MicroRNA‐373, a new regulator of protein phosphatase 6, functions as an oncogene in hepatocellular carcinoma

Wu, Nannan; Liu, Xuyuan; Xu, Xuemei; Fan, Xing‐Xing; Liu, Min; Li, Xin; Qi-ping, Zhong; Tang, Hua

doi:10.1111/j.1742-4658.2011.08120.x

Cited by 65 publications

(51 citation statements)

References 35 publications

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“…In human cancer cells, PP6 is reported as being involved in G1-to-S transition [6]. More recently, it was demonstrated that PP6-C is a target of microRNA-373, which is overexpressed in HCC [7], and that microRNA-373 has oncogenic activity dependent on regulation of PP6-C. These observations were consistent with the designation of PP6 as a tumor suppressor.…”

Section: Discussionsupporting

confidence: 69%

“…Studies in Saccharomyces cerevisiae have implicated Sit4 and its regulatory subunits SAP155, SAP185, SAP190, and SAP4 in G1 to S progression [5]. PP6 has been shown to function similarly in human cancer cells [6, 7]. Other studies in yeast have shown that PP6 contributes to the response to mitochondrial DNA damage [8].…”

Section: Introductionmentioning

confidence: 99%

“…More recent studies suggest a broader role for PP6 in endoplasmic reticulum-to-Golgi trafficking [19], pre-mRNA splicing [20], formation of adherens junctions through interaction with E-cadherin [21], control of apoptosis in immune cells [22], response to mitochondrial DNA damage [8], and modulation of signaling through the Hippo pathway [23]. With regard to its role in liver cells, PP6 has been identified as a tumor suppressor based on its ability to induce G1/S cell cycle arrest in two human hepatocellular carcinoma (HCC) cell lines [7]. Additional data on a hepatic role for PP6 are lacking.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Adaptation of HepG2 cells to a steady-state reduction in the content of protein phosphatase 6 (PP6) catalytic subunit

Boylan

Salomon

Tantravahi

et al. 2015

Experimental Cell Research

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Protein phosphatase 6 (PP6) is a ubiquitous Ser/Thr phosphatase involved in an array of cellular processes. To assess the potential of PP6 as a therapeutic target in liver disorders, we attenuated expression of the PP6 catalytic subunit in HepG2 cells using lentiviral-transduced shRNA. Two PP6 knock-down (PP6KD) cell lines (90% reduction of PP6-C protein content) were studied in depth. Both proliferated at a rate similar to control cells. However, flow cytometry indicated G2/M cell cycle arrest that was accounted for by a shift of the cells from a diploid to tetraploid state. PP6KD cells did not show an increase in apoptosis, nor did they exhibit reduced viability in the presence of bleomycin or taxol. Gene expression analysis by microarray showed attenuated anti-inflammatory signaling. Genes associated with DNA replication were downregulated. Mass spectrometry-based phosphoproteomic analysis yielded 80 phosphopeptides representing 56 proteins that were significantly affected by a stable reduction in PP6-C. Proteins involved in DNA replication, DNA damage repair and pre-mRNA splicing were overrepresented among these. PP6KD cells showed intact mTOR signaling. Our studies demonstrated involvement of PP6 in a diverse set of biological pathways and an adaptive response that may limit the effectiveness of targeting PP6 in liver disorders.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Adaptation of HepG2 cells to a steady-state reduction in the content of protein phosphatase 6 (PP6) catalytic subunit

Boylan

Salomon

Tantravahi

et al. 2015

Experimental Cell Research

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“…However, recently they have been associated also with cancer. In particular, the miR-520/373 family seems to have a dual role in tumor progression, depending on the cancer type and context: miR-373 has been described to function as an oncogene in testicular germ tumors (Voorhoeve et al, 2006), esophageal cancer (Lee et al, 2009) and hepatocellular carcinoma (Wu et al, 2011), while in cholangiocarcinoma this miRNA has been shown to act as tumor suppressor (Chen et al, 2010). Huang et al (2008) identified miR-373 and miR-520c as promoters of breast cancer metastasis by suppressing the expression of CD44.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways

et al. 2011

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MicroRNAs (miRNAs) as modulators of gene expression have been described to display both tumor-promoting and tumor-suppressive functions. Although their role has been studied in different tumor types, little is known about how they regulate nuclear factor jB (NF-jB) signaling in breast cancer. Here, we performed an unbiased whole genome miRNA (miRome) screen to identify novel modulators of NF-jB pathway in breast cancer. The screen identified 13 miRNA families whose members induced consistent effects on NF-jB activity. Among those, the miR-520/373 family inhibited NF-jB signaling through direct targeting of RELA and thus strongly reduced expression and secretion of the pro-inflammatory cytokines interleukin (IL)-6 and IL-8. With a combination of in vitro and in vivo approaches, we propose a metastasis-suppressive role of miR-520/373 family. miR520c and miR-373 abrogated both in vitro cell invasion and in vivo intravasation of highly invasive MDA-MB-231 cells. However, knockdown of RELA did not affect their metastatic ability. mRNA profiling of MDA-MB-231 cells on overexpression of miR-520/373 members revealed a strong downregulation of transforming growth factor-b (TGF-b) signaling. Mechanistically, the metastasis-suppressive role of miR-520/373 can be attributed to direct suppression of TGFBR2, as the silencing of TGFBR2 phenocopied the effects of miR-520/373 overexpression on suppression of Smad-dependent expression of the metastasis-promoting genes parathyroid hormone-related protein, plasminogen activator inhibitor-1 and angiopoietin-like 4 as well as tumor cell invasion, in vitro and in vivo. A negative correlation between miR-520c and TGFBR2 expression was observed in estrogen receptor negative (ER À ) breast cancer patients but not in the ER positive (ER þ ) subtype. Remarkably, decreased expression of miR-520c correlated with lymph node metastasis specifically in ER À tumors. Taken together, our findings reveal that miR-520/373 family has a tumor-suppressive role in ER À breast cancer by acting as a link between the NF-jB and TGF-b pathways and may thus contribute to the interplay of tumor progression, metastasis and inflammation.

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“…miR-373 has been shown to regulate cell cycle progression by targeting PPP6C transcripts in vitro. The expression of miR-373 may also promote HCC cell proliferation (32).…”

Section: Discussionmentioning

confidence: 99%

Regression of A549 lung cancer tumors by anti-miR-150 vector

Lv¹

2011

Oncol Rep

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Abstract. microRNAs (miRNAs) have been shown to play a role in cancer. Antisense oligonucleotides can bind directly to miRNAs and block their activity, which are generally named anti-miRNAs. To suppress A549 cell proliferation in vitro and in vivo by anti-miRNAs, an anti-miR-150 expression vector (PR-ASO-150), regulated by the H1 promoter and containing a 'TTTTT' sequence following a hairpin to stop transcription, was constructed. A549 cell proliferation in vitro or in nude mice was observed after PR-ASO-150 treatment. Our results showed that miR-150 expression was inhibited and the growth inhibition rate of A549 cells was higher in the PR-ASO-150-treated group compared with the control, which indicated that PR-ASO-150 could inhibit A549 cell proliferation by regulating miR-150 expression. Following establishment of A549 cancer cell xenografts in nude mice, PR-ASO-150 was delivered intratumorally to investigate the suppressive action to tumor proliferation by regulating miR-150 expression. The results indicate that the tumor volume and weight were lower compared to the control group. Our results further showed that p53 expression was higher after tumor tissue was treated with PR-ASO-150, indicating that up-regulation of p53 contributed to the suppression to tumor growth. Our study provides a novel strategy for cancer therapy through the development of antimiRNAs.Introduction microRNAs (miRNAs) are small non-coding RNA molecules (19-22 nucleotides) that bind to mRNA in a sequence-specific manner (1). Through complementary binding to mRNA targets, each microRNA has the distinct capability to potentially regulate the expression of hundreds of genes and thereby modulates several cellular pathways including proliferation and apoptosis (2).Importantly, miRNAs play critical roles in the development and progression of several types of cancers (3,4). Dependent upon the nature of their target gene(s), miRNAs may function as tumor suppressors by down-regulating target oncogenes (e.g. let-7 and miR-15/16) or as oncogenes by negatively controlling genes that regulate tumor cell differentiation and apoptosis (e.g. miR-155 and miR-21) (5). Indeed, several miRNAs are reported to have important roles in different types of cancer, including acute myelogenous leukemia (6,7), chronic myelogenous leukemia (CML) (8-10), lung cancer (11,12), and breast cancer (13), among others. miRNAs have also been shown to play a role in cancer progression through the modulation of cellular adhesion, cell matrix and signaling activities (14,15). In addition, miRNAs have been shown to regulate the expression of hypoxia-related genes and of the vascular endothelial growth factor (16,17).Emerging evidence shows that deregulation of miRNAs may be a primary driver of cancer initiation and progression. The rules of Watson and Crick base-pairing guide the binding of miRNAs to their target genes. In order to circumvent this interaction, anti-microRNA oligonucleotides (AMOs) have been generated to directly compete with endogenous miRNAs (18). Several modifi...

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MicroRNA‐373, a new regulator of protein phosphatase 6, functions as an oncogene in hepatocellular carcinoma

Cited by 65 publications

References 35 publications

Adaptation of HepG2 cells to a steady-state reduction in the content of protein phosphatase 6 (PP6) catalytic subunit

Adaptation of HepG2 cells to a steady-state reduction in the content of protein phosphatase 6 (PP6) catalytic subunit

MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways

Regression of A549 lung cancer tumors by anti-miR-150 vector

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