Mucin1 promotes the migration and invasion of hepatocellular carcinoma cells via JNK-mediated phosphorylation of Smad2 at the C-terminal and linker regions

Wang, Juan; Liu, Guomu; Li, Qiongshu; Wang, Fang; Xie, Fei; Zhai, Rui; Guo, Yingying; Chen, Tanxiu; Zhang, Nannan; Ni, Weihua; Yuan, Hongyan; Tai, Guihua

doi:10.18632/oncotarget.4267

Cited by 41 publications

(43 citation statements)

References 46 publications

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“…Studies have highlighted the increased expression of MUC1 and its role in tumorigenesis in various cancer types including prostate cancer274546. Our results illustrated both transcriptional and translational regulations of MUC1 by solamargine, and demonstrated a critical role of MUC1 expression in mediating the effect of solamargine on inhibition of growth of CRPC cell.…”

Section: Discussionsupporting

confidence: 62%

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

Xiang

Zhang

Tang

et al. 2016

Sci Rep

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Prostate cancer is the second most common cause of cancer-related deaths worldwide. The mucin 1 (MUC1) oncoprotein is highly expressed in human prostate cancers with aggressive features. However, the role for MUC1 in occurrence and progression of castration-resistant prostate cancer (CRPC) remained elusive. In this study, we showed that solamargine, a major steroidal alkaloid glycoside, inhibited the growth of CRPC cells, which was enhanced in the presence of metformin. Furthermore, we found that solamargine increased phosphorylation of AMPKα, whereas reducing the protein expression and promoter activity of MUC1. A greater effect was observed in the presence of metformin. In addition, solamargine reduced NF-κB subunit p65 protein expression. Exogenously expressed p65 resisted solamargine-reduced MUC1 protein and promoter activity. Interestingly, exogenously expressed MUC1 attenuated solamargine-stimulated phosphorylation of AMPKα and, more importantly reversed solamargine-inhibited cell growth. Finally, solamargine increased phosphorylation of AMPKα, while inhibiting MUC1, p65 and tumor growth were observed in vivo. Overall, our results show that solamargine inhibits the growth of CRPC cells through AMPKα-mediated inhibition of p65, followed by reduction of MUC1 expression in vitro and in vivo. More importantly, metformin facilitates the antitumor effect of solamargine on CRPC cells.

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Section: Discussionsupporting

confidence: 62%

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

Xiang

Zhang

Tang

et al. 2016

Sci Rep

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“…These results are consistent with reported JNK regulation by MUC1 signaling. 60,61 The results demonstrate that MUC1 signaling effects c-Jun activation as well as expression.…”

Section: Discussionmentioning

confidence: 79%

MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs

et al. 2017

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The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in acute myeloid leukemia (AML), but little is known about its regulation. We investigated the role of the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post-transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA-processing. MUC1 signaling decreased the expression of the microRNA-processing protein DICER, via the suppression of c-Jun activity. NanoString (Seattle, WA, USA) array of MUC1-silenced AML cells demonstrated an increase in the majority of probed microRNAs. In an immunocompetent murine AML model, targeting of MUC1 led to a significant increase in leukemia-specific T cells. In concert, targeting MUC1 signaling in human AML cells resulted in enhanced sensitivity to T-cell-mediated lysis. These findings suggest MUC1 is a critical regulator of PD-L1 expression via its effects on microRNA levels and represents a potential therapeutic target to enhance anti-tumor immunity.

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“…Molecular profiling of HCC permits the progress of novel approaches to disease diagnosis, prognosis prediction, and treatment management as a paradigm of stratified medicine adapted to tumor biology through integration of clinical staging systems and molecular-based information to support clinical decision making. For up-to-date and comprehensive description of the molecular mechanisms involved in hepatocellular carcinogenesis, refer to some recent articles [44][45][46][47][48][49][50][51][52].…”

Section: The Genomic Landscape Of Hepatocarcinogenesismentioning

confidence: 99%

Management strategies for hepatocellular carcinoma: old certainties and new realities

et al. 2015

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Hepatocellular carcinoma (HCC) is a highly prevalent disease ranking among the ten most common cancers worldwide with increasing trend of incidence in most developed countries. The great healthcare costs and economic burden of HCC dictate proper preventive interventions as well as surveillance and screening programs to decrease disease incidence and allow early diagnosis. HCC treatment outcomes are affected by several variables, including liver function, patient's performance status, and tumor stage. In line with the Barcelona Clinic Liver Cancer (BCLC) staging curative treatments, such as surgery or radio-frequency ablation, are indicated in early-stage HCC (BCLC-A), and the noncurative treatments are indicated in intermediate and advanced stages of HCC (BCLC-B, C). Transarterial chemoembolization (TACE) represents the treatment of choice for intermediate-stage HCC with Child-Pugh A cirrhosis, and the long-term survival after liver transplantation is inferior to that of early-stage HCCs. In advanced-stage HCC or when complete necrosis is not achieved or early recurrence after TACE develops, individualized treatments such as systemic treatment or combined radiation therapy are indicated. The increasing knowledge of the genomic landscape of HCC and the development of molecular-targeted therapies is heading toward expanding the armamentarium for HCC management.

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Mucin1 promotes the migration and invasion of hepatocellular carcinoma cells via JNK-mediated phosphorylation of Smad2 at the C-terminal and linker regions

Cited by 41 publications

References 46 publications

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs

Management strategies for hepatocellular carcinoma: old certainties and new realities

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