Silencing PRDM14 expression by an innovative RNAi therapy inhibits stemness, tumorigenicity, and metastasis of breast cancer

Taniguchi, Hiroaki; Hoshino, Daisuke; Moriya, Chiharu; Zembutsu, Hitoshi; Nishiyama, Nobuhiro; Yamamoto, Hiroyuki; Kataoka, Kazunori; Imai, Kohzoh

doi:10.18632/oncotarget.16776

Cited by 27 publications

(46 citation statements)

References 58 publications

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“…Subsequently, shRNA‐transduced HCC1937 cells were treated with the inhibitors. The number of CD24 − CD44 + cells in shPRDM14 was significantly reduced as compared with that in sh control cells ( P < .001) (Figure E), as previously reported . The inhibitors did not significantly change cell population in shPRDM14 cells (Figure E).…”

Section: Resultssupporting

confidence: 86%

“…The cells were cultured in DMEM (Thermo Fisher Scientific, San Jose, CA, USA) containing 10% FBS (GE Healthcare, Uppsala, Sweden). Two TNBC cell lines, HCC1937 and MDA‐MB231 cells, were obtained and cultured as described previously . All cell lines were incubated at 37°C in a humidified atmosphere containing 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…The plasmid vectors used were HaloTag fusion human PRDM14 (Halo‐PRDM14; EX‐W1089‐Lv110; GeneCopoeia), and HaloTag fusion EGFP (Halo‐con; EX‐EGFP‐Lv110; GeneCopoeia). HCC1937 and MDA‐MB231 cells were transduced using the Lenti‐pack HIV Expression Packaging Kit (GeneCopoeia) . shRNA‐transduced HCC1937 cells (control shRNA and two anti‐human PRDM14 shRNAs [sh#1 and sh#3]) were prepared as previously described …”

Section: Methodsmentioning

confidence: 99%

“…PRDM14 overexpression in several cancers has been shown to be related to cancer properties such as proliferation, drug resistance, and differentiation . We have previously reported that knockdown of PRDM14 expression decreased cancer stem‐like phenotypes, which are considered responsible for cancer initiation and progression in breast and pancreatic cancer cells . Because siRNA‐based therapy targeting PRDM14 by tail vein injection decreased xenograft tumor and metastasis in mice, PRDM14 is considered a promising target for the treatment of these cancers.…”

Section: Introductionmentioning

confidence: 99%

“…However, TNBC, which lack all three types of receptor, are often more aggressive with poor prognosis and are more difficult to treat. We have reported that inhibition of PRDM14 decreased s.c. xenografted tumor growth and metastasis of TNBC cell lines, suggesting that PRDM14 is a good target for treating TNBC in patients . Elucidation of the binding partners of PRDM14 will help elucidate the mechanism whereby PRDM14 regulates cancer phenotypes, which could contribute to the development of a less costly treatment for patients with these cancers.…”

Section: Introductionmentioning

confidence: 99%

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PRDM14 directly interacts with heat shock proteins HSP90α and glucose‐regulated protein 78

et al. 2017

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PRDM14 is overexpressed in various cancers and can regulate cancer phenotype under certain conditions. Inhibiting PRDM14 expression in breast and pancreatic cancers has been reported to reduce cancer stem‐like phenotypes, which are associated with aggressive tumor properties. Therefore, PRDM14 is considered a promising target for cancer therapy. To develop a pharmaceutical treatment, the mechanism and interacting partners of PRDM14 need to be clarified. Here, we identified the proteins interacting with PRDM14 in triple‐negative breast cancer (TNBC) cells, which do not express the three most common types of receptor (estrogen receptors, progesterone receptors, and HER2). We obtained 13 candidates that were pulled down with PRDM14 in TNBC HCC1937 cells and identified them by mass spectrometry. Two candidates—glucose‐regulated protein 78 (GRP78) and heat shock protein 90‐α (HSP90α)—were confirmed in immunoprecipitation assay in two TNBC cell lines (HCC1937 and MDA‐MB231). Surface plasmon resonance analysis using GST‐PRDM14 showed that these two proteins directly interacted with PRDM14 and that the interactions required the C‐terminal region of PRDM14, which includes zinc finger motifs. We also confirmed the interactions in living cells by NanoLuc luciferase‐based bioluminescence resonance energy transfer (NanoBRET) assay. Moreover, HSP90 inhibitors (17DMAG and HSP990) significantly decreased breast cancer stem‐like CD24− CD44+ and side population (SP) cells in HCC1937 cells, but not in PRDM14 knockdown HCC1937 cells. The combination of the GRP78 inhibitor HA15 and PRDM14 knockdown significantly decreased cell proliferation and SP cell number in HCC1937 cells. These results suggest that HSP90α and GRP78 interact with PRDM14 and participate in cancer regulation.

