Expression and role of nestin in human cervical intraepithelial neoplasia and cervical cancer

Sato, Atsuki; Ishiwata, Toshiyuki; Matsuda, Yoko; Yamamoto, Tetsushi; Asakura, Hirobumi; Takeshita, Toshiyuki; Naito, Zenya

doi:10.3892/ijo.2012.1473

Cited by 23 publications

(19 citation statements)

References 47 publications

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“…Inhibition of nestin in pancreatic cancer cells does not alter cell differentiation [17]. We reported previously that shRNA that targets nestin suppresses sphere formation by melanoma cells [32], while overexpression of nestin induces increased sphere formation by cervical cancer cells [70]. We observed the same results using pancreatic cancer cell lines, but there have been no reports describing correlations between nestin expression levels and the tumor formation ratio using the dilution method in immunodeficient animals.…”

Section: Nestin In Pancreatic Cancer Stemnesssupporting

confidence: 65%

The Roles and Molecular Mechanisms of Nestin Expression in Cancer with a Focus on Pancreatic Cancer

Matsuda¹,

Yoshimura²,

Naito³

et al. 2013

J Carcinogene Mutagene

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Nestin is a class VI intermediate filament protein that is expressed in a variety of stem and progenitor cells, including primitive neuroepithelial cells and pancreatic exocrine progenitor cells. Nestin expression is closely associated with rapidly proliferating progenitor cells during development and repair processes, and higher nestin expression levels correlate with poor prognosis in some cancers. Nestin regulates many molecules during cell processes in both normal and neoplastic tissues, and its transcription is regulated by enhancer regions in the second intron of the nestin gene that bind to SOX, Class III POU, and N-Myc. Nestin forms heterodimers with other intermediate filaments, with the class III intermediate filament protein vimentin being its main partner. Nestin/ vimentin copolymers provide an anchor for glucocorticoid receptors, regulate insulin-degrading enzyme, and promote the phosphorylation-dependent disassembly of vimentin during mitosis. Nestin regulates cell proliferation, the cell cycle, cell survival, and apoptosis by regulating cyclin-dependent kinase-5 (Cdk5), phosphoinositide 3-kinase, and AKT. We reported previously that nestin regulates cell motility, invasiveness, and cell morphology in a pancreatic cancer cell line via regulation of F-actin and E-cadherin. This review focuses on the roles of nestin in cancer stem cells and in tumor-initiating cells in the pancreas. In the pancreas, nestin plays important roles in the proliferation, differentiation, and survival of both progenitor cells and cancer cells.

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Section: Nestin In Pancreatic Cancer Stemnesssupporting

confidence: 65%

The Roles and Molecular Mechanisms of Nestin Expression in Cancer with a Focus on Pancreatic Cancer

Matsuda¹,

Yoshimura²,

Naito³

et al. 2013

J Carcinogene Mutagene

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“…We herein isolated sphere-forming cells derived from the cervical cancer cell line, SiHa (HPV16-positive squamous cell carcinoma), according to the standard protocol for sphere formation using a low-attachment plate and serum-free media [23]. A representative microscopic picture showed that several sphere-forming, but not monolayer cells were observed on the low-attachment plate (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of endoplasmic reticulum (ER) stress sensors sensitizes cancer stem-like cells to ER stress-mediated apoptosis

