive features of cancer. Here, we investigated the CSC-like properties induced by CD63-BCAR4 fusion gene, previously reported as an oncogenic fusion, and its potential contribution for the enhanced metastasis as a notable characteristic of CD63-BCAR4. CD63-BCAR4 overexpression facilitates sphere formation in immortalized bronchial epithelial cells. The significantly enhanced sphere-forming activity observed in tumor-derived cells from xenografted mice of CD63-BCAR4 overexpressing cells was suppressed by silencing of BCAR4. RNA microarray analysis revealed that ALDH1A1 was upregulated in the BCAR4 fusion-overexpressing cells. Increased activity and expression of ALDH1A1 were observed in the spheres of CD63-BCAR4 overexpressing cells compared with those of the empty vector. CD133 and CD44 levels were also elevated in BCAR4 fusion-overexpressing cells. Increased NANOG, SOX2, and OCT-3/4 protein levels were observed in metastatic tumor cells derived from mice injected with CD63-BCAR4 overexpressing cells. Moreover, DEAB, an ALDH1A1 inhibitor, reduced the migration activity induced by CD63-BCAR4 as well as the sphere-forming activity. Our findings suggest that CD63-BCAR4 fusion induces CSC-like properties by upregulating ALDH1A1, which contributes to its metastatic features.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"2282-2290"},"PeriodicalIF":4.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971496","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
{"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":"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":" ","pages":"2425-2440"},"PeriodicalIF":4.3,"publicationDate":"2024-12-01","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}
{"title":"ROR2 promotes cell cycle progression and cell proliferation through the PI3K/AKT signaling pathway in gastric cancer.","authors":"Qi Liu, Xin Zhao, Xiaowen Shao, Ping Cheng, Jingyi Cui, Shuyi Han","doi":"10.1002/mc.23811","DOIUrl":"10.1002/mc.23811","url":null,"abstract":"<p><p>Proliferation is a critical characteristic of the progression of gastric cancer (GC). Receptor tyrosine kinase-like orphan receptor 2 (ROR2), the orphan receptor tyrosine kinase-like receptor, exhibits effects on tumor growth due to its abnormal expression in cancer. The goal of our study was to assess the potential regulatory role exerted by the ROR2 on GC cells. Through previous bioinformatics analysis, we discovered an association between ROR2 and the G2/M phase of the GC cell cycle. However, little is known about the link between ROR2 and the G2/M phase cell cycle in GC. Here, the findings of our study indicate that ROR2, after transcribed expression by Twist1, activates the PI3K/AKT/mTOR/S6K signal transduction pathway, thus leading to the acceleration of the G2/M phase and subsequent promotion of cell proliferation in GC. Furthermore, the functional link among ROR2, Twist1, and G2/M phase of cell cycle was also confirmed in mouse xenograft tissues and human tissues. ROR2 expression was correlated with Twist expression and lower survival in vivo. Notably, our suggestion is that focusing on ROR2 as a potential therapeutic approach could show potential for the management of GC.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"2316-2331"},"PeriodicalIF":4.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988398","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}
Dan Wu, MingHang Chen, Nan Zheng, Ying Lu, Xiang Wang, Chuan Jiang, HongTao Xu
{"title":"The efficacy and safety of pH-responsive and photothermal-sensitive multifunctional nanoparticles loaded with cryptotanshinone for the treatment of gastric cancer.","authors":"Dan Wu, MingHang Chen, Nan Zheng, Ying Lu, Xiang Wang, Chuan Jiang, HongTao Xu","doi":"10.1002/mc.23814","DOIUrl":"10.1002/mc.23814","url":null,"abstract":"<p><p>A multifunctional polydopamine/mesoporous silica nanoparticles loaded cryptotanshinone (PDA/MSN@CTS) was synthesized and subjected to investigating its physicochemical properties and anti-gastric cancer (GC) effects. Utilizing network pharmacology and molecular docking techniques, CTS was identified as our final research target. The structural morphology and physicochemical properties of PDA/MSN@CTS were examined. Near-infrared (NIR) laser was employed to evaluate the photothermal properties of the PDA/MSN@CTS, along with pH-responsive and NIR-triggered release assessments. In vitro experiments evaluated the impact of PDA/MSN@CTS on the malignant behavior of AGS