IL‑6 plays a crucial role in epithelial‑mesenchymal transition and pro‑metastasis induced by sorafenib in liver cancer

Zhang, Kewei; Wang, Dong; Cai, Hao; Cao, Manqing; Zhang, Yuanyuan; Zhuang, Peng–Yuan; Shen, Jun

doi:10.3892/or.2021.7926

Cited by 10 publications

(3 citation statements)

References 49 publications

(70 reference statements)

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“…It also sheds light, at least in part, on the underlying mechanisms of EMT associated with IL-6 in CRC cells. Several in vivo studies have shown that the IL-6 knockdown could attenuate tumor metastasis in mice models [ 65 ], while IL-6 over-expression has also been validated with enhancing head and neck tumor growth and EMT change, eventually leading to tumor metastasis to the lung site [ 46 ]. Given these existing studies that IL-6 indeed alters EMT change in mice tumor models and leads to tumor metastasis, future efforts will be made to develop the co-culture system of CRC cell lines with immune cells as macrophages or stroma cells to mimic the IL-6 secreting TME system and elaborate to its consequence of CRC EMT change.…”

Section: Discussionmentioning

confidence: 99%

Src-FAK Signaling Mediates Interleukin 6-Induced HCT116 Colorectal Cancer Epithelial–Mesenchymal Transition

Huang

Chen

Hsu

et al. 2023

IJMS

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Colorectal cancer is one of the most prevalent and lethal malignancies, affecting approximately 900,000 individuals each year worldwide. Patients with colorectal cancer are found with elevated serum interleukin-6 (IL-6), which is associated with advanced tumor grades and is related to their poor survival outcomes. Although IL-6 is recognized as a potent inducer of colorectal cancer progression, the detail mechanisms underlying IL-6-induced colorectal cancer epithelial–mesenchymal transition (EMT), one of the major process of tumor metastasis, remain unclear. In the present study, we investigated the regulatory role of IL-6 signaling in colorectal cancer EMT using HCT116 human colorectal cancer cells. We noted that the expression of epithelial marker E-cadherin was reduced in HCT116 cells exposed to IL-6, along with the increase in a set of mesenchymal cell markers including vimentin and α-smooth muscle actin (α-SMA), as well as EMT transcription regulators—twist, snail and slug. The changes of EMT phenotype were related to the activation of Src, FAK, ERK1/2, p38 mitogen-activated protein kinase (p38MAPK), as well as transcription factors STAT3, κB and C/EBPβ. IL-6 treatment has promoted the recruitment of STAT3, κB and C/EBPβ toward the Twist promoter region. Furthermore, the Src-FAK signaling blockade resulted in the decline of IL-6 induced activation of ERK1/2, p38MAPK, κB, C/EBPβ and STAT3, as well as the decreasing mesenchymal state of HCT116 cells. These results suggested that IL-6 activates the Src-FAK-ERK/p38MAPK signaling cascade to cause the EMT of colorectal cancer cells. Pharmacological approaches targeting Src-FAK signaling may provide potential therapeutic strategies for rescuing colorectal cancer progression.

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Section: Discussionmentioning

confidence: 99%

Src-FAK Signaling Mediates Interleukin 6-Induced HCT116 Colorectal Cancer Epithelial–Mesenchymal Transition

Huang

Chen

Hsu

et al. 2023

IJMS

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“…Moreover, sorafenib increased the IL-6 expression in HCC cells and promoted metastasis and EMT progression in HCC cells. Knockdown of IL-6 could significantly decrease sorafenib resistance in HCC cells [ 97 ]. IL-6 is one of the pro-inflammatory cytokines secreted by TAMs, and sorafenib was shown to induce IL-6 secretion by TAMs [ 57 , 58 ].…”

Section: Tkis-induced Tme Remodelingmentioning

confidence: 99%

Modulation of the tumour microenvironment in hepatocellular carcinoma by tyrosine kinase inhibitors: from modulation to combination therapy targeting the microenvironment

Chen

et al. 2022

Cancer Cell Int

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Tyrosine kinase inhibitors (TKIs) remain the backbone of systematic therapy for advanced hepatocellular carcinoma. Sorafenib and lenvatinib are currently approved as first-line therapeutic drugs, and regorafenib and cabozantinib are applied as second-line treatments. With inhibition of angiogenesis as the main target, TKIs exert a profound effect on the tumour microenvironment (TME). The TME is a complex mixture of cellular and noncellular components surrounding the tumour mass, and is associated with tumour progression partially through the epithelial–mesenchymal transition. Specifically, the TME of HCC is characterized by profound extracellular matrix remodelling and an immunosuppressive microenvironment. The purpose of this review is to provide a summary of TME remodelling mediated by four Food and Drug Administration approved TKIs in HCC and thus summarize the rationale and potential targets for combination therapy. The modulatory effect of TKIs on the TME of HCC was reported to enhance the antitumour effect of TKIs through pyroptosis of macrophages and subsequent natural killer cell activation, T cell activation, regulatory T cell reduction in HCC. Meanwhile, TKIs also induce drug resistance via M2 polarization and accumulation, recruitment of tumour-associated neutrophils, and induction of the epithelial–mesenchymal transition. In conclusion, the effect of TKIs on TME can enhance its antitumour effect, but might also partially contribute to the drug resistance that hinders the progression of TKIs as treatment for HCC. Additionally, the effect of TKIs also provides the rationale for combination therapy, including combining TKIs with immune checkpoint inhibitors, to facilitate increased drug efficacy of TKIs.

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“…The ability of IL-6 to trigger an EMT and enhance cancer cell motility has been extended to colorectal cancer, cancer stem cells in blood vessels in head and neck squamous cell carcinomas, hepatocellular cancer, and laryngeal squamous cell carcinoma [ 51 , 52 , 53 , 54 ]. The ability of IL-6/STAT3 to modulate additional tumor-promoting and tumor-suppressing pathways have been extensively investigated [ 11 , 51 , 55 , 56 , 57 , 58 , 59 ].…”

Section: Il-6 Triggers Enhanced Cell Motility and An Epithelial To Me...mentioning

confidence: 99%

Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells

Sehgal

2022

Cells

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It was recognized over 30 years ago that the polyfunctional cytokine interleukin-6 (IL-6) was an almost invariant presence at the host-tumor interface. The IL-6 in the tumor microenvironment was produced either by the cancer cell or by host stromal cells, or by tumor-infiltrating immune cells, or all of them. IL-6 effects in this context included local changes in tumor cell-cell and cell-substrate adhesion, enhanced motility, epithelial to mesenchymal transformation (EMT), and changes in cell proliferation rates in both solid tumors as well as hematologic dyscrasias. Locally produced IL-6 enhanced cancer-targeting functions of tumor-infiltrating macrophages and immune cells. Additionally, the sex-biased phenotype of certain cancers (e.g., hepatocellular carcinoma (HCC) which is 3-5-fold more common in men] was related to the inhibition of macrophage-derived IL-6 production by estradiol-17β (E2). In many circumstances, locally produced IL-6 reached the peripheral circulation and elicited systemic effects such as cachexia and paraneoplastic syndrome (including fever, increased erythrocyte sedimentation rate, increased levels of C-reactive protein in serum, hypoalbuminemia). This review highlights the EMT produced by IL-6 in cancer cells, as well as mechanisms underlying sex bias in HCC, enhanced IL-6 expression in cancer cells resulting from mutations in p53, consequent alterations in STAT3 transcriptional signaling, and the newer understanding of STAT3 nuclear bodies in the cancer cell as phase-separated biomolecular condensates and membraneless organelles (MLOs). Moreover, the perplexing issue of discrepant measurements of IL-6 in human circulation using different assays, especially in patients undergoing immunotherapy, is discussed. Additionally, the paradoxical chaperone (enhancing) effect of anti-IL-6 “neutralizing” antibodies on IL-6 in vivo and consequent limitations of immunotherapy using anti-IL-6 mAb is considered.

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IL‑6 plays a crucial role in epithelial‑mesenchymal transition and pro‑metastasis induced by sorafenib in liver cancer

Cited by 10 publications

References 49 publications

Src-FAK Signaling Mediates Interleukin 6-Induced HCT116 Colorectal Cancer Epithelial–Mesenchymal Transition

Src-FAK Signaling Mediates Interleukin 6-Induced HCT116 Colorectal Cancer Epithelial–Mesenchymal Transition

Modulation of the tumour microenvironment in hepatocellular carcinoma by tyrosine kinase inhibitors: from modulation to combination therapy targeting the microenvironment

Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells

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