bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2023–04–02
sixteen papers selected by
Caner Geyik, Istinye University
  1. The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis.
  2. Molecular Basis of the KEAP1-NRF2 Signaling Pathway.
  3. Correction to: NSUN2 alleviates doxorubicin-induced myocardial injury through Nrf2-mediated antioxidant stress.
  4. Emerging Role of NRF2 Signaling in Cancer Stem Cell Phenotype.
  5. The Multifaceted Roles for NRF2 in Regulating Tumor Development and Progression: An Update.
  6. Anti-Ferroptotic Effects of Nrf2: Beyond the Antioxidant Response.
  7. DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination.
  8. Stimulation of Nuclear Factor (Erythroid-Derived 2)-like 2 Signaling by Nucleus Targeted Irradiation with Proton Microbeam.
  9. NRF2 and STAT3: friends or foes in carcinogenesis?
  10. The Transcription Factor NRF2 Has Epigenetic Regulatory Functions Modulating HDACs, DNMTs, and miRNA Biogenesis.
  11. Modulation of Nrf2/HO-1 by Natural Compounds in Lung Cancer.
  12. Jie Geng Tang reverses cisplatin resistance through the Nrf2 pathway in lung cancer.
  13. CYP2E1 overexpression protects COS-7 cancer cells against ferroptosis.
  14. Mitochondrial TSPO Promotes Hepatocellular Carcinoma Progression through Ferroptosis Inhibition and Immune Evasion.
  15. Control of Redox Homeostasis by Short-Chain Fatty Acids: Implications for the Prevention and Treatment of Breast Cancer.
  16. NGS-based profiling identifies miRNAs and pathways dysregulated in cisplatin-resistant esophageal cancer cells.
  1. Mol Cells. 2023 Mar 31. 46(3): 176-186
    The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis.
    Christopher J Occhiuto, Jessica A Moerland, Ana S Leal, Kathleen A Gallo, Karen T Liby.
      The oxidative balance of a cell is maintained by the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. This cytoprotective pathway detoxifies reactive oxygen species and xenobiotics. The role of the KEAP1/NRF2 pathway as pro-tumorigenic or anti-tumorigenic throughout stages of carcinogenesis (including initiation, promotion, progression, and metastasis) is complex. This mini review focuses on key studies describing how the KEAP1/NRF2 pathway affects cancer at different phases. The data compiled suggest that the roles of KEAP1/NRF2 in cancer are highly dependent on context; specifically, the model used (carcinogen-induced vs genetic), the tumor type, and the stage of cancer. Moreover, emerging data suggests that KEAP1/NRF2 is also important for regulating the tumor microenvironment and how its effects are amplified either by epigenetics or in response to co-occurring mutations. Further elucidation of the complexity of this pathway is needed in order to develop novel pharmacological tools and drugs to improve patient outcomes.
    Keywords:  NRF2; cancer; initiation; metastasis; promotion; transformation
    DOI:  https://doi.org/10.14348/molcells.2023.2191
  2. Mol Cells. 2023 Mar 31. 46(3): 133-141
    Molecular Basis of the KEAP1-NRF2 Signaling Pathway.
    Takafumi Suzuki, Jun Takahashi, Masayuki Yamamoto.
      Transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. NRF2 induces expression of detoxification and antioxidant enzymes and suppresses inductions of pro-inflammatory cytokine genes. KEAP1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of CULLIN 3 (CUL3)-based E3 ubiquitin ligase. KEAP1 regulates the activity of NRF2 and acts as a sensor for oxidative and electrophilic stresses. NRF2 has been found to be activated in many types of cancers with poor prognosis. Therapeutic strategies to control NRF2-overeactivated cancers have been considered not only by targeting cancer cells with NRF2 inhibitors or NRF2 synthetic lethal chemicals, but also by targeting host defense with NRF2 inducers. Understanding precise molecular mechanisms how the KEAP1-NRF2 system senses and regulates the cellular response is critical to overcome intractable NRF2-activated cancers.
    Keywords:  KEAP1; NRF2; cancer therapy; defense system; stress sensing
    DOI:  https://doi.org/10.14348/molcells.2023.0028
  3. Cell Death Discov. 2023 Mar 27. 9(1): 105
    Correction to: NSUN2 alleviates doxorubicin-induced myocardial injury through Nrf2-mediated antioxidant stress.
