Fibronectin promotes tumor cells growth and drugs resistance through a CDC42‐YAP‐dependent signaling pathway in colorectal cancer

Yu, Yan; Zhang, Ruifeng; Feng, Haiyang

doi:10.1002/cbin.11390

Cited by 36 publications

(29 citation statements)

References 37 publications

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“…Interestingly, Fibronectin, a high-molecular-weight glycoprotein of ECM, was overexpressed in the ASM model. It has been reported that Fibronectin was observed in drug-resistant tumor tissues [35]. Fibronectin production occurred in the actual tumor microenvironment and appeared to promote drug resistance [36,37].…”

Section: Discussionmentioning

confidence: 99%

3D-Hepatocellular Carcinoma (3D-HCC) Models of Diffused and Aggregated Spheroids using a 96-Pillar/Well Plate

Lee¹,

Teng²,

Son³

et al. 2021

Preprint

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Background: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer-related mortality worldwide. The genetic and physiological complexity of HCC is a major barrier to the study of tumorigenesis and identification of therapeutic targets. The three-dimensional (3D) culture of cancer cells within an extracellular matrix (ECM) provides an in vitro tumor model that best recapitulates in vivo tumor pathophysiology.Methods: In the current study, we cultured cells and made spheroids by aggregating cells or diffusing cells in Matrigel attached on the tip of the 96-pillar plate. According to the initial cell position in Matrigel, two 3D-HCC cancer in-vitro models (diffused spheroid model and aggregated spheroid model) were established. These two models were applied to drug sensitivity assays to identify drug sensitivity changes. The protein expression and cytokine activation related to the drug resistance and maintenance of the physiological properties of HCC cells were analyzed in both models. This 3D culture method not only maintained the phenotype of the tumor but allowed easy high-throughput screening (HTS) due to its 96-array plate configuration.Results: The Aggregated Spheroid Model (ASM) showed higher expression of cancer markers associated with proliferation, tight junctions formation and epithelial cell identity in HCC cells, as well as cytokine factors associated with immune cell recruitment/activation, ECM regulation, cancer interaction, and angiogenesis regulation.Conclusions: Overall, the proposed ASM better recapitulates the tumor microenvironment, demonstrating the involvement of the ECM/tight junctions in the cell-to-cell signaling processes. This provides more instructive data for in vitro screening of tumor cells.

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Section: Discussionmentioning

confidence: 99%

3D-Hepatocellular Carcinoma (3D-HCC) Models of Diffused and Aggregated Spheroids using a 96-Pillar/Well Plate

Lee¹,

Teng²,

Son³

et al. 2021

Preprint

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“…Therefore, cilengitide has the most obvious antagonistic effect on cell adhesion to vitronectin compared to on laminin or fibronectin, which is consistent with our current results. In addition to α v β 3 , α v β 1 is also found as a receptor of vitronectin (Ding et al, 2002), whereas the main binding receptors of fibronectin are α v β 1 (Ye et al, 2020), α v β 6 (Mould et al, 2014), and α 5 β 1 (Mould et al, 2014) and the main binding receptor of laminin is α 6 β 1 (Corsini and Martin-Villalba, 2010). Previous research also confirmed that M21 human melanoma cells not only lost the ability to attach to vitronectin but showed a dramatic reduction in tumorigenicity when lacking integrin α v gene expression (Lacaria et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Matrix Proteins Confer Cell Adhesion-Mediated Drug Resistance Through Integrin αv in Glioblastoma Cells

Xiao

Sun

et al. 2021

Front. Cell Dev. Biol.

