HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis through upregulating TLR4 and PTK2

Feng, Weibo; Chen, Jiawen; Huang, Wenjie; Wang, Guodong; Chen, Xilang; Duan, Lili; Yin, Yulong; Chen, Xiaoping; Zhang, Bixiang; Sun, Mengyu; Luo, Xun-Jiang; Nie, Yongzhan; Fan, Daiming; Wu, Kaichun; Xia, Limin

doi:10.7150/thno.84388

Cited by 10 publications

(1 citation statement)

References 48 publications

(79 reference statements)

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“…Importantly, it has been reported that HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis by upregulating TLR4 and PTK2 [21]. Furthermore, the cross-talk between MyD88-dependent TLR signaling and FAK is critically implicated in the production of proinflammatory cytokine via NF-B activation [22].…”

Section: Introductionmentioning

confidence: 99%

PTK2 promotes lung cancer progression via cross-talk regulation between EGFR- and TLR-mediated signaling

Kim,

Shin,

Kim

et al. 2024

Preprint

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Introduction Protein tyrosine kinase 2 (PTK2) plays a pivotal role in various cancers via cross-talk with growth factor signaling pathways. PTK2 is amplified in non-small cell lung cancer (NSCLC). However, the functional role of PTK2 has not been elucidated yet. Here, we report that PTK2 is functionally implicated in epidermal growth factor receptor (EGFR)- and toll-like receptors (TLRs)-mediated signaling for progression of lung cancer. Methods Microarray data of NSCLC tumor tissues and matched normal tissues of 42 NSCLC patients were used to gain insights into associations of PTK2 and EGFR expression with patient’s prognosis and cancer progression. CRISPR-Cas9 gene editing method and cancer progression assay were utilized for functional validation of PTK2 in human A549 and H1299 lung cancer cells. In vitro and in vivo tumorigenic assays were performed using a three-dimensional (3D) tumor spheroid formation and a xenografted NOD scid gamma mouse (NSG, NOD/SCID/IL-2Rγnull) model, respectively. Results Patients with up-regulated PTK2 exhibited a poor prognosis after clinical treatments. Gene set enrichment assay (GSEA) revealed that patients with up-regulated PTK2 exhibited high enrichments of gene sets related to lung cancer progression and EGFR- or TLRs-mediated signaling. The functional association between PTK2 and EGFR or TLRs was verified. PTK2-knockout (KO) lung cancer cells exhibited marked attenuations of cancer progression, and in vivo tumorigenic and metastatic activity in xenografted NSG mice. In response to TLR agonists, EGF, or TLR agonists plus EGF, the severe decreases of 3D-tumor spheroid formation could be observed in PTK2-KO lung cancer cells. We further elucidated the molecular mechanism by which PTK2 regulated the cross-talk between EGFR- and TLRs-mediated signaling. PTK2 specifically regulated their downstream molecules for the activation of NF-κB. Conclusions Up-regulated PTK2 might be a reliable marker for EGFR- or TLRs-induced lung cancer progression in NSCLC patients. It could be potentially considered as a therapeutic target in the field of precision or personalized cancer medicine aiming for NSCLC intervention.

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Section: Introductionmentioning

confidence: 99%

PTK2 promotes lung cancer progression via cross-talk regulation between EGFR- and TLR-mediated signaling

Kim,

Shin,

Kim

et al. 2024

Preprint

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OTUD6B promotes cholangiocarcinoma growth by regulating STAT3 phosphorylation through deubiquitination of PTK2

Xing,

Chen,

Guo

et al. 2024

Cell Biology International

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Cholangiocarcinoma (CCA) is a hepatobiliary carcinoma with uncontrolled cell proliferation, poor prognosis, and high mortality. The ovarian tumor structural domain (OTU) containing protein 6B (OTUD6B) belongs to the OTU deubiquitin family and is vital in tumor development. However, its expression and biological function in CCA remain unknown. The expression of OTUD6B in CCA was analyzed using TIMER2.0, UALCAN, and GEO databases. MTT, clonal formation assay, immunofluorescence staining, immunohistochemistry staining, and flow cytometry examined the regulation of OTUD6B on cell proliferation, cycle, and apoptosis. The effects of OTUD6B on tumor volume and weight were assessed using the xenograft tumor model. The activities of PTK2 and STAT3 were detected by western blot and CO‐IP. The biological database identified that OTUD6B was upregulated in CCA. In CCA cells, OTUD6B knockdown reduced CCA cell proliferation and promoted apoptosis. Cell cycle analysis indicated that the cycle stopped at the G0/G1 phase after OTU6B downregulation. Furthermore, OTUD6B knockdown resulted in a decrease in tumor volume and weight in xenograft tumor models. Mechanistically, OTUD6B is involved in the deubiquitination of PTK2. PTK2 further affected the phosphorylation of STAT3 thereby regulating the CCA process. Our study demonstrates that OTUD6B knockdown participates in the ubiquitination of PTK2 and phosphorylation of STAT3 to alleviate the process of CCA. These results suggest that OTUD6B may be a potential new strategy for CCA treatment.

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Cell death pathways: molecular mechanisms and therapeutic targets for cancer

Wang,

Guo,

Guo

et al. 2024

MedComm

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Cell death regulation is essential for tissue homeostasis and its dysregulation often underlies cancer development. Understanding the different pathways of cell death can provide novel therapeutic strategies for battling cancer. This review explores several key cell death mechanisms of apoptosis, necroptosis, autophagic cell death, ferroptosis, and pyroptosis. The research gap addressed involves a thorough analysis of how these cell death pathways can be precisely targeted for cancer therapy, considering tumor heterogeneity and adaptation. It delves into genetic and epigenetic factors and signaling cascades like the phosphatidylinositol 3‐kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen‐activated protein kinase/extracellular signal‐regulated kinase (MAPK/ERK) pathways, which are critical for the regulation of cell death. Additionally, the interaction of the microenvironment with tumor cells, and particularly the influence of hypoxia, nutrient deprivation, and immune cellular interactions, are explored. Emphasizing therapeutic strategies, this review highlights emerging modulators and inducers such as B cell lymphoma 2 (BCL2) homology domain 3 (BH3) mimetics, tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL), chloroquine, and innovative approaches to induce ferroptosis and pyroptosis. This review provides insights into cancer therapy's future direction, focusing on multifaceted approaches to influence cell death pathways and circumvent drug resistance. This examination of evolving strategies underlines the considerable clinical potential and the continuous necessity for in‐depth exploration within this scientific domain.

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HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis through upregulating TLR4 and PTK2

Cited by 10 publications

References 48 publications

PTK2 promotes lung cancer progression via cross-talk regulation between EGFR- and TLR-mediated signaling

PTK2 promotes lung cancer progression via cross-talk regulation between EGFR- and TLR-mediated signaling

OTUD6B promotes cholangiocarcinoma growth by regulating STAT3 phosphorylation through deubiquitination of PTK2

Cell death pathways: molecular mechanisms and therapeutic targets for cancer

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