Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

Gutiérrez‐Hoya, Adriana; Soto‐Cruz, Isabel

doi:10.3390/cells9102297

Cited by 86 publications

(58 citation statements)

References 174 publications

(200 reference statements)

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“…It is well accepted that the functional inactivation of p53 and Rb tumor suppressor proteins by the HPV E6 and E7 oncoproteins is a crucial mechanism in the carcinogenesis of cervical cancer ( Yim and Park, 2005 ; Jiang et al, 2019 ; Gutiérrez-Hoya and Soto-Cruz, 2020 ). Therefore, in subsequent studies, we investigated the potential of the HPV16 E6-binding affibody as a synergistic agent to enhance the antitumor effect of Z HPV16E6 384, an HPV16 E7-binding affibody molecule previously reported to show promising therapeutic value in HPV16-positive tumors ( Jiang et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells

Zhu

Kamara

Wang

et al. 2021

Front. Cell Dev. Biol.

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Despite prophylactic vaccination campaigns, high-risk human papillomavirus (HPV)-induced cervical cancer remains a significant health threat among women, especially in developing countries. The initial occurrence and consequent progression of this cancer type primarily rely on, E6 and E7, two key viral oncogenes expressed constitutively, inducing carcinogenesis. Thus, E6/E7 have been proposed as ideal targets for HPV-related cancer diagnosis and treatment. In this study, three novel HPV16 E6-binding affibody molecules (ZHPV16E61115, ZHPV16E61171, and ZHPV16E61235) were isolated from a randomized phage display library and cloned for bacterial production. These affibody molecules showed high binding affinity and specificity for recombinant and native HPV16 E6 as determined by surface plasmon resonance, indirect immunofluorescence, immunohistochemistry, and near-infrared small animal optical imaging in vitro and in vivo. Moreover, by binding to HPV16 E6 protein, ZHPV16E61235 blocked E6-mediated p53 degradation, which increased the expression of some key p53 target genes, including BAX, PUMA and p21, and thereby selectively reduced the viability and proliferation of HPV16-positive cells. Importantly, ZHPV16E61235 was applied in combination with HPV16 E7-binding affibody ZHPV16E7384 to simultaneously target the HPV16 E6/E7 oncoproteins, and this combination inhibited cell proliferation more potently than either modality alone. Mechanistic studies revealed that the synergistic antiproliferative activity depends primarily on the induction of cell apoptosis and senescence but not cell cycle arrest. Our findings provide strong evidence that three novel HPV16 E6-binding affibody molecules could form a novel basis for the development of rational strategies for molecular imaging and targeted therapy in HPV16-positive preneoplastic and neoplastic lesions.

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Section: Discussionmentioning

confidence: 99%

Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells

Zhu

Kamara

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…Receptor dimerization induces phosphorylation of JAKs and of the receptor's cytoplasmic tyrosine residue sequentially. STATs then bind and are phosphorylated to form dimers which translocate to the nucleus [154,155]. This mechanism also controls immune responses and in viral immunity.…”

Section: Jak/stat Pathwaymentioning

confidence: 99%

“…These STATs seem to play minor roles in tumorigenesis, and only STAT3 is truly considered an oncogene [158]. In the presence of E6, STAT3, after being activated mainly by the IL-6 cytokine family (it could also be activated by EGF and other cytokines and growth factors), mediates expression of genes such as VEGF and c-myc (also anti-apoptotic Cyclin-D and cell-cycle progression Bcl-xL), which play important roles in tumor growth, proliferation, and angiogenesis [154,159]. Even more relevant is the finding that a high HPV-16 viral load is associated with a high STAT3 phosphorylation (Figure 3).…”