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Chemotherapy resistance to glioblastoma (GBM) remains an obstacle that is difficult to overcome, leading to poor prognosis of GBM patients. Many previous studies have focused on resistance mechanisms intrinsic to cancer cells; the microenvironment surrounding tumor cells has been found more recently to have significant impacts on the response to chemotherapeutic agents. Extracellular matrix (ECM) proteins may confer cell adhesion-mediated drug resistance (CAMDR). Here, expression of the ECM proteins laminin, vitronectin, and fibronectin was assessed in clinical GBM tumors using immunohistochemistry. Then, patient-derived GBM cells grown in monolayers on precoated laminin, vitronectin, or fibronectin substrates were treated with cilengitide, an integrin inhibitor, and/or carmustine, an alkylating chemotherapy. Cell adhesion and viability were quantified. Transcription factor (TF) activities were assessed over time using a bioluminescent assay in which GBM cells were transduced with lentiviruses containing consensus binding sites for specific TFs linked to expression a firefly luciferase reporter. Apoptosis, mediated by p53, was analyzed by Western blotting and immunocytofluorescence. Integrin αv activation of the FAK/paxillin/AKT signaling pathway and effects on expression of the proliferative marker Ki67 were investigated. To assess effects of integrin αv activation of AKT and ERK pathways, which are typically deregulated in GBM, and expression of epidermal growth factor receptor (EGFR), which is amplified and/or mutated in many GBM tumors, shRNA knockdown was used. Laminin, vitronectin, and fibronectin were abundant in clinical GBM tumors and promoted CAMDR in GBM cells cultured on precoated substrates. Cilengitide treatment induced cell detachment, which was most pronounced for cells cultured on vitronectin. Cilengitide treatment increased cytotoxicity of carmustine, reversing CAMDR. ECM adhesion increased activity of NFκB and decreased that of p53, leading to suppression of p53-mediated apoptosis and upregulation of multidrug resistance gene 1 (MDR1; also known as ABCB1 or P-glycoprotein). Expression of Ki67 was correlative with activation of the integrin αv-mediated FAK/paxillin/AKT signaling pathway. EGFR expression increased with integrin αv knockdown GBM cells and may represent a compensatory survival mechanism. These results indicate that ECM proteins confer CAMDR through integrin αv in GBM cells.

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“…The Hippo signaling pathway is dysregulated in numerous types of cancer, including CRC (32-34). Its inactivation is associated with CRC progression (35)(36)(37). YAP is a major effector in the Hippo signaling pathway and p-YAP exists in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Curcumol inhibits the viability and invasion of colorectal cancer cells via miR‑30a‑5p and Hippo signaling pathway

Qin

et al. 2021

Oncol Lett

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MicroRNA-30a-5p (miR-30a-5p), which functions as a tumor suppressor, has been reported to be downregulated in colorectal cancer (CRC) tissues and to be associated with cancer invasion. However, the detailed regulatory mechanism of curcumol in the malignant progression of CRC remains unknown. MTT, Transwell, scratch, western blotting and reverse transcription-quantitative PCR assays were performed to examine how curcumol inhibited CRC cell viability, invasion and migration, and to detect the role of miR-30a-5p and curcumol in the invasion and Hippo signaling pathways of CRC cells. The present study revealed that miR-30a-5p expression was downregulated in human CRC tissues and cells. The results demonstrated that miR-30a-5p downregulation was accompanied by the inactivation of the Hippo signaling pathway, which was demonstrated to promote CRC cell viability, invasion and migration. Curcumol treatment was identified to increase miR-30a-5p expression and to activate the Hippo signaling pathway, which in turn inhibited the invasion and migration of CRC cells. Overexpression of miR-30a-5p enhanced the effects of curcumol on cell invasion and migration, and the Hippo signaling pathway in CRC cells. Furthermore, downregulation of miR-30a-5p reversed the effects of curcumol on cell invasion and migration, and the Hippo signaling pathway in CRC cells. These findings identified novel signaling pathways associated with miR-30a-5p and revealed the effects of curcumol on miR-30a-5p expression. Therefore, curcumol may serve as a potential therapeutic strategy to delay CRC progression.

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Fibronectin promotes tumor cells growth and drugs resistance through a CDC42‐YAP‐dependent signaling pathway in colorectal cancer

Cited by 36 publications

References 37 publications

3D-Hepatocellular Carcinoma (3D-HCC) Models of Diffused and Aggregated Spheroids using a 96-Pillar/Well Plate

3D-Hepatocellular Carcinoma (3D-HCC) Models of Diffused and Aggregated Spheroids using a 96-Pillar/Well Plate

Extracellular Matrix Proteins Confer Cell Adhesion-Mediated Drug Resistance Through Integrin αv in Glioblastoma Cells

Curcumol inhibits the viability and invasion of colorectal cancer cells via miR‑30a‑5p and Hippo signaling pathway

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