Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer

Lee, Seungho; Choi, Seowon; Lee, Yoo Kyung; Chung, Dong-Hae; Park, Noh-Hyun

doi:10.1111/jog.13181

Cited by 44 publications

(44 citation statements)

References 25 publications

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“…Interestingly, the upregulation of phospho-ERK by rHE4 was only observed sporadically in OVCAR8 and SKOV3 cells at 24 h ( Figure 1E). We and others have reported activation of ERK by HE4 [9,15,16]; specifically, we found that rHE4 suppressed phospho-ERK levels at 1 and 4 h but increased them at 24 and 48 h [9]. While we did not perform a time course in the present study, the inconsistent results in this study suggest that the exact timing of phospho-ERK regulation by rHE4 may be variable.…”

Section: He4 Regulates Dusp6 Levels In Ovarian Cancer Cellscontrasting

confidence: 67%

“…One oncogenic pathway that has consistently been shown to interact with HE4 in several studies is the extracellular signal regulated kinase (ERK) pathway. Several reports indicate that ERK activation is enhanced with HE4 treatment or overexpression, while ERK activation is conversely reduced with HE4 knockdown [9,15,16]. Our lab has revealed a complex response of ERK to recombinant HE4 treatment; specifically, we have observed downregulation of ERK phosphorylation at early time points following treatment with recombinant HE4, and its upregulation at later time points [9].…”

Section: Introductionsupporting

confidence: 50%

“…Inclusion of preoperative serum HE4 levels into the diagnostic Risk of Ovarian Malignancy Algorithm (ROMA) results in demonstrably improved specificity and sensitivity in detection and monitoring of the disease over Cancer Antigen 125 (CA 125), pelvic sonography, and menopausal status alone [5]. Research has also shown its ability to support EOC pathogenesis, including the promotion of proliferation, chemoresistance, antiestrogen resistance, adhesion, invasion, and migration [6][7][8][9][10][11][12][13][14][15][16][17]. One oncogenic pathway that has consistently been shown to interact with HE4 in several studies is the extracellular signal regulated kinase (ERK) pathway.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes

et al. 2019

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Dual specificity phosphatase 6 (DUSP6) is a protein phosphatase that deactivates extracellular-signal-regulated kinase (ERK). Since the ovarian cancer biomarker human epididymis protein 4 (HE4) interacts with the ERK pathway, we sought to determine the relationship between DUSP6 and HE4 and elucidate DUSP6's role in epithelial ovarian cancer (EOC). Viability assays revealed a significant decrease in cell viability with pharmacological inhibition of DUSP6 using (E/Z)-BCI hydrochloride in ovarian cancer cells treated with carboplatin or paclitaxel, compared to treatment with either agent alone. Quantitative PCR was used to evaluate levels of ERK pathway response genes to BCI in combination with recombinant HE4 (rHE4), carboplatin, and paclitaxel. Expression of EGR1, a promoter of apoptosis, was higher in cells co-treated with BCI and paclitaxel or carboplatin than in cells treated with chemotherapeutic agents alone, while expression of the proto-oncogene c-JUN was decreased with co-treatment. The effect of BCI on the expression of these two genes opposed that of rHE4. Pathway focused quantitative PCR also revealed suppression of ERBB3 in cells co-treated with BCI plus carboplatin or paclitaxel. Finally, expression levels of DUSP6 in EOC tissue were evaluated by immunohistochemistry, revealing significantly increased levels of DUSP6 in serous EOC tissue compared to adjacent normal tissue. A positive correlation between HE4 and DUSP6 levels was determined by Spearman Rank correlation. In conclusion, DUSP6 inhibition sensitizes ovarian cancer cells to chemotherapeutic agents and alters gene expression of ERK response genes, suggesting that DUSP6 could plausibly function as a novel therapeutic target to reduce chemoresistance in EOC.

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Section: He4 Regulates Dusp6 Levels In Ovarian Cancer Cellscontrasting

confidence: 67%

Section: Introductionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

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Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes

et al. 2019

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“…Emerging studies suggest that HE4 over-expression promotes ovarian tumour growth and imparts strong resistance against the most commonly used therapeutics [20][21][22][23][24]. Emerging studies suggest that HE4 over-expression promotes ovarian tumour growth and imparts strong resistance against the most commonly used therapeutics [20][21][22][23][24].…”

