S100A4 promotes colon inflammation and colitis-associated colon tumorigenesis

Zhang, Jinhua; Hou, Shasha; Gu, Jian; Tian, Tian; Qi, Yuan; Jia, Jun; Qin, Zhihai; Chen, Zhi‐Nan

doi:10.1080/2162402x.2018.1461301

Cited by 19 publications

(21 citation statements)

References 49 publications

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“… 33 Knockout of S100A4 in mice dampens the release of proinflammatory cytokines such as TNF-α, IL-6, and IL-17 and thus results in reduction in colon inflammation. 34 Partially coincident with our results, shRNA-mediated suppression of S100A4 enhances the autophagy of lung cancer cells, corresponding to LC3-II protein abundance. 18 In line with our data, the levels of VEGF and TNF-α are reduced by silencing S100A4 in corneal tissues, by which S100A4 affects pathologic CNV induced by alkali burns.…”

Section: Discussionsupporting

confidence: 88%

S100A4 Silencing Facilitates Corneal Wound Healing After Alkali Burns by Promoting Autophagy via Blocking the PI3K/Akt/mTOR Signaling Pathway

Wang

Gao

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose This study investigated the role of S100 calcium binding protein A4 (S100A4) in corneal wound healing and the underlying mechanism of the S100A4-mediated PI3K/Akt/mammalian target of rapamycin (mTOR) pathway. Methods The rabbit corneal alkali burn model was established in vivo. S100A4 expression, wound healing, inflammation, and autophagy in rabbit cornea after alkali burn were detected. The NaOH-treated rabbit corneal stromal cells (rCSCs) were transfected with overexpressed S100A4 or silencing S100A4 to examine the effect of S100A4 on corneal wound healing in vitro. The effect of S100A4 on cell viability, proliferation, migration, invasion, fibrosis, and autophagy of rCSCs after alkali burn was analyzed. Then the functional rescue experiments were carried out. The PI3K inhibitor, LY294002, was used to elucidate the PI3K/Akt/mTOR signaling pathway in rCSCs. Results S100A4 silencing promoted rabbit corneal wound healing by inhibiting fibrosis and inflammation and promoting autophagy in alkali-burned cornea, corresponding to increased levels of LC3, Beclin 1, and Atg4B but lowered α-smooth muscle actin, TNF-ɑ, and p62 levels. Moreover, silencing S100A4 inhibited proliferation, migration, invasion, and fibrosis of NaOH-treated rCSCs and promoted the differentiation of rCSCs into corneal cells and the autophagy of damaged rCSCs. The inhibitory role of S100A4 in wound healing was achieved via activation of the PI3K/Akt/mTOR pathway. Conclusions S100A4 silencing confers a promising effect on wound healing of alkali-burned cornea by blocking the PI3K/Akt/mTOR pathway, supporting the advancement of corneal gene therapies for wound healing.

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Section: Discussionsupporting

confidence: 88%

S100A4 Silencing Facilitates Corneal Wound Healing After Alkali Burns by Promoting Autophagy via Blocking the PI3K/Akt/mTOR Signaling Pathway

Wang

Gao

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…Our data show that two different pro-inflammatory molecules, with a distinct mode of actions, TNFα and LPS, capable of inducing typical M1 markers, such as NOX2, as well as cytoskeletal rearrangements towards an activated state, both converge on a dramatic and long-lasting up-regulation of S100A4 expression in primary microglia. In parallel with what occurs in macrophages [38,39,40], we could speculate that S100A4 in microglia could be involved both in triggering pro-inflammatory processes as cytokine release, as well as in promoting cellular movement towards a site of injury. In this vein, we have demonstrated that niclosamide, an inhibitor of S100A4 transcription [41,42], can revert the induction of pro-inflammatory parameters as NOX2, NF-κB, mTOR, morphological microglia rearrangements, as well as migration and the phagocytotic activity of microglia.…”

Section: Discussionmentioning

confidence: 69%

“…Further studies will be necessary to establish whether the effects of niclosamide in microglia are dependent on the specific inhibition of S100A4, and how this, in turn, affects the signaling processes regulated by this protein. Indeed, S100A4 is known to influence not only pathways dealing with cytoskeletal rearrangements, but also NF-κB signaling [38], and to modulate autophagy through interaction with mTOR [46]. Moreover, S100A4 is known to exert its effects by two different mechanisms: an intracellular pathway and an extracellular one [47].…”

