ZnAs@SiO 2  nanoparticles as a potential anti-tumor drug for targeting stemness and epithelial-mesenchymal transition in hepatocellular carcinoma via SHP-1/JAK2/STAT3 signaling

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Abstract

Rationale: Current therapies for hepatocellular carcinoma (HCC) are hampered by treatment failure and recurrence due to the remaining treatment-resistant liver cancer stem cells (CSCs). Stemness and epithelial-mesenchymal transition (EMT) are regarded as two fundamental characteristics of liver CSCs necessary for cancer progression; thus, drugs that simultaneously target both characteristics should prove effective in eliminating HCC and impeding recurrence. In this study, we developed new arsenic trioxide (ATO)-based nanoparticles (NPs), which are expected to be more effective than the current HCC therapy, and explored their potential mechanism.

Methods: A “one-pot” reverse emulsification approach was employed to prepare the ZnAs@SiO ₂ NPs. HCC cell lines, MHCC97L and Hep3b, were used to analyze the antitumor activity of ZnAs@SiO ₂ NPs in vitro and in vivo by quantifying cell growth and metastasis as well as to study the effect on stemness and EMT. SHP-1 siRNA was used to validate the role of the SHP-1/JAK2/STAT3 signaling pathway in mediating inhibition of stemness and EMT by ZnAs@SiO ₂.

Results: Compared with the current ATO treatment, ZnAs@SiO ₂ NPs promoted apoptosis and significantly inhibited proliferation, migration, and invasion of both MHCC97L and Hep3b cells. In the in vivo assay, ZnAs@SiO ₂ NPs inhibited tumor growth by 2.2-fold and metastasis by 3.5-fold as compared to ATO. The ZnAs@SiO ₂ NPs also inhibited tumor spheroid formation in vitro and tumor initiation in vivo and induced significant changes in the expression of stemness markers (CD133, Sox-2, and Oct-4) and EMT markers (E-cadherin, Vimentin, and Slug) both in vitro and in vivo. These effects of ZnAs@SiO ₂ that correlated with prognosis of HCC were mediated by the SHP-1/JAK2/STAT3 signaling.

Conclusions: ZnAs@SiO ₂ NPs can effectively suppress tumor initiation, growth, metastasis, and inhibit stemness and EMT through regulation of SHP-1/JAK2/STAT3 signaling pathway in liver cancer cells in vitro and in vivo. Thus, ZnAs@SiO ₂ NPs have immense potential for HCC treatment in the future.

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Cell plasticity and heterogeneity in cancer.

Nemanja D Marjanovic, Robert Weinberg, Christine L Chaffer (2013)

Heterogeneity within a given cancer arises from diverse cell types recruited to the tumor and from genetic and/or epigenetic differences amongst the cancer cells themselves. These factors conspire to create a disease with various phenotypes. There are 2 established models of cancer development and progression to metastatic disease. These are the clonal evolution and cancer stem cell models. The clonal evolution theory suggests that successive mutations accumulating in a given cell generate clonal outgrowths that thrive in response to microenvironmental selection pressures, dictating the phenotype of the tumor. The alternative cancer stem cell (CSC) model suggests that cancer cells with similar genetic backgrounds can be hierarchically organized according to their tumorigenic potential. Accordingly, CSCs reside at the apex of the hierarchy and are thought to possess the majority of a cancer's tumor-initiating and metastatic ability. A defining feature of this model is its apparent unidirectional nature, whereby CSCs undergo symmetric division to replenish the CSC pool and irreversible asymmetric division to generate daughter cells (non-CSCs) with low tumorigenic potential. However, evolving evidence supports a new model of tumorigenicity, in which considerable plasticity exists between the non-CSC and CSC compartments, such that non-CSCs can reacquire a CSC phenotype. These findings suggest that some tumors may adhere to a plastic CSC model, in which bidirectional conversions are common and essential components of tumorigenicity. Accumulating evidence surrounding the plasticity of cancer cells, in particular, suggests that aggressive CSCs can be created de novo within a tumor. Given the current focus on therapeutic targeting of CSCs, we discuss the implications of non-CSC-to-CSC conversions on the development of future therapies. © 2012 American Association for Clinical Chemistry

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Mechanisms of action of arsenic trioxide.

