A Transcriptome-proteome Integrated Network Identifies Endoplasmic Reticulum thiol oxidoreductase (ERp57) as a Hub that Mediates Bone Metastasis

Santana-Codina, Naiara; Carretero, Rafael; Sanz‐Pamplona, Rebeca; Cabrera, Teresa; Güney, Emre; Oliva, Baldo; Clézardin, Philippe; Olarte, Omar E.; Loza-Álvarez, Pablo; Méndez-Lucas, Andrés; Perales, José C.; Sierra, Àngels

doi:10.1074/mcp.m112.022772

Cited by 36 publications

(28 citation statements)

References 73 publications

(55 reference statements)

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“…Notably, the expression levels of EMT-associated proteins MMP1, MMP2, MMP9 and vimentin were lower in SKOV3/tax cells than that in SKOV3 cells, suggesting that SKOV3/tax cells exhibited less metastasis than SKOV3 cells. In the present study, ERp57 was highly expressed in less metastatic cells (SKOV3/tax), which was not in agreement with Naiara's observation that overexpression ERp57 was related to bone metastasis in breast cancer cell (53).…”

Section: Discussioncontrasting

confidence: 99%

ERp57‑small interfering RNA silencing can enhance the sensitivity of drug‑resistant human ovarian cancer cells to paclitaxel

Chang

et al. 2018

Int J Oncol

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ERp57 has been identified to be associated with the chemoresistance of human ovarian cancer. However, its biological roles in the chemoresistance phenotype remain unclear. In the present study, the association of ERp57 with paclitaxel-resistant cellular behavior was investigated and the sensitivity enhancement of chemoresistant human ovarian cancer cells to paclitaxel was examined using ERp57-small interfering (si)RNA silencing. Cell viability, cell proliferation, cell apoptosis and cell migration were detected using an MTT assay, clonogenic assay, flow cytometry analysis and transwell assay. Furthermore, mRNA expression levels of ERp57 and protein expression levels of ERp57, STAT3, phosphorylated STAT3, PCNA, nucelolin, TUBB3, P-gp, vimentin, Bcl-2, Bax, Bcl-xl, p53, MMP1, MMP2 and MMP9 of paclitaxel-sensitive human SKOV3 ovarian cancer cells were compared with paclitaxel-resistant counterpart SKOV3/tax using the real-time PCR and western blot analysis. ERp57 was highly expressed in the paclitaxel-resistant SKOV3/tax cells, and experimental results concluded that the paclitaxel-resistance phenotype was due primarily to the activation of the STAT3 signaling pathway. ERp57 overexpression by lentiviral particle infection decreased the sensitivity of SKOV3 cells to paclitaxel. Furthermore, ERp57-siRNA silencing restored paclitaxel sensitivity of SKOV3/tax cells. Notably, the IC 50 value of ERp57-siRNA silenced SKOV3/tax cells was reduced to the original level and colony survival was significantly decreased in comparison with that of SKOV3/tax cells. Additionally, co-treatment of ERp57-siRNA silencing and paclitaxel could inhibit the STAT3 signaling pathway and downregulate the expression levels of downstream proteins. Notably, ERp57-siRNA and 100 nM paclitaxel co-treatment downregulated Bcl-2, Bcl-xl, MMP2, MMP9, TUBB3 and P-gp expression levels and upregulated the expression of Bax protein. Furthermore, co-treatment promoted change of the isoform of p53 to p53/p47. Bioinformatics analyses supported the experimental observations that ERp57 was associated with drug resistance in ovarian cancer. The present study implies that ERp57 is a potential therapeutic target for the treatment of paclitaxel-resistant human ovarian cancer.