Section: Discussionmentioning

confidence: 99%

“…HE4 is known to be over-expressed highly in ovarian cancer, but its causal relationship to ovarian cancer pathogenesis has not been established firmly. Emerging studies suggest that HE4 over-expression promotes ovarian tumour growth and imparts strong resistance against the most commonly used therapeutics [20][21][22][23][24]. Interestingly, ovarian cancer patients who experienced greater HE4 reduction during neoadjuvant chemotherapy exhibit improved overall survival [24].…”

Section: Discussionmentioning

confidence: 99%

HE4 suppresses the expression of osteopontin in mononuclear cells and compromises their cytotoxicity against ovarian cancer cells

James

Cantillo

Oliver

et al. 2018

Clinical and Experimental Immunology

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Ovarian cancers are known to evade immunosurveillance and to orchestrate a suppressive immune microenvironment. Here we examine the role of human epididymis protein 4 (HE4), an ovarian cancer biomarker, in immune evasion. Through modified subtractive hybridization analyses we have characterized the gene targets of HE4 in human peripheral blood mononuclear cells (PBMCs), and established a preliminary mechanism for HE4-mediated immune failure in ovarian tumours. Upon exposure of purified PMBCs to HE4, osteopontin (OPN) and dual-specificity phosphatase 6 (DUSP6) emerged as the most suppressed and up-regulated genes, respectively. SKOV3 and OVCAR8, human ovarian carcinoma cell lines, exhibited enhanced proliferation in conditioned media from HE4-exposed PBMCs, an effect that was attenuated by the addition of recombinant OPN or OPN-inducible cytokines [interleukin (IL)-12 and interferon (IFN)-Ɣ]. Additionally, upon co-culture with PBMCs, HE4-silenced SKOV3 cells were found to be more susceptible to cytotoxic cell death. The relationship between HE4 and OPN was reinforced further through the analysis of serous ovarian cancer patient samples. In these biopsy specimens, the number of OPN T cells correlated positively with progression free survival (PFS) and inversely with serum HE4 level. Taken together, these findings show that HE4 enhances ovarian cancer tumorigenesis by compromising OPN-mediated T cell activation.

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Serum RelB is correlated with renal fibrosis and predicts chronic kidney disease progression

Sun

Xie

Wang³

et al. 2021

Clinical & Translational Med

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Dear Editor, Chronic kidney disease (CKD) with characteristics of progressive deterioration of renal function is regarded as one major public health problem around the world. The patients are often diagnosed at advanced stages with most kidney functions lost, since they have few signs or symptoms at early stage. Renal fibrosis is the pathologic hallmark and prognostic indicator for CKD. The effective methods except biopsy for early detection of renal fibrosis are required to improve the diagnosis of CKD. Our data revealed that RelB can not only discriminate CKD patients from normal subjects but also can distinguish CKD patients at different stages. We prove that RelB is capable to work as a promising serum biomarker to diagnose and monitor the renal fibrosis in CKD patients.Renal inflammation is actively participating in the evolution of renal fibrosis and CKD. 1 In kidney tubular cells, hyperactivation of noncanonical NF-κB signaling induced by TWEAK, TNF-like weak inducer of apoptosis, contributes to inflammatory responses. 2 Through analyzing a whole transcriptome RNA sequencing of mouse renal fibrosis model with unilateral ureteral obstruction (UUO), we found that RelB, the key transactivator of noncanonical NF-κB signaling pathway, was profoundly elevated in fibrotic renal tissues (Figure S1). 3 Therefore, we established UUO model to validate the upregulation of RelB in the progressive renal fibrosis. The results showed a consistent and significant increase in RelB along with α-SMA and Col1α1 at mRNA and protein levels in fibrotic kidneys after UUO (Figure 1A and B), and the level of RelB mRNA was positively correlated with α-SMA, Col1α1, and Tgfβ1 (Figure S2A-C), while the RelB protein was correlated with fibrosis (Figure S2D and E). Then, we measured the concentration of serum RelB in mice with ureteric ligation and found it increased significantly from the 8th day after UUO as well (Figure 1C). The immunohistochemical analysis further showed that RelB, specifically expressed in the renal tubular epithelial cells, gradually increased with the fibrosis progression (Figure 1D-F ), and was pos-This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer

Abstract: HE4 induces chemoresistance against anti-cancer drugs and activates the AKT and Erk pathways to enhance tumor survival. HE4 expression in ovarian cancer tissue is associated with a worse prognosis for epithelial ovarian cancer patients.

Cited by 44 publications

References 25 publications

Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes

Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes

HE4 suppresses the expression of osteopontin in mononuclear cells and compromises their cytotoxicity against ovarian cancer cells

Serum RelB is correlated with renal fibrosis and predicts chronic kidney disease progression

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