Section: Discussionmentioning

confidence: 99%

The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis

Serrano

Apolloni

Rossi

et al. 2019

Cells

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S100A4, belonging to a large multifunctional S100 protein family, is a Ca2+-binding protein with a significant role in stimulating the motility of cancer and immune cells, as well as in promoting pro-inflammatory properties in different cell types. In the CNS, there is limited information concerning S100A4 presence and function. In this study, we analyzed the expression of S100A4 and the effect of the S100A4 transcriptional inhibitor niclosamide in murine activated primary microglia. We found that S100A4 was strongly up-regulated in reactive microglia and that niclosamide prevented NADPH oxidase 2, mTOR (mammalian target of rapamycin), and NF-κB (nuclear factor-kappa B) increase, cytoskeletal rearrangements, migration, and phagocytosis. Furthermore, we found that S100A4 was significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic rat SOD1-G93A model of amyotrophic lateral sclerosis. Finally, we demonstrated the increased expression of S100A4 also in fibroblasts derived from amyotrophic lateral sclerosis (ALS) patients carrying SOD1 pathogenic variants. These results ascribe S100A4 as a marker of microglial reactivity, suggesting the contribution of S100A4-regulated pathways to neuroinflammation, and identify niclosamide as a possible drug in the control and attenuation of reactive phenotypes of microglia, thus opening the way to further investigation for a new application in neurodegenerative conditions.

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“…As a metastasin, S100A4 is associated with numerous cytoskeletal proteins, such as actin, myosin, and tropomyosin, increasing the tumor progression and metastasis (19,(25)(26)(27). Cathepsin B belongs to a family of lysosomal cysteine proteases comprising disulfide-linked heavy and light chains, which can directly or indirectly degrade the extracellular matrix in tumor tissues (28).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Fei

et al. 2020

Front. Oncol.

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Recently, an increasing number of evidences have shown that polyploid giant cancer cells (PGCCs) could generate daughter cells with a strong migration and invasion ability, which have been implicated in cancer recurrence and metastasis. However, the underlying molecular mechanisms of PGCCs with their daughter cells remain largely unclear. In vitro and in vivo experiments combined with 222 cases of human colorectal cancer (CRC) samples were used to identify the molecular mechanisms of S100A4-related proteins regulating the invasion and metastasis of PGCCs with their daughter cells. PGCCs with their daughter cells had high migration, invasion, and proliferation abilities compared to control cells; these were significantly inhibited after S100A4 knockdown. The high expression of cathepsin B, cyclin B1, TRIM21, and Annexin A2 were significantly downregulated after S100A4 knockdown, while the overexpression of S100A4, cathepsin B, cyclin B1, and S100A10 were significantly downregulated after TRIM21 knockdown in PGCCs with their daughter cells. The tumorigenic and metastatic ability of PGCCs with their daughter cells in vivo was significantly stronger compared to the untreated cells, which was significantly decreased after S100A4 knockdown. Moreover, the expression of S100A4-related proteins was positively correlated with the malignancy degree of human CRC, and maintained a high level in lymph node metastasis. S100A4 and TRIM21 may regulate each other to affect the expression and subcellular localization of cyclin B1, and participate in regulating the structure and function of Annexin A2/S100A10 complex, affecting downstream cathepsin B, resulting in the invasion and metastasis of PGCCs with their daughter cells. Besides, 14-3-3 ζ/δ and Ezrin may be involved in the motility and invasion of PGCCs with their daughter cells via cytoskeletal constructions with S100A4.

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S100A4 promotes colon inflammation and colitis-associated colon tumorigenesis

Cited by 19 publications

References 49 publications

S100A4 Silencing Facilitates Corneal Wound Healing After Alkali Burns by Promoting Autophagy via Blocking the PI3K/Akt/mTOR Signaling Pathway

S100A4 Silencing Facilitates Corneal Wound Healing After Alkali Burns by Promoting Autophagy via Blocking the PI3K/Akt/mTOR Signaling Pathway

The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

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