    Yi Wang, Yuxin Zan, Yingying Huang, Xiaoyun Peng, Shinan Ma, Ji Ren, Xiao Li, Lin Wei, Xiaoli Wang, Yahong Yuan, Junming Tang, Zhongqun Zhan, Zhixiao Wang, Yan Ding.
      
    DOI:  https://doi.org/10.1038/s41420-023-01377-2
  4. Mol Cells. 2023 Mar 31. 46(3): 153-164
    Emerging Role of NRF2 Signaling in Cancer Stem Cell Phenotype.
    Steffanus P Hallis, Jin Myung Kim, Mi-Kyoung Kwak.
      Cancer stem cells (CSCs) are a small population of tumor cells characterized by self-renewal and differentiation capacity. CSCs are currently postulated as the driving force that induces intra-tumor heterogeneity leading to tumor initiation, metastasis, and eventually tumor relapse. Notably, CSCs are inherently resistant to environmental stress, chemotherapy, and radiotherapy due to high levels of antioxidant systems and drug efflux transporters. In this context, a therapeutic strategy targeting the CSC-specific pathway holds a promising cure for cancer. NRF2 (nuclear factor erythroid 2-like 2; NFE2L2) is a master transcription factor that regulates an array of genes involved in the detoxification of reactive oxygen species/electrophiles. Accumulating evidence suggests that persistent NRF2 activation, observed in multiple types of cancer, supports tumor growth, aggressive malignancy, and therapy resistance. Herein, we describe the core properties of CSCs, focusing on treatment resistance, and review the evidence that demonstrates the roles of NRF2 signaling in conferring unique properties of CSCs and the associated signaling pathways.
    Keywords:  NRF2/NFE2L2; antioxidant system; cancer plasticity; cancer stem cell; therapy resistance
    DOI:  https://doi.org/10.14348/molcells.2023.2196
  5. Mol Cells. 2023 Mar 31. 46(3): 131-132
    The Multifaceted Roles for NRF2 in Regulating Tumor Development and Progression: An Update.
    Su-Jung Kim, Young-Joon Surh.
      
    DOI:  https://doi.org/10.14348/molcells.2023.0044
  6. Mol Cells. 2023 Mar 31. 46(3): 165-175
    Anti-Ferroptotic Effects of Nrf2: Beyond the Antioxidant Response.
    Aryatara Shakya, Nicholas W McKee, Matthew Dodson, Eli Chapman, Donna D Zhang.
      The transcription factor Nrf2 was originally identified as a master regulator of redox homeostasis, as it governs the expression of a battery of genes involved in mitigating oxidative and electrophilic stress. However, the central role of Nrf2 in dictating multiple facets of the cellular stress response has defined the Nrf2 pathway as a general mediator of cell survival. Recent studies have indicated that Nrf2 regulates the expression of genes controlling ferroptosis, an ironand lipid peroxidation-dependent form of cell death. While Nrf2 was initially thought to have anti-ferroptotic function primarily through regulation of the antioxidant response, accumulating evidence has indicated that Nrf2 also exerts anti-ferroptotic effects via regulation of key aspects of iron and lipid metabolism. In this review, we will explore the emerging role of Nrf2 in mediating iron homeostasis and lipid peroxidation, where several Nrf2 target genes have been identified that encode critical proteins involved in these pathways. A better understanding of the mechanistic relationship between Nrf2 and ferroptosis, including how genetic and/or pharmacological manipulation of Nrf2 affect the ferroptotic response, should facilitate the development of new therapies that can be used to treat ferroptosis-associated diseases.
    Keywords:  Nrf2; cancer; ferroptosis
    DOI:  https://doi.org/10.14348/molcells.2023.0005
  7. Adv Sci (Weinh). 2023 Mar 25. e2204438
    DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination.
    Xin Wang, Tangjun Zhou, Xiao Yang, Xiankun Cao, Gu Jin, Pu Zhang, Jiadong Guo, Kewei Rong, Baixing Li, Yibin Hu, Kexin Liu, Peixiang Ma, An Qin, Jie Zhao.
      Chemoresistance is the main obstacle in osteosarcoma (OS) treatment; however, the underlying mechanism remains unclear. In this study, it is discovered that DDRGK domain-containing protein 1 (DDRGK1) plays a fundamental role in chemoresistance induced in OS. Bioinformatic and tissue analyses indicate that higher expression of DDRGK1 correlates with advanced tumor stage and poor clinical prognosis of OS. Quantitative proteomic analyses suggest that DDRGK1 plays a critical role in mitochondrial oxidative phosphorylation. DDRGK1 knockout trigger the accumulation of reactive oxygen species (ROS) and attenuate the stability of nuclear factor erythroid-2-related factor 2 (NRF2), a major antioxidant response element. Furthermore, DDRGK1 inhibits ubiquitin-proteasome-mediated degradation of NRF2 via competitive binding to the Kelch-like ECH-associated protein 1 (KEAP1) protein, which recruits NRF2 to CULLIN(CUL3). DDRGK1 knockout attenuates NRF2 stability, contributing to ROS accumulation, which promotes apoptosis and enhanced chemosensitivity to doxorubicin (DOX) and etoposide in cancer cells. Indeed, DDRGK1 knockout significantly enhances osteosarcoma chemosensitivity to DOX in vivo. The combination of DDRGK1 knockdown and DOX treatment provides a promising new avenue for the effective treatment of OS.
    Keywords:  DDRGK domain-containing protein 1; chemoresistance; doxorubicin; osteosarcoma; redox homeostasis
    DOI:  https://doi.org/10.1002/advs.202204438
  8. Biology (Basel). 2023 Mar 09. pii: 419. [Epub ahead of print]12(3):
    Stimulation of Nuclear Factor (Erythroid-Derived 2)-like 2 Signaling by Nucleus Targeted Irradiation with Proton Microbeam.
    Jun Wang, Masakazu Oikawa, Teruaki Konishi.
      Nuclear factor (erythroid-derived 2)-like 2 (NRF2), well-known as a master antioxidative response regulator in mammalian cells, is considered as a potential target for radiation protection and cancer therapy sensitization. We examined the response of NRF2 signaling in normal human lung fibroblast WI-38 cells to nucleus targeted irradiation by 3.4 MeV proton microbeam. Nucleus targeted irradiation stimulated the nucleus accumulation of NRF2 and the expression of its target gene, heme oxygenase 1 (HO-1). The nucleus accumulation of NRF2 increased from 3 h to 12 h post 500 proton irradiation. In the 500 protons range, higher number of protons resulted in increased NRF2 nucleus accumulation. Activating NRF2 with tert-butylhydroquinone reduced DNA double-strand break (DSB) formation in nucleus targeted irradiation by 15%. Moreover, ATM phosphorylation was found in nucleus targeted irradiation. Inhibiting ATM with ku55933 prevented NRF2 nucleus accumulation. Furthermore, nucleus targeted irradiation activated ERK 1/2, and ROS-ERK 1/2 signaling regulated NRF2 nucleus accumulation. Taken together, NRF2 signaling was activated by nucleus targeted irradiation and mitigated DNA DSB. The discovery of ATM and ERK 1/2 as upstream regulators of NRF2 signaling in nucleus targeted cells revealed new information regarding radiation protection.
    Keywords:  ATM; ERK 1/2; NRF2; microbeam; nucleus targeted irradiation
    DOI:  https://doi.org/10.3390/biology12030419
  9. Discov Oncol. 2023 Mar 31. 14(1): 37
    NRF2 and STAT3: friends or foes in carcinogenesis?
    Andrea Arena, Maria Anele Romeo, Rossella Benedetti, Maria Saveria Gilardini Montani, Roberta Santarelli, Roberta Gonnella, Gabriella D'Orazi, Mara Cirone.
      NRF2 is a transcription factor that plays a pivotal role in carcinogenesis, also through the interaction with several pro-survival pathways. NRF2 controls the transcription of detoxification enzymes and a variety of other molecules impinging in several key biological processes. This perspective will focus on the complex interplay of NRF2 with STAT3, another transcription factor often aberrantly activated in cancer and driving tumorigenesis as well as immune suppression. Both NRF2 and STAT3 can be regulated by ER stress/UPR activation and their cross-talk influences and is influenced by autophagy and cytokines, contributing to shape the microenvironment, and both control the execution of DDR, also by regulating the expression of HSPs. Given the importance of these transcription factors, more investigations aimed at better elucidating the outcome of their networking could help to discover new and more efficacious strategies to fight cancer.
    Keywords:  Cytokines; DDR; NRF2; STAT3; p62/SQSTM1
    DOI:  https://doi.org/10.1007/s12672-023-00644-z
  10. Antioxidants (Basel). 2023 Mar 04. pii: 641. [Epub ahead of print]12(3):
    The Transcription Factor NRF2 Has Epigenetic Regulatory Functions Modulating HDACs, DNMTs, and miRNA Biogenesis.
