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Ji J.,Xian Jiaotong University | Zheng P.-S.,Xian Jiaotong University | Zheng P.-S.,Section of Cancer Stem Cell Research
Human Pathology | Year: 2010

Sox2 is a key transcription factor for embryonic development and plays a critical role in determining the fate of stem cells. Recently, Sox2 has been detected in several human tumors, indicating a potential function in tumorigenesis. We initially reported remarkably increased nuclear Sox2 staining in cervical carcinomas compared with normal cervix (P < .05). Furthermore, Sox2 staining was detected in most tumorsphere cells isolated from fresh cervical cancer tissues but not among the differentiated tumorsphere cells. When Sox2 was stably expressed in cervical cancer cells (SiHa and HeLa), Sox2-overexpressing cells had increased proliferation, clonogenicity, and tumorigenicity in vitro and in vivo than control cells. These results suggest that Sox2 may participate in carcinogenesis of cervical carcinomas and may be a potential therapeutic target molecule for cervical cancers. © 2010 Elsevier Inc. All rights reserved. Source


Zhang Y.,Xian Jiaotong University | Li B.,Xian Jiaotong University | Ji Z.-Z.,Xian Jiaotong University | Zheng P.-S.,Xian Jiaotong University | Zheng P.-S.,Section of Cancer Stem Cell Research
Cancer | Year: 2010

BACKGROUND: The aberrant activation of the Notch signaling has been associated with the development of colon cancers. However, the role of Notch1 in the pathogenesis of colon cancers is poorly understood. METHODS: The expression of Notch1 in colon cancer tissues and nontumor tissues and in colon cancer cell lines was examined by Western blot analysis and immunohistochemistry. The impact of small interfering RNA (siRNA)-mediated Notch1 knockdown or Notch1 intracellular domain (NICD)-based transgene-induced Notch1 overexpression on the proliferation, cell cycling, apoptosis, colony formation, and tumorsphere formation in vitro and the development and growth of implanted tumors in vivo was characterized. RESULTS: Notch1 was overexpressed in colon cancer tissues, and the levels of Notch1 expression in different types of colon cancers were associated with the pathologic grade, progression, and metastasis of colon cancers. Furthermore, knockdown of Notch1 significantly inhibited the proliferation, colony formation, and tumorsphere formation of SW480 and HT-29 cells, induced apoptosis and cell cycle arrest at G0/G1 phase, and mitigated the development and growth of implanted colon cancers in vivo. In contrast, Notch1 overexpression promoted the proliferation, colony formation, cell cycling, and tumorsphere formation of colon cancer cells in vitro and the development and growth of implanted colon cancers in vivo, but it inhibited spontaneous apoptosis. CONCLUSIONS: The current results indicated that Notch1 signaling positively regulates the growth of colon cancers. Conceivably, the modulation of Notch1-related signaling may be a promising therapy for human colon cancers. © 2010 American Cancer Society. Source


Liu X.,Xian Jiaotong University | Yang W.-T.,Xian Jiaotong University | Zheng P.-S.,Xian Jiaotong University | Zheng P.-S.,Section of Cancer Stem Cell Research
Oncotarget | Year: 2014

Musashi RNA-binding protein1 (Msi1), a member of the RNA-binding protein family, has been reported to be a diagnostic marker and potential therapeutic target in some cancers, its function in cervical cancer remains unknown. In this study, we found Msi1 was highly expressed in cervical cancer tissues, and over-expressing Msi1 in cervical cancer cells enhanced tumor formation and cell proliferation and accelerated cells into the S phase. Whereas, down-regulating Msi1 by shRNA in cervical cancer cells inhibited tumor formation and cell proliferation and slowed cell into the S phase, suggesting that Msi1 might act as cell cycle regulator. Immunohistochemistry assay showed the negative correlation between Msi1 and p21, p27 and p53, suggesting that Msi1 might regulate these cycle regulators in cervical cancer. Moreover, the expression of the p21, p27 and p53 proteins were down-regulated in Msi1 overexpressing cervical cancer cells and up-regulated in shMsi1 cervical cancer cells. Luciferase assays and RNA-protein binding assays confirmed that Msi1 could bind to the mRNA 3'UTRs of p21, p27 and p53 and suppress the translation of these proteins. Our findings provide new evidence that Msi1 might promote cell proliferation by accelerating the cell cycle by directly targeting p21, p27 and p53. Source


Li B.,Xian Jiaotong University | Wang Z.Y.,Xian Jiaotong University | Zheng P.S.,Xian Jiaotong University | Zheng P.S.,Section of Cancer Stem Cell Research
Free Radical Research | Year: 2014

Stromal interaction molecule (STIM) proteins are parts of elaborate eukaryotic Ca2+ signaling systems and are considered to be important players in regulating neuronal Ca2+ homeostasis under normal ageing and pathological conditions. Here, we investigated the potential role of STIM1 in 6-hydroxydopamine (6-OHDA)-induced toxicity in undifferentiated PC12 cell lines. Cells exposed to 6-OHDA demonstrated alterations in the generation of reactive oxygen species (ROS) in a Ca2+-dependent manner. Downregulation of STIM1 expression by specific small interfering RNA (siRNA) attenuated apoptotic cell death, reduced intracellular ROS production, and partially prevented the impaired endogenous antioxidant enzyme activities after 6-OHDA treatment. Furthermore, STIM1 knockdown significantly attenuated 6-OHDA-induced intracellular Ca2+ overload by inhibiting endogenous store-operated calcium entry (SOCE). The effect of STIM1 siNRA on SOCE was related to orai1 and L-type Ca2+ channels, but not to transient receptor potential canonical type 1 (TRPC1) channel. In addition, silencing of STIM1 increased the Ca2+ buffering capacity of the endoplasmic reticulum (ER) in 6-OHDA-injured cells. ER vacuoles formed from the destruction of ER structural integrity and activation of ER-related apoptotic factors (CHOP and Caspase-12) were partially prevented by STIM1 knockdown. Moreover, STIM1 knockdown attenuated 6-OHDA-induced mitochondrial Ca2+ uptake and mitochondrial dysfunction, including the collapse of mitochondrial membrane potential (MMP) and the decrease of ATP generation. Taken together, our data provide the first evidence that inhibition of STIM1-meditated intracellular Ca2+ dyshomeostasis protects undifferentiated PC12 cells against 6-OHDA toxicity and indicate that STIM1 may be responsible for neuronal oxidative stress induced by ER stress and mitochondrial dysfunction in PD. © 2014 Informa UK, Ltd. Source


Liu S.-Y.,Xian Jiaotong University | Zheng P.-S.,Xian Jiaotong University | Zheng P.-S.,Section of Cancer Stem Cell Research
Oncotarget | Year: 2013

High aldehyde dehydrogenase (ALDH) activity characