Cancer-associated Fibroblast-derived IL-6 Promotes Head and Neck Cancer Progression via the Osteopontin-NF-kappa B Signaling Pathway

Qin, Xing; Yan, Ming; Wang, Xu; Xu, Qin; Wang, Xiaoning; Zhu, Xueqiong; Shi, Jianbo; Li, Zhihui; Zhang, Jianjun; Chen, Wantao

doi:10.7150/thno.22182

Cited by 141 publications

(104 citation statements)

References 63 publications

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“…Furthermore, the JAK/STAT3 pathway, the IL-6 downstream target (47,48), was downregulated in ATF3-overexpressing HDFs. IL-6 has been shown to play a promoting role in the pathogenesis and development of malignancies in many kinds of tumors, including melanoma, and was also shown to be highly expressed by CAFs contacting different tumor types (34,(49)(50)(51). Therefore, we could conclude that the inhibitory effect of ATF3-overexpressing HDFs on melanoma cell growth and migration is mainly through the IL-6/STAT3 pathway.…”

Section: Discussionmentioning

confidence: 86%

Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine Pathway

Wen

et al. 2020

Front. Oncol.

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The treatment of melanoma has remained a difficult challenge. Targeting the tumor stroma has recently attracted attention for developing novel strategies for melanoma therapy. Activating transcription factor 3 (ATF3) plays a crucial role in regulating tumorigenesis and development, but whether the expression of ATF3 in human dermal fibroblasts (HDFs) can affect melanoma development hasn't been studied. Our results show that ATF3 expression is downregulated in stromal cells of human melanoma. HDFs expressing high levels of ATF3 suppressed the growth and migration of melanoma cells in association with downregulation of different cytokines including IL-6 in vitro. In vivo, HDFs with high ATF3 expression reduced tumor formation. Adding recombinant IL-6 to melanoma cells reversed those in vitro and in vivo effects, suggesting that ATF3 expression by HDFs regulates melanoma progression through the IL-6/STAT3 pathway. More importantly, HDFs pretreated with cyclosporine A or phenformin to induce ATF3 expression inhibited melanoma cell growth in vitro and in vivo. In summary, our study reveals that ATF3 suppresses human melanoma growth and that inducing the expression of ATF3 in HDFs can inhibit melanoma growth, a new potential melanoma therapeutic approach. ELISAELISA assays were carried out using R&D Systems kits according to the manufacturer's protocols. Briefly, total protein concentrations in CM were measured using a BCA Protein Assay Kit (Solarbio Science & Technology, Beijing), then CM were Frontiers in Oncology | www.frontiersin.org

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Section: Discussionmentioning

confidence: 86%

Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine Pathway

Wen

et al. 2020

Front. Oncol.

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“…Mounting evidence suggests that the NF-κB signaling pathway is involved in the progression of various human tumors, including those of ovarian cancer (43), prostate cancer (44), cervical cancer (45), as well as head and neck cancer (46). A recent study demonstrated that TRIM22 negatively regulates the tumor necrosis factor receptor-associated factor 6 (TRAF6)-stimulated NF-κB pathway by binding to the TRIM22 N-terminal RING domain (47).…”

Section: Discussionmentioning

confidence: 99%

TRIM22 inhibits endometrial cancer progression through the NOD2/NF‑κB signaling pathway and confers a favorable prognosis

et al. 2020

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Endometrial cancer (EnC) is a malignant gynecological tumor commonly observed in developed countries, specifically among post-menopausal women. Although numerous patients with EnC receive promising prognoses, those with advanced or metastatic disease often have a poor prognosis and an impaired quality of life. Tripartite motif-containing 22 (TRIM22) has been confirmed to play many crucial roles in different biological processes, from inflammatory to tumorigenesis. However, the multifaceted roles of TRIM22 in EnC remain uncharacterized. Herein, comparing normal endometrial tissues with tumor tissues obtained from patients, it was concluded that TRIM22 expression was decreased in tumor tissues. However, the overexpression of TRIM22 served to inhibit the migratory, invasive, proliferative and cell cycle activity of EnC cells. Moreover, the knockdown of TRIM22 increased the migratory, invasive, and proliferative activity of the EnC cells. Furthermore, it was found that TRIM22 effectively suppressed EnC progression through the nucleotide binding oligomerization domain containing 2 (NOD2)/nuclear factor (NF)-κB pathway. The data also demonstrated that TRIM22 functions as an inhibitor of EnC tumor xenograft growth in vivo. Overall, the findings of the present study define a novel regulatory role for TRIM22 in EnC progression. Moreover, TRIM22 may serve as an important prognostic predictor for EnC.

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“…In addition to these possible fibroblast activation models by C2 cells, our data further revealed a potential mechanism for reciprocal fibroblast–tumour cell communication. Studies have shown a proproliferative effect of IL‐6 on CAFs and have correlated its expression with increased levels of the CAF marker ACTA2 [55,56]. However, IL‐6 is also an important mediator of a dynamic tumour cell–CAF crosstalk by not only promoting fibroblast activation, but also supporting tumour cell growth in humans [57].…”

Section: Discussionmentioning

confidence: 99%

Deregulation of miR‐27a may contribute to canine fibroblast activation after coculture with a mast cell tumour cell line

et al. 2020

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The tumour microenvironment comprises a diverse range of cells, including fibroblasts, immune cells and endothelial cells, along with extracellular matrix. In particular, fibroblasts are of significant interest as these cells are reprogrammed during tumorigenesis to become cancer‐associated fibroblasts (CAFs), which in turn support cancer cell growth. MicroRNAs (miRNAs) have been shown to be involved in this intercellular crosstalk in humans. To assess whether miRNAs are also involved in the activation of fibroblasts in dogs, we cocultured primary canine skin fibroblasts with the canine mast cell tumour cell line C2 directly or with C2‐derived exosomes, and measured differential abundance of selected miRNAs. Expression of the CAF markers alpha‐smooth muscle actin (ACTA2) and stanniocalcin 1 confirmed the activation of our fibroblasts after coculture. We show that fibroblasts displayed significant downregulation of miR‐27a and let‐7 family members. These changes correlated with significant upregulation of predicted target mRNAs. Furthermore, RNA interference knockdown of miR‐27a revealed that cyclin G1 (CCNG1) exhibited negative correlation at the mRNA and protein level, suggesting that CCNG1 is a target of miR‐27a in canine fibroblasts and involved in their activation. Importantly, miR‐27a knockdown itself resulted in fibroblast activation, as demonstrated by the formation of ACTA2 filaments. In addition, interleukin‐6 (IL‐6) was strongly induced in our fibroblasts when cocultured, indicating potential reciprocal signalling. Taken together, our findings are consistent with canine fibroblasts being reprogrammed into CAFs to further support cancer development and that downregulation of miR‐27a may play an important role in the tumour–microenvironment crosstalk.

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Cancer-associated Fibroblast-derived IL-6 Promotes Head and Neck Cancer Progression via the Osteopontin-NF-kappa B Signaling Pathway

Cited by 141 publications

References 63 publications

Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine Pathway

Up-Regulation of Activating Transcription Factor 3 in Human Fibroblasts Inhibits Melanoma Cell Growth and Migration Through a Paracrine Pathway

TRIM22 inhibits endometrial cancer progression through the NOD2/NF‑κB signaling pathway and confers a favorable prognosis

Deregulation of miR‐27a may contribute to canine fibroblast activation after coculture with a mast cell tumour cell line

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