J Singer, Samuel Waxman, S Lee … (2002)

Arsenic trioxide has shown substantial efficacy in treating both newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL). As a single agent, it induces complete remissions, causing few adverse effects and only minimal myelosuppression. These successes have prompted investigations to elucidate the mechanisms of action underlying these clinical responses. Substantial data show that arsenic trioxide produces remissions in patients with APL at least in part through a mechanism that results in the degradation of the aberrant PML-retinoic acid receptor alpha fusion protein. Studies have also investigated concerns about the toxicity and potential carcinogenicity of long-term exposure to environmental arsenic. Arsenic apparently affects numerous intracellular signal transduction pathways and causes many alterations in cellular function. These actions of arsenic may result in the induction of apoptosis, the inhibition of growth and angiogenesis, and the promotion of differentiation. Such effects have been observed in cultured cell lines and animal models, as well as clinical studies. Because arsenic affects so many cellular and physiological pathways, a wide variety of malignancies, including both hematologic cancer and solid tumors derived from several tissue types, may be susceptible to therapy with arsenic trioxide. These multiple actions of arsenic trioxide also highlight the need for additional mechanistic studies to determine which actions mediate the diverse biological effects of this agent. This information will be critical to realizing the potential for synergy between arsenic trioxide and other chemotherapeutic agents, thus providing enhanced benefit in cancer therapy.

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Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression

Caitlin May, Nathalie Sphyris, Kurt W Evans … (2011)

Aberrant activation of a latent embryonic program - known as the epithelial-mesenchymal transition (EMT) - can endow cancer cells with the migratory and invasive capabilities associated with metastatic competence. The induction of EMT entails the loss of epithelial characteristics and the de novo acquisition of a mesenchymal phenotype. In breast cancer, the EMT state has been associated with cancer stem cell properties including expression of the stem cell-associated CD44+/CD24-/low antigenic profile, self-renewal capabilities and resistance to conventional therapies. Intriguingly, EMT features are also associated with stem cells isolated from the normal mouse mammary gland and human breast reduction tissues as well as the highly aggressive metaplastic and claudin-low breast tumor subtypes. This has implications for the origin of these breast tumors as it remains unclear whether they derive from cells that have undergone EMT or whether they represent an expansion of a pre-existing stem cell population that expresses EMT-associated markers to begin with. In the present review, we consider the current evidence connecting EMT and stem cell attributes and discuss the ramifications of these newly recognized links for our understanding of the emergence of distinct breast cancer subtypes and breast cancer progression.

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Author and article information

Journal

Journal ID (nlm-ta): Theranostics

Journal ID (iso-abbrev): Theranostics

Journal ID (publisher-id): thno

Title: Theranostics

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1838-7640

Publication date Collection: 2019

Publication date (Electronic): 9 June 2019

Volume: 9

Issue: 15

Pages: 4391-4408

Affiliations

[1 ]Department of Ultrasound, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China

[2 ]Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China

[3 ]Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China

[4 ]State Key Laboratory of Physical Chemistry of Solid Surfaces, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory for Chemical Biology of Fujian Province, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian Province 361005, China

Author notes

✉ Corresponding authors: shanhong@ 123456mail.sysu.edu.cn , lidan25@ 123456mail.sysu.edu.cn , pangpf@ 123456mail.sysu.edu.cn

# These authors contributed equally to this article.

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: thnov09p4391

DOI: 10.7150/thno.32462

PMC ID: 6599649

PubMed ID: 31285768

SO-VID: 739947a0-fe1b-4743-8314-70a75d3e509f

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This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

ZnAs@SiO ₂ nanoparticles as a potential anti-tumor drug for targeting stemness and epithelial-mesenchymal transition in hepatocellular carcinoma via SHP-1/JAK2/STAT3 signaling

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Most cited references 31

Cell plasticity and heterogeneity in cancer.

Mechanisms of action of arsenic trioxide.

Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression

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