et al. 2016

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Although cancer stem cells (CSC) have been implicated in the development of resistance to anti-cancer therapy including chemotherapy, the mechanisms underlying chemo-resistance by CSC have not yet been elucidated. We herein isolated sphere-forming (cancer stem-like) cells from the cervical cancer cell line, SiHa, and examined the unfolded protein reaction (UPR) to chemotherapeutic-induced endoplasmic reticulum (ER) stress. We revealed that tunicamycin-induced ER stress-mediated apoptosis occurred in monolayer, but not sphere-forming cells. Biochemical assays demonstrated that sphere-forming cells were shifted to pro-survival signaling through the inactivation of IRE1 (XBP-1 splicing) and activation of PERK (elF2α phosphorylation) branches under tunicamycin-induced ER stress conditions. The proportion of apoptotic cells among sphere-forming cells was markedly increased by the tunicamycin+PERK inhibitor (PERKi) treatment, indicating that PERKi sensitized sphere-forming cells to tunicamycin-induced apoptosis. Cisplatin is also known to induce ER stress-mediated apoptosis. A low concentration of cisplatin failed to shift sphere-forming cells to apoptosis, although IRE1 branch, but not PERK, was activated. ER stress-mediated apoptosis occurred in sphere-forming cells by the cisplatin+IRE1α inhibitor (IRE1i) treatment. IRE1i, synergistic with cisplatin, up-regulated elF2α phosphorylation, and this was followed by the induction of CHOP in sphere-forming cells. The results of the present study demonstrated that the inhibition of ER stress sensors, combined with ER stress-inducible chemotherapy, shifted cancer stem-like cells to ER stress-mediated apoptosis.

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“…In addition, recent research has characterized nestin as a cancer stem cell marker in various cancers; these include brain tumors, ovarian, head and neck, prostate, and pancreatic cancers (26)(27)(28)(29)(30). Nestin has also been implicated in pancreas development and pancreatic cancer progression (30).…”

Section: Introductionmentioning

confidence: 99%

Stem Cell Marker Nestin Is Critical for TGF-β1-Mediated Tumor Progression in Pancreatic Cancer

Weng

Hsiao

et al. 2013

Molecular Cancer Research

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The stem cell marker nestin is an intermediate filament protein that plays an important role in cell integrity, migration, and differentiation. Nestin expression occurs in approximately one third of pancreatic ductal adenocarcinoma (PDAC), and its expression strongly correlates with tumor staging and metastasis. Little is known about the mechanisms by which nestin influences PDAC progression. Here, nestin overexpression in PDAC cells increased cell motility and drove phenotypic changes associated with the epithelial-mesenchymal transition (EMT) in vitro; conversely, knockdown of endogenous nestin expression reduced the migration rate and reverted cells to a more epithelial phenotype. Mouse xenograft studies showed that knockdown of nestin significantly reduced tumor incidence and volume. Nestin protein expression was associated with Smad4 status in PDAC cells; hence, nestin expression might be regulated by the TGF-b1/Smad4 pathway in PDAC. We examined nestin expression after TGF-b1 treatment in human pancreatic cancer PANC-1 and PANC-1 shSmad4 cells. The TGF-b1/Smad4 pathway induced nestin protein expression in PDAC cells in a Smad4-dependent manner. Moreover, increased nestin expression caused a positive feedback regulator of the TGF-b1 signaling system. In addition, hypoxia was shown to induce nestin expression in PDAC cells, and the hypoxiainduced expression of nestin is mediated by the TGF-b1/Smad4 pathway. Finally, the antimicrotubule inhibitors, cytochalasin D and withaferin A, exhibited anti-nestin activity; these inhibitors might be potential antimetastatic drugs. Our findings uncovered a novel role of nestin in regulating TGF-b1-induced EMT. Antinestin therapeutics may serve as a potential treatment for PDAC metastasis. Mol Cancer Res; 11(7); 768-79. Ó2013 AACR. IntroductionThe incidence of pancreatic ductal adenocarcinoma (PDAC) is rising to the fifth leading cause of cancerrelated mortality. The condition is associated with the poorest prognosis among all gastrointestinal cancers, with a 5-year survival rate less than 4% (1, 2). A main reason for this extremely poor prognosis is the cancer's tendency to invade adjacent tissues and metastasize to regional lymph at a relatively early stage. Patients with PDAC frequently

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Expression and role of nestin in human cervical intraepithelial neoplasia and cervical cancer

Cited by 23 publications

References 47 publications

The Roles and Molecular Mechanisms of Nestin Expression in Cancer with a Focus on Pancreatic Cancer

The Roles and Molecular Mechanisms of Nestin Expression in Cancer with a Focus on Pancreatic Cancer

Inhibition of endoplasmic reticulum (ER) stress sensors sensitizes cancer stem-like cells to ER stress-mediated apoptosis

Stem Cell Marker Nestin Is Critical for TGF-β1-Mediated Tumor Progression in Pancreatic Cancer

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