S100A4/Nonmuscle Myosin IIA/p53 Axis Contributes to Aggressive Features in Ovarian High-Grade Serous Carcinoma

Hiruta, Ai; Oguri, Yasuko; Yokoi, Ako; Matsumoto, Toshihide; Oda, Yusuke; Tomohiro, Mikihisa; Hashimura, Miki; Jiang, Zesong; Tochimoto, Masataka; Nakagawa, Mayu; Saegusa, Makoto

doi:10.1016/j.ajpath.2020.07.014

“…Of note, we found that FGF2 induces the nuclear accumulation of c-Rel and its recruitment within the S100A4 promoter region toward the upregulation of S100A4 expression and secretion. These findings add novel insights to previous studies suggesting that S100A4 plays a role in the epithelial mesenchymal transition (EMT) process and in the pre-metastatic niche formation and is correlated with high tumor grade and poor survival of cancer patients [33,56,57,90,91].…”

Section: Discussionsupporting

confidence: 76%

S100A4 Is Involved in Stimulatory Effects Elicited by the FGF2/FGFR1 Signaling Pathway in Triple-Negative Breast Cancer (TNBC) Cells

Santolla¹,

Talia²,

Maggiolini³

2021

IJMS

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Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype characterized by poor clinical outcome. In recent years, numerous advancements have been made to better understand the biological landscape of TNBC, though appropriate targets still remain to be determined. In the present study, we have determined that the expression levels of FGF2 and S100A4 are higher in TNBC with respect to non-TNBC patients when analyzing “The Invasive Breast Cancer Cohort of The Cancer Genome Atlas” (TCGA) dataset. In addition, we have found that the gene expression of FGF2 is positively correlated with S100A4 in TNBC samples. Performing quantitative PCR, Western blot, CRISPR/Cas9 genome editing, promoter studies, immunofluorescence analysis, subcellular fractionation studies, and ChIP assays, we have also demonstrated that FGF2 induces in TNBC cells the upregulation and secretion of S100A4 via FGFR1, along with the ERK1/2–AKT–c-Rel transduction signaling. Using conditioned medium from TNBC cells stimulated with FGF2, we have also ascertained that the paracrine activation of the S100A4/RAGE pathway triggers angiogenic effects in vascular endothelial cells (HUVECs) and promotes the migration of cancer-associated fibroblasts (CAFs). Collectively, our data provide novel insights into the action of the FGF2/FGFR1 axis through S100A4 toward stimulatory effects elicited in TNBC cells.

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“…A FLAG-tagged S100A1 expression plasmid generated by polymerase chain reaction (PCR) was cloned into a p3xFLAG-CMV14 vector (Sigma-Aldrich Chemicals, St. Louis, MO, USA). S100A1-specific short hairpin RNA (shRNA) oligonucleotides were designed as described previously [ 14 ]. Single-stranded S100A1 oligonucleotides were annealed and then cloned into BamH 1- EcoRI sites of RNAi-Ready pSIREN-RetroQ vector (Takara, Shiga, Japan), according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

“…Based on our previous work [ 13 , 14 ], we hypothesized that S100 family members might regulate endometrial glandular cell biology and tumorigenesis through modulation of the p53/MDM2 axis. To test this, we first examined the expression of several S100 family members in Em Ca cell lines, and interrogated the Cancer Genome Atlas (TGCA) data to determine whether S100 expression had prognostic significance in Em Ca.…”

Section: Introductionmentioning

confidence: 99%

Functional interaction between S100A1 and MDM2 may modulate p53 signaling in normal and malignant endometrial cells

Nakagawa

¹

,

Higuchi

²

,

Hashimura

³

et al. 2022

BMC Cancer

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3

0

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Background S100A1 expression is deregulated in a variety of human malignancies, but its role in normal and malignant endometrial cells is unclear. Methods We used endometrial carcinoma (Em Ca) cell lines to evaluate the physical and functional interaction of S100A1 with p53 and its negative regulator, mouse double minute 2 (MDM2). We also evaluated the expression of S100A1, p53, and MDM2 in clinical samples consisting of 89 normal endometrial and 189 Em Ca tissues. Results S100A1 interacted with MDM2 but not p53 in Em Ca cell lines. Treatment of cells stably overexpressing S100A1 with Nutlin-3A, an inhibitor of the p53/MDM2 interaction, increased expression of p53-target genes including p21waf1 and BAX. S100A1 overexpression enhanced cellular migration, but also sensitized cells to the antiproliferative and proapoptotic effects of Adriamycin, a genotoxic agent; these phenotypes were abrogated when S100A1 was knocked down using shRNA. In clinical samples from normal endometrium, S100A1 expression was significantly higher in endometrial glandular cells of the middle/late secretory and menstrual stages when compared to cells in the proliferative phases; high S100A1 was also positively correlated with expression of MDM2 and p21waf1 and apoptotic status, and inversely correlated with Ki-67 scores. However, such correlations were absent in Em Ca tissues. Conclusion The interaction between S100A1 and MDM2 may modulate proliferation, susceptibility to apoptosis, and migration through alterations in p53 signaling in normal- but not malignant-endometrial cells.

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“…Plasmids and cell lines FLAG-tagged S100A1 expression plasmid generated by polymerase chain reaction (PCR) was cloned into p3xFLAG-CMV14 vector (Sigma-Aldrich Chemicals, St. Louis, MO, USA). S100A1-speci c short hairpin RNA (shRNA) oligonucleotides were designed as described previously [14]. Single-stranded S100A1 oligonucleotides were annealed and then cloned into BamH1-EcoRI sites of RNAi-Ready pSIREN-RetroQ vector (Takara, Shiga, Japan), according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…Based on our previous works [13,14], we hypothesized that S100 family members might regulate endometrial glandular cell biology and tumorigenesis through modulation of the p53/MDM2 axis. To test this, we rst examined the expression of several S100 family members in Em Ca cell lines, and interrogated the TGCA data to determine whether S100 expression had prognostic signi cance in Em Ca.…”

Section: Introductionmentioning

confidence: 99%

Functional Interaction Between S100A1 and MDM2 May Modulate p53 Signaling in Normal and Malignant Endometrial Cells

Nakagawa

¹

,

S

²

,

Hashimura

³

et al. 2021

Preprint

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0

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Background S100A1 expression is deregulated in a variety of human malignancies, but its role in normal and malignant endometrial cells is unclear. Methods We used endometrial carcinoma (Em Ca) cell lines to evaluate the physical and functional interaction of S100A1 with p53 and its negative regulator, mouse double minute 2 (MDM2). We also evaluated the expression of S100A1, p53, and MDM2 in clinical samples consisting of 89 normal endometrial and 189 Em Ca tissues. Results S100A1 interacted with MDM2 but not p53 in Em Ca cell lines. Treatment of cells stably overexpressing S100A1 with Nutlin-3A, an inhibitor of the p53/MDM2 interaction, increased expression of p53-target genes including p21waf1 and BAX. S100A1 overexpression enhanced cellular migration, but also sensitized cells to the antiproliferative and proapoptotic effects of Adriamycin, a genotoxic agent; these phenotypes were abrogated when S100A1 was knocked down using shRNA. In clinical samples from normal endometrium, S100A1 expression was significantly higher in endometrial glandular cells of the middle/late secretory and menstrual stages when compared to cells in the proliferative phases; high S100A1 was also positively correlated with expression of MDM2 and p21waf1 and apoptotic status, and inversely correlated with Ki-67 scores. However, such correlations were absent in Em Ca tissues. Conclusion The interaction between S100A1 and MDM2 may modulate proliferation, susceptibility to apoptosis, and migration through alterations in p53 signaling in normal-but not malignant-endometrial cells.

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S100A4/Nonmuscle Myosin IIA/p53 Axis Contributes to Aggressive Features in Ovarian High-Grade Serous Carcinoma

Cited by 11 publications

References 47 publications

S100A4 Is Involved in Stimulatory Effects Elicited by the FGF2/FGFR1 Signaling Pathway in Triple-Negative Breast Cancer (TNBC) Cells

S100A4 Is Involved in Stimulatory Effects Elicited by the FGF2/FGFR1 Signaling Pathway in Triple-Negative Breast Cancer (TNBC) Cells

Functional interaction between S100A1 and MDM2 may modulate p53 signaling in normal and malignant endometrial cells

Functional Interaction Between S100A1 and MDM2 May Modulate p53 Signaling in Normal and Malignant Endometrial Cells

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