    Ignacio Silva-Llanes, Chang Hoon Shin, José Jiménez-Villegas, Myriam Gorospe, Isabel Lastres-Becker.
      The epigenetic regulation of gene expression is a complex and tightly regulated process that defines cellular identity and is associated with health and disease processes. Oxidative stress is capable of inducing epigenetic modifications. The transcription factor NRF2 (nuclear factor erythroid-derived 2-like 2) is a master regulator of cellular homeostasis, regulating genes bearing antioxidant response elements (AREs) in their promoters. Here, we report the identification of ARE sequences in the promoter regions of genes encoding several epigenetic regulatory factors, such as histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and proteins involved in microRNA biogenesis. In this research, we study this possibility by integrating bioinformatic, genetic, pharmacological, and molecular approaches. We found ARE sequences in the promoter regions of genes encoding several HDACs, DNMTs, and proteins involved in miRNA biogenesis. We confirmed that NRF2 regulates the production of these genes by studying NRF2-deficient cells and cells treated with dimethyl fumarate (DMF), an inducer of the NRF2 signaling pathway. In addition, we found that NRF2 could be involved in the target RNA-dependent microRNA degradation (TDMD) of miR-155-5p through its interaction with Nfe2l2 mRNA. Our data indicate that NRF2 has an epigenetic regulatory function, complementing its traditional function and expanding the regulatory dimensions that should be considered when developing NRF2-centered therapeutic strategies.
    Keywords:  DMF; DNMT; HDAC; NRF2; TDMD; epigenetics; miRNA; oxidative stress
    DOI:  https://doi.org/10.3390/antiox12030641
  11. Antioxidants (Basel). 2023 Mar 16. pii: 735. [Epub ahead of print]12(3):
    Modulation of Nrf2/HO-1 by Natural Compounds in Lung Cancer.
    Somayyeh Ghareghomi, Faezeh Moosavi-Movahedi, Luciano Saso, Mehran Habibi-Rezaei, Ali Khatibi, Jun Hong, Ali A Moosavi-Movahedi.
      Oxidative stresses (OSs) are considered a pivotal factor in creating various pathophysiological conditions. Cells have been able to move forward by modulating numerous signaling pathways to moderate the defects of these stresses during their evolution. The company of Kelch-like ECH-associated protein 1 (Keap1) as a molecular sensing element of the oxidative and electrophilic stress and nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) as a master transcriptional regulator of the antioxidant response makes a master cytoprotective antioxidant pathway known as the Keap1/Nrf2 pathway. This pathway is considered a dual-edged sword with beneficial features for both normal and cancer cells by regulating the gene expression of the array of endogenous antioxidant enzymes. Heme oxygenase-1 (HO-1), a critical enzyme in toxic heme removal, is one of the clear state indicators for the duality of this pathway. Therefore, Nrf2/HO-1 axis targeting is known as a novel strategy for cancer treatment. In this review, the molecular mechanism of action of natural antioxidants on lung cancer cells has been investigated by relying on the Nrf2/HO-1 axis.
    Keywords:  Heme oxygenase-1; Keap/Nrf2 pathway; antioxidants; lung cancer; oxidative stress
    DOI:  https://doi.org/10.3390/antiox12030735
  12. J Pharm Pharmacol. 2023 Mar 27. pii: rgad018. [Epub ahead of print]
    Jie Geng Tang reverses cisplatin resistance through the Nrf2 pathway in lung cancer.
    Jing Zhao, Manting Hou, Kaixin Ding, Shixiong Li, Hui Li, Xili Zhang, Zhaofang Bai, Wenlong Liu.
       OBJECTIVES: Jie Geng Tang (JGT) is an ancient traditional Chinese herbal decoction that exhibits various pharmacological activities, however, is poorly understood in the sensitivity of lung cancer to chemotherapy. Here, we explored the effect of JGT on sensitizing cisplatin (DDP)-resistant A549 cells (A549/DDP).
    METHODS: Cell viability was assessed using cell counting kit-8 assay. Flow cytometry was applied to detected cell apoptosis, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels. Western blotting and qRT-PCR were performed to determine protein and mRNA levels.
    KEY FINDINGS: The results demonstrated that DDP co-treatment with JGT significantly increased the cytotoxicity of A549/DDP cells and exhibited efficacy in suppressing the migration and proliferation. The rate of apoptosis was increased by co-treatment with DDP and JGT, along with a higher rate of Bax/Bcl-2, and increased loss of MMP. Furthermore, the combination promoted ROS accumulation and increased γ-H2AX levels. Moreover, Nrf2 levels were suppressed in a dose- and time-dependent manner, Nrf2 stability was reduced following treatment with JGT. Notably, the combination induced inhibition of the Nrf2/ARE pathway at the mRNA and protein levels.