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Section: Resultssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PRDM14 directly interacts with heat shock proteins HSP90α and glucose‐regulated protein 78

et al. 2017

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PRDM14 is overexpressed in chronic pancreatitis prior to pancreatic cancer

2018

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Pancreatic ductal adenocarcinoma ( PDAC ) is an aggressive and lethal cancer that is typically diagnosed at a later stage with metastases and is difficult to treat. Therefore, investigating the mechanism of PDAC initiation is important to aid early‐stage cancer detection. PRDM 14 is a transcription factor that maintains pluripotency in embryonic stem cells and is overexpressed in several cancers. We previously reported that PRDM 14 is overexpressed and regulates cancer stem‐like phenotypes in PDAC , and herein, we assess whether PRDM 14 expression increases prior to tumorigenesis. Through immunohistochemistry analyses of clinical tissues, we detected PRDM 14‐positive cells in precursor pancreatic intraepithelial neoplasia and chronic pancreatitis, which is a risk factor for PDAC , lesions. PRDM 14 staining in chronic pancreatitis was as high as that in PDAC and cancer adjacent tissues. We induced pancreatitis in mouse models by cerulein injection, and observed that PRDM 14 expression increased in chronic pancreatitis models but not in control or acute pancreatitis mice. Moreover, cerulein treatment increased PRDM 14 expression in PK ‐1 and As PC ‐1 pancreatic cancer cell lines. Our results suggest that inflammation increases the expression of PRDM 14, which regulates cancer stem‐like phenotypes, and this occurs prior to PDAC initiation and progression.

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Treatment of primary and metastatic breast and pancreatic tumors upon intravenous delivery of a PRDM14‐specific chimeric siRNA/nanocarrier complex

Taniguchi

Natori

Miyagi

et al. 2021

Intl Journal of Cancer

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PRDM14 is highly expressed in several cancers but is not detected in normal tissues.It confers cancer stem cell-like properties, including chemoresistance and distant metastasis, to cancer cells. Herein, we aimed to develop a highly effective therapy against advanced stage cancer based on intravenously delivered PRDM14-targeted siRNA. First, we examined PRDM14 expression and gene amplification in breast and pancreatic tumors and cell lines. PRDM14 was expressed in breast cancer, including the triple-negative subtype, and pancreatic cancer. PRDM14 was amplified in 23.8% of patients with PRDM14 + breast cancer. Next, we investigated the inoculated tumor growth and distant metastasis following PRDM14 depletion by administering mice with PRDM14-specific chimeric siRNA combined with a novel branched PEGylated poly-L-ornithine (PLO)-based intravenous drug delivery system, designated PRDM14 unit polyion complex (uPIC) (n = 6/group). Inhibition of PRDM14 expression with PRDM14 uPIC by systemic intravenous injection effectively reduced tumor size and metastasis in vivo, thereby improving survival. Finally, pharmacokinetic/toxicokinetic analyses were performed on PRDM14 uPIC, which was intravenously administered to rats (n = 10-15/group) and cynomolgus monkeys (n = 3-5/group), twice weekly for 4 weeks. This revealed that PRDM14 uPIC was relatively nontoxic and the siRNA exposure in serum was greater than that predicted by the administered dose ratio when delivered as a uPIC. Taken together, our study indicated that PRDM14 uPIC

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Silencing PRDM14 expression by an innovative RNAi therapy inhibits stemness, tumorigenicity, and metastasis of breast cancer

Cited by 27 publications

References 58 publications

PRDM14 directly interacts with heat shock proteins HSP90α and glucose‐regulated protein 78

PRDM14 directly interacts with heat shock proteins HSP90α and glucose‐regulated protein 78

PRDM14 is overexpressed in chronic pancreatitis prior to pancreatic cancer

Treatment of primary and metastatic breast and pancreatic tumors upon intravenous delivery of a PRDM14‐specific chimeric siRNA/nanocarrier complex

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