gastric cells. A subcutaneous tumor model was further established to evaluate the in vivo safety of PDA/MSN@CTS. Furthermore, the in vivo photothermal efficacy of PDA/MSN@CTS, in addition to its combined effect with photothermal therapy (PTT), was investigated. Uniform and stable PDA/MSN@CTS had been successfully synthesized and demonstrated efficient release under tumor environment and NIR irradiation. Upon increasing NIR laser conditions, in vivo cytotoxicity, apoptosis rate, reactive oxygen species scavenging ability, and suppression of migration and invasion of AGS cells by PDA/MSN@CTS were significantly enhanced. In vivo assessments revealed excellent blood compatibility and biosafety of PDA/MSN@CTS, alongside robust tumor tissue targeting. Combining nanoparticles with PTT facilitated the anti-GC effects of PDA/MSN@CTS. Compared to free drugs, PDA/MSN@CTS exhibits higher selectivity towards cancer cells, demonstrating effective anticancer activity and biocompatibility both in vitro and in vivo. Furthermore, our nanomaterial possesses excellent photothermal properties, and under NIR conditions, PDA/MSN@CTS exhibits synergistic therapeutic effects.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"2346-2362"},"PeriodicalIF":4.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056126","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}
{"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":"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":" ","pages":"2441-2455"},"PeriodicalIF":4.3,"publicationDate":"2024-12-01","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}
Marianna Rita Brogna, Francesca Collina, Maria Grazia Chiofalo, Debora De Bartolo, Angela Montone, Maria Rosaria Schiano, Michele Del Sesto, Nubia Pizza, Gerardo Ferrara
{"title":"Case report & review: Bilateral NIFTP harboring concomitant HRAS and KRAS mutation: Report of an unusual case and literature review.","authors":"Marianna Rita Brogna, Francesca Collina, Maria Grazia Chiofalo, Debora De Bartolo, Angela Montone, Maria Rosaria Schiano, Michele Del Sesto, Nubia Pizza, Gerardo Ferrara","doi":"10.1002/mc.23813","DOIUrl":"10.1002/mc.23813","url":null,"abstract":"<p><p>Diagnosis and treatment of thyroid disease are affected by the wide range of thyroid cancer subtypes and their varying degrees of aggressiveness. To better describe the indolent nature of thyroid neoplasms previously classified as noninvasive follicular variant of papillary thyroid carcinoma (NI-FVPTC), the Endocrine Pathology Society working group has recently coined the term \"noninvasive follicular thyroid neoplasm with papillary-like nuclear features\" (NIFTP). The purpose of this nomenclature change is to avoid patients the distress of cancer diagnosis and to decrease the overtreatment of thyroid nodules with a RAS-LIKE molecular profile similar to follicular adenoma. Consequently, the reclassification has a significant impact on thyroid nodule clinical care as well as histopathologic and cytopathologic diagnosis. This paper will focus on a unique case of Bilateral NIFTP harboring concomitant HRAS and KRAS mutation; we will also review the background, molecular features, and clinical implications of NIFTP as well as the factors behind the nomenclature update. It also seemed helpful to emphasize the impact of NIFTP on clinical practice to avoid overtreating nodules that could be safely managed with lobectomy alone. Actually, despite the diagnosis is postsurgery, a comprehensive preoperative evaluation may raise a suspicion of NIFTP and suggest a more careful plan for treatment. Here, we present a unique case of bilateral NIFTP after total thyroidectomy; subsequent molecular analysis revealed that the patient's right nodule harbored an isolated p.(Q61K) HRAS mutation, while the left a p.(Q61K) KRAS mutation. To the best of our knowledge, this is the first case report of this nature. The existence of simultaneous mutations highlights the occurrence of intratumoral heterogeneity (ITH) also in the context of FVPTC, which requires comprehensive investigation. The available information shows that NIFTP, identified in accordance with stringent inclusion and exclusion criteria, exhibits a very latent clinical behavior even in the face of conservative lobectomy, lacking of radioactive iodine therapy. However, it cannot be regarded as a benign lesion because there is a small but significant incidence of adverse events, such as lymph nodes and distant metastases. Currently, NIFTP can only be suspected before surgery: several efforts could be explored to identify key molecular, cytological, and ultrasonographic traits that may be helpful in raising the possibility of NIFTP in the preoperative context. Additionally, our discovery of simultaneous mutations within the same lesion strengthens the evidence of ITH even in FVPTC. Although the extent and biological impact of this phenomenon in NIFTP are still debated, a deeper understanding is essential to ensure appropriate clinical management.