Section: Jak/stat Pathwaymentioning

confidence: 99%

Human Papillomavirus and Cellular Pathways: Hits and Targets

2021

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The Human Papillomavirus (HPV) is the causative agent of different kinds of tumors, including cervical cancers, non-melanoma skin cancers, anogenital cancers, and head and neck cancers. Despite the vaccination campaigns implemented over the last decades, we are far from eradicating HPV-driven malignancies. Moreover, the lack of targeted therapies to tackle HPV-related tumors exacerbates this problem. Biomarkers for early detection of the pathology and more tailored therapeutic approaches are needed, and a complete understanding of HPV-driven tumorigenesis is essential to reach this goal. In this review, we overview the molecular pathways implicated in HPV infection and carcinogenesis, emphasizing the potential targets for new therapeutic strategies as well as new biomarkers.

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“…The JAK-STAT signal pathway is a cytokine-stimulated signal transduction pathway discovered in recent years. It participates in many important biological processes such as cell proliferation, differentiation, in ammation, apoptosis and immune regulation [6,7] . Janus kinase (JAK) can sense extracellular signals by binding to receptors such as interferon, interleukin, growth factor, etc.…”

Section: Introductionmentioning

confidence: 99%

Genistein Protects Epilepsy-Induced Brain Injury Through Regulating The JAK2/STAT3 and Keap1/Nrf2 Signaling Pathways in The Developing Rats

Huang

Feng

et al. 2021

Preprint

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Background: Epilepsy is a common chronic neurological disease caused by the over-synchronization of neurons that lead to brain dysfunction. Recurrent seizures or status epilepticus can cause irreversible brain damage. The JAK2-STAT3 signal transduction pathway is stimulated by cytokines and involved in various pathological processes including inflammation, apoptosis and immune regulation in central system diseases. Keap1/Nrf2 is an important anti-oxidative stress pathway, which can reduce the toxic effects of oxygen free radicals and endogenous toxins on neurons. Genistein (Gen) can modulate inflammation and neuronal apoptosis, and may thereby have antiepileptic effects. This study aimed to explore the regulation of Genistein on JAK2/STAT3 and Keap1/Nrf2 signaling pathway and the protective effects on brain injury after epilepsy. Methods: Pentylenetetrazole (PTZ) was used to induce epilepsy in developing rats and Genistein was used for pretreatment of epilepsy. The seizure latency, grade scores and duration of the first generalized tonic-clonic seizure (GTCs) were recorded. Hippocampus tissue was sampled at 24 hours post-epilepsy. Immunofluorescence staining was used to observe the number of mature neurons, activated microglia and astrocytes in the hippocampal CA1 region. Western blot and qRT-PCR were used to determine the protein and mRNA levels of p-JAK2, p-STAT3, TNF-α, IL-1β, Keap1, Nrf2, HO-1, NQO1, caspase3, Bax and Bcl2 in the hippocampus. Results: Immunofluorescence showed that the number of neurons significantly decreased, and activated microglia and astrocytes significantly increased after epilepsy; Western blot and q-PCR showed that the expressions of p-JAK2, p-STAT3, TNF-α, IL-1β, Keap1, caspase3 and Bax significantly increased, while Nrf2, HO-1, NQO1 and Bcl-2 were significantly reduced after epilepsy. These effects were reversed by Genistein treatment. Moreover, Genistein was found to prolong seizure latency and reduce seizure intensity score and duration of generalized tonic-clonic seizures(GTCs). Conclusions: Genistein can activate the Keap1/Nrf2 antioxidant stress pathway and attenuate the activation of microglia and astrocytes. Genistein also inhibits the JAK2-STAT3 inflammation pathway and expression of apoptotic proteins, and increases the number of surviving neurons, thus having a protective effect on epilepsy-induced brain damage.

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Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

Cited by 86 publications

References 174 publications

Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells

Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells

Human Papillomavirus and Cellular Pathways: Hits and Targets

Genistein Protects Epilepsy-Induced Brain Injury Through Regulating The JAK2/STAT3 and Keap1/Nrf2 Signaling Pathways in The Developing Rats

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