    CONCLUSIONS: Collectively, these results indicate that co-treatment with JGT and DDP can be considered a combinational approach to treating DDP resistance.
    Keywords:  Jie Geng Tang; Nrf2; cisplatin; lung cancer
    DOI:  https://doi.org/10.1093/jpp/rgad018
  13. Res Sq. 2023 Mar 22. pii: rs.3.rs-2702878. [Epub ahead of print]
    CYP2E1 overexpression protects COS-7 cancer cells against ferroptosis.
    Andres A Caro, Daniel Barrett, Cristobal Garcia, Weston Northington, Jamya Pinkney, Rayan Shuja, Hannah Stovall.
      Ferroptosis is a recently described form of regulated cell death initiated by the iron-mediated one-electron reduction of lipid hydroperoxides (LOOH). Cytochrome P450 2E1 (CYP2E1) induction, a consequence of genetic polymorphisms or/and gene induction by xenobiotics, may promote ferroptosis by contributing to the cellular pool of LOOH. However, CYP2E1 induction also increases the transcription of anti-ferroptotic genes that regulate the activity of glutathione peroxidase 4 (GPX4), the main ferroptosis inhibitor. Based on the above, we hypothesize that the impact of CYP2E1 induction on ferroptosis depends on the balance between pro- and anti-ferroptotic pathways triggered by CYP2E1. To test our hypothesis, ferroptosis was induced with class 2 inducers (RSL-3 or ML-162) in mammalian COS-7 cancer cells that don’t express CYP2E1 (Mock cells), and in cells engineered to express human CYP2E1 (WT cells), and the impact on viability, lipid peroxidation and GPX4 was assessed. CYP2E1 overexpression protected COS-7 cancer cells against ferroptosis, evidenced by an increase in the IC 50 and a decrease in lipid ROS in WT versus Mock cells after exposure to class 2 inducers. CYP2E1 overexpression produced an 80% increase in the levels of the GPX4 substrate glutathione (GSH). Increasing GSH in Mock cells protected cells against ferroptosis by ML-162. Depleting GSH, or inhibiting Nrf2 in WT cells reverted the protective effect mediated by CYP2E1, causing a decrease in the IC 50 and an increase in lipid ROS after exposure to ML-162. These results show that CYP2E1 overexpression protects COS-7 cancer cells against ferroptosis, an effect probably mediated by Nrf2-dependent GSH induction.
    DOI:  https://doi.org/10.21203/rs.3.rs-2702878/v1
  14. Adv Sci (Weinh). 2023 Mar 30. e2206669
    Mitochondrial TSPO Promotes Hepatocellular Carcinoma Progression through Ferroptosis Inhibition and Immune Evasion.
    Deguo Zhang, Da Man, Jiahua Lu, Yifan Jiang, Bo Ding, Rong Su, Rongliang Tong, Junru Chen, Beng Yang, Shusen Zheng, Diyu Chen, Jian Wu.
      Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor prognosis, and novel treatment strategies are urgently needed. Mitochondria are key regulators of cellular homeostasis and potential targets for tumor therapy. Here, the role of mitochondrial translocator protein (TSPO) in the regulation of ferroptosis and antitumor immunity is investigated and the potential therapeutic implications for HCC are assessed. TSPO is highly expressed in HCC and associated with poor prognosis. Gain- and loss-of-function experiments present that TSPO promotes HCC cell growth, migration, and invasion in vitro and in vivo. In addition, TSPO inhibits ferroptosis in HCC cells via enhancing the Nrf2-dependent antioxidant defense system. Mechanistically, TSPO directly interacts with P62 and interferes with autophagy, leading to the accumulation of P62. The P62 accumulation competes with KEAP1, preventing it from targeting Nrf2 for proteasomal degradation. Furthermore, TSPO promotes HCC immune escape by upregulating PD-L1 expression through Nrf2-mediated transcription. Notably, TSPO inhibitor PK11195 combines with anti-PD-1 antibody showing a synergistic anti-tumor effect in a mouse model. Overall, the results demonstrated that mitochondrial TSPO promotes HCC progression by inhibiting ferroptosis and antitumor immunity. Targeting TSPO can be a promising new strategy for HCC treatment.