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"2273-2281"},"PeriodicalIF":4.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133256","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}
Dongsheng He, Chao Niu, Rilan Bai, Naifei Chen, Jiuwei Cui
{"title":"ADAR1 Promotes Invasion and Migration and Inhibits Ferroptosis via the FAK/AKT Pathway in Colorectal Cancer.","authors":"Dongsheng He, Chao Niu, Rilan Bai, Naifei Chen, Jiuwei Cui","doi":"10.1002/mc.23818","DOIUrl":"10.1002/mc.23818","url":null,"abstract":"<p><p>The role of adenosine deaminase acting on RNA1 (ADAR1) in colorectal cancer (CRC) is poorly understood. This study investigated the roles and underlying molecular mechanisms of ADAR1 and its isoforms, explored the correlations between ADAR1 expression and the immune microenvironment and anticancer drug sensitivity, and examined the potential synergy of using ADAR1 expression and clinical parameters to determine the prognosis of CRC patients. CRC samples showed significant upregulation of ADAR1, and high ADAR1 expression was correlated with poor prognosis. Silencing ADAR1 inhibited the proliferation, invasion, and migration of CRC cells and induced ferroptosis by suppressing FAK/AKT activation, and the results of rescue assays were consistent with these mechanisms. Both ADAR1-p110 and ADAR1-p150 were demonstrated to regulate the FAK/AKT pathway, with ADAR1-p110 playing a particularly substantial role. In evaluating the prognosis of CRC patients, combining ADAR1 expression with clinical parameters produced a substantial synergistic effect. The in vivo tumorigenesis of CRC was significantly inhibited by silencing ADAR1. Furthermore, ADAR1 expression was positively correlated with tumor mutational burden (TMB) and microsatellite status (p < 0.05), indicating that ADAR1 plays a complex role in CRC immunotherapy. In conclusion, ADAR1 plays oncogenic roles in CRC both in vitro and in vivo, potentially by inhibiting ferroptosis via downregulation of the FAK/AKT pathway. Thus, ADAR1 serves as a potential prognostic biomarker and a promising target for CRC therapy.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"2401-2413"},"PeriodicalIF":4.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140594","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}
{"title":"SIRT1 promotes doxorubicin-induced breast cancer drug resistance and tumor angiogenesis via regulating GSH-mediated redox homeostasis.","authors":"Shashikanta Sahoo, Sunita Kumari, Sriravali Pulipaka, Yogesh Chandra, Srigiridhar Kotamraju","doi":"10.1002/mc.23809","DOIUrl":"10.1002/mc.23809","url":null,"abstract":"<p><p>Sirtuin 1 (SIRT1), a member of histone deacetylase III family, plays a pivotal role in mediating chemoresistance in several cancers, including breast cancer. However, the molecular mechanism by which the deregulated SIRT1 promotes doxorubicin (Dox) resistance is still elusive. Here, we showed that the cell proliferation rates and invasive properties of MDA-MB-231 breast cancer cells were increased from low- to high-Dox-resistant cells. In agreement, severe combined immunodeficiency disease (SCID) mice bearing labeled MDA-MB-231<sup>high Dox-Res</sup> cells showed significantly higher tumor growth, angiogenesis, and metastatic ability than parental MDA-MB-231 cells. Interestingly, the levels of SIRT1 and glutathione (GSH) were positively correlated with the degree of Dox-resistance. Dox-induced SIRT1 promoted NRF2 nuclear translocation with an accompanying increase in the antioxidant response element promotor activity and GSH levels. In contrast, inhibition of SIRT1 by EX527 greatly reversed these events. More so, Dox-resistance-induced pro-proliferative, proangiogenic, and invasive effects were obviated with depletion of either SIRT1 or GSH. Together, Dox-induced SIRT1 promotes dysregulation of redox homeostasis leading to breast cancer chemoresistance, tumor aggressiveness, angiogenesis, and metastasis.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"2291-2304"},"PeriodicalIF":4.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971498","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}
Yasir Suhail, Yamin Liu, Wenqiang Du, Junaid Afzal, Xihua Qiu, Amina Atiq, Paola Vera-Licona, Eran Agmon, Kshitiz
{"title":"Oscillatory hypoxia induced gene expression predicts low survival in human breast cancer patients.","authors":"Yasir Suhail, Yamin Liu, Wenqiang Du, Junaid Afzal, Xihua Qiu, Amina Atiq, Paola Vera-Licona, Eran Agmon, Kshitiz","doi":"10.1002/mc.23810","DOIUrl":"10.1002/mc.23810","url":null,"abstract":"<p><p>Hypoxia is one of the key factors in the tumor microenvironment regulating nearly all steps in the metastatic cascade in many cancers, including in breast cancer. The hypoxic regions can however be dynamic with the availability of oxygen fluctuating or oscillating. The canonical response to hypoxia is relayed by transcription factor Hypoxia-Inducible Factor 1 (HIF-1), which is stabilized in hypoxia and acts as the master regulator of a large number of downstream genes. However, HIF-1 transcriptional activity can also fluctuate either due to unstable hypoxia, or by lactate mediated noncanonical degradation of HIF-1. Our understanding of how oscillatory hypoxia or HIF-1 activity specifically influences cancer malignancy is very limited. Here, using MDA-MB-231 cells as a model of triple negative breast cancer characterized by severe hypoxia, we measured the gene expression changes induced specifically by oscillatory hypoxia. We found that oscillatory hypoxia can specifically regulate gene expression differently, and at times opposite to stable hypoxia. Using the Cancer Genome Atlas RNAseq data of human cancer samples, we show that the oscillatory specific gene expression signature in MDA-MB-231 is enriched in most human cancers, and prognosticates low survival in breast cancer patients. In particular, we found that oscillatory hypoxia, unlike stable hypoxia, induces unfolded protein folding response in cells resulting in gene expression predicting reduced survival.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"2305-2315"},"PeriodicalIF":4.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988397","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}
{"title":"Inhibition of XPR1-dependent phosphate efflux induces mitochondrial dysfunction: A potential molecular target therapy for hepatocellular carcinoma?","authors":"Zi-Qiang Liao, Yang-Feng Lv, Mei-Diao Kang, Yu-Long Ji, Yue Liu, Le-Ran Wang, Jia-Liang Tang, Zhi-Qiang Deng, Yun Yi, Qun Tang","doi":"10.1002/mc.23812","DOIUrl":"10.1002/mc.23812","url":null,"abstract":"<p><p>Xenotropic and polytropic retrovirus receptor 1 (XPR1) is the only known transporter associated with Pi efflux in mammals, and its impact on tumor progression is gradually being revealed. However, the role of XPR1 in hepatocellular carcinoma (HCC) is unknown. A bioinformatics screen for the phosphate exporter XPR1 was performed in HCC patients. The expression of XPR1 in clinical specimens was analyzed using quantitative real-time PCR, Western blot analysis, and immunohistochemical assays. Knockdown of the phosphate exporter XPR1 was performed by shRNA transfection to investigate the cellular phenotype and phosphate-related cytotoxicity of the Huh7 and HLF cell lines. In vivo tests were conducted to investigate the tumorigenicity of HCC cells xenografted into immunocompromised mice after silencing XPR1. Compared with that in paracancerous tissue, XPR1 expression in HCC tissues was markedly upregulated. High XPR1 expression significantly correlated with poor patient survival. Silencing of XPR1 leads to decreased proliferation, migration, invasion, and colony formation in HCC cells. Mechanistically, knockdown of XPR1 causes an increase in intracellular phosphate levels; mitochondrial dysfunction characterized by reduced mitochondrial membrane potential and adenosine triphosphate levels; increased reactive oxygen species levels; abnormal mitochondrial morphology; and downregulation of key mitochondrial fusion, fission, and inner membrane genes. This ultimately results in mitochondria-dependent apoptosis. These findings reveal the prognostic value of XPR1 in HCC progression and, more importantly, suggest that XPR1 might be a potential therapeutic target.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"2332-2345"},"PeriodicalIF":4.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971494","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}