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Section: Discussioncontrasting

confidence: 99%

ERp57‑small interfering RNA silencing can enhance the sensitivity of drug‑resistant human ovarian cancer cells to paclitaxel

Chang

et al. 2018

Int J Oncol

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“…Conversely, Pdia3 was highly expressed in cervical cancer patients, and knockdown of Pdia3 led to decreased cell invasiveness both in vivo and in vitro . Furthermore, Pdia3 promotes the development of bone metastasis in breast cancer . In the present study, we found that knockdown of Pdia3 expression inhibited proliferation and migration of mouse keratinocytes.…”

Section: Discussionsupporting

confidence: 55%

miR‐330‐5p inhibits proliferation and migration of keratinocytes by targeting Pdia3 expression

et al. 2015

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The microRNAs (miRNAs) are a class of small non-coding RNA molecules that play important roles in cellular processes by regulating gene expression at the post-transcriptional level. In skin biology, several miRNAs have been shown to be associated with differentiation, migration and apoptosis of keratinocytes, and regulation of the hair cycle. Although the biological role of miR-330-5p has been reported in several cancers and cells, the function and molecular mechanism of miR-330-5p in skin keratinocytes have not been identified. In this study, we found that miR-330-5p inhibited the proliferation and migration of mouse keratinocytes. Among the candidate target genes of miR-330-5p searched using microarray analysis, we found that the expression of Pdia3 was directly regulated by miR-330-5p in the mouse keratinocyte. Moreover, inhibition of Pdia3 expression caused decreased proliferation and migration ability of mouse keratinocytes. Additionally, expressions of miR-330-5p and Pdia3 displayed an inverse correlation with respect to the hair cycle stage. These results indicated that regulation of Pdia3 expression by miR-330-5p is important in maintaining the hair cycle through regulation of the proliferation and migration capability of keratinocytes.

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“…Of related interest, depletion of PDIA3 in MDA-MB-231 breast cancer cells reduced chemoresistance-associated proliferation [ 23 ]. In vitro , differential transcriptome and proteome analyses of the bone metastasis-prone MDA-MB-231-BO2 breast cancer cell line versus parental MDA-MB-231 cells identified PDIA3 as a mediator of bone metastasis-associated proteins [ 24 ]. PDIA3 was also shown to be involved in EGF receptor signalling in MDA-MB-468 breast cancer cells [ 25 ] and to promote growth of SUM159PT mammosphere cultures [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Impairment of cell adhesion and migration by inhibition of protein disulphide isomerases in three breast cancer cell lines

et al. 2020

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Protein disulphide isomerase A3 (PDIA3) is an ER-resident disulphide isomerase and oxidoreductase with known substrates that include some extracellular matrix proteins. PDIA3 is upregulated in invasive breast cancers and correlates in a mouse orthotopic xenograft model with breast cancer metastasis to bone. However, the underlying cellular mechanisms remain unclear. Here we investigated the function of protein disulphide isomerases in attachment, spreading and migration of three human breast cancer lines representative of luminal (MCF-7) or basal (MDA-MB-231 and HCC1937) tumour phenotypes. Pharmacological inhibition by 16F16 in cells decreased initial cell spreading more effectively than inhibition by PACMA-31. Cells displayed diminished cortical F-actin projections, stress fibres and focal adhesions. Cell migration was reduced in a quantified “scratch wound” assay. To examine whether these effects might result from alterations to secreted proteins in the absence of functional PDIA3, adhesion and migration were quantified in the above cells exposed to media conditioned by wild-type or Pdia3-/- mouse embryo fibroblasts. The conditioned medium of Pdia3-/- fibroblasts was less effective in promoting cell spreading and F-actin organisation or supporting “scratch wound” closure. Similarly, extracellular matrix prepared from HCC1937 cells after 16F16 inhibition was less effective than control ECM to support spreading of untreated HCC1937 cells. Overall, these results advance the concept that protein disulphide isomerases including PDIA3 drive the production of secreted proteins that promote a microenvironment favourable to breast cancer cell adhesion and motility, characteristics that are integral to tumour invasion and metastasis. Inhibition of PDIA3 or related isomerases may have potential for anti-metastatic therapies.

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A Transcriptome-proteome Integrated Network Identifies Endoplasmic Reticulum thiol oxidoreductase (ERp57) as a Hub that Mediates Bone Metastasis

Cited by 36 publications

References 73 publications

ERp57‑small interfering RNA silencing can enhance the sensitivity of drug‑resistant human ovarian cancer cells to paclitaxel

ERp57‑small interfering RNA silencing can enhance the sensitivity of drug‑resistant human ovarian cancer cells to paclitaxel

miR‐330‐5p inhibits proliferation and migration of keratinocytes by targeting Pdia3 expression

Impairment of cell adhesion and migration by inhibition of protein disulphide isomerases in three breast cancer cell lines

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