    Keywords:  ferroptosis; hepatocellular carcinoma; immunotherapy; mitochondria; translocator protein
    DOI:  https://doi.org/10.1002/advs.202206669
  15. Pathogens. 2023 Mar 19. pii: 486. [Epub ahead of print]12(3):
    Control of Redox Homeostasis by Short-Chain Fatty Acids: Implications for the Prevention and Treatment of Breast Cancer.
    Carmen González-Bosch, Patricia A Zunszain, Giovanni E Mann.
      Breast cancer is the leading cause of death among women worldwide, and certain subtypes are highly aggressive and drug resistant. As oxidative stress is linked to the onset and progression of cancer, new alternative therapies, based on plant-derived compounds that activate signaling pathways involved in the maintenance of cellular redox homeostasis, have received increasing interest. Among the bioactive dietary compounds considered for cancer prevention and treatment are flavonoids, such as quercetin, carotenoids, such as lycopene, polyphenols, such as resveratrol and stilbenes, and isothiocyanates, such as sulforaphane. In healthy cells, these bioactive phytochemicals exhibit antioxidant, anti-apoptotic and anti-inflammatory properties through intracellular signaling pathways and epigenetic regulation. Short-chain fatty acids (SCFAs), produced by intestinal microbiota and obtained from the diet, also exhibit anti-inflammatory and anti-proliferative properties related to their redox signaling activity-and are thus key for cell homeostasis. There is evidence supporting an antioxidant role for SCFAs, mainly butyrate, as modulators of Nrf2-Keap1 signaling involving the inhibition of histone deacetylases (HDACs) and/or Nrf2 nuclear translocation. Incorporation of SCFAs in nutritional and pharmacological interventions changes the composition of the the intestinal microbiota, which has been shown to be relevant for cancer prevention and treatment. In this review, we focused on the antioxidant properties of SCFAs and their impact on cancer development and treatment, with special emphasis on breast cancer.
    Keywords:  Keap1-Nrf2; antioxidants; breast cancer; butyrate; epigenetics; microbiota; redox signaling; short-chain fatty acids
    DOI:  https://doi.org/10.3390/pathogens12030486
  16. Funct Integr Genomics. 2023 Mar 30. 23(2): 111
    NGS-based profiling identifies miRNAs and pathways dysregulated in cisplatin-resistant esophageal cancer cells.
    Prerna Pandey, Geetika Suyal, Aprajita, Kiran Pasbola, Rinu Sharma.
      Esophageal cancer (EC) incidence remains to be on a global rise supported by an unchanged recurrence and 5-year survival rate owing to the development of chemoresistance. Resistance to cisplatin, one of the majorly used chemotherapeutic drugs in EC, is a major nuisance. This study sheds light on miRNA dysregulation and its inverse relation with dysregulated mRNAs to guide pathways into the manifestation of cisplatin resistance in EC. A cisplatin-resistant version of an EC cell line was established and comparative profiling by NGS with the parental cell line was employed to identify dysregulation in miRNA and mRNA levels. Protein-protein interaction network analysis was done using Cytoscape, followed by Funrich pathway analysis. Furthermore, selective significant miRNAs were validated using qRT-PCR. miRNA-mRNA integrated analysis was carried out using the Ingenuity Pathway Analysis (IPA) tool. Expression of various established resistance markers supported the successful establishment of cisplatin-resistant cell line. Whole-cell small RNA sequencing and transcriptome sequencing identified 261 miRNAs and 1892 genes to be significantly differentially expressed (DE), respectively. Pathway analysis indicated enrichment of EMT signaling, supported by NOTCH, mTOR, TNF receptor, and PI3K-mediated AKT signaling pathways, in chemoresistant cells. Validation by qRT-PCR confirmed upregulation of miR-10a-5p, miR-618, miR-99a-5p, and miR-935 and downregulation of miR-335-3p, miR-205-5p, miR-944, miR-130a-3p, and miR-429 in resistant cells. Pathway analysis that followed IPA analysis indicated that the dysregulation of these miRNAs and their target genes may be instrumental in the development and regulation of chemoresistance via p53 signaling, xenobiotic metabolism, and NRF2-mediated oxidative stress. This study concludes the interplay between miRNA and mRNA as an important aspect and occurrence in guiding the regulation, acquisition, and maintenance of chemoresistance in esophageal cancer in vitro.
    Keywords:  Akt signaling pathway; EMT; Esophageal carcinoma; NGS; miRNA
    DOI:  https://doi.org/10.1007/s10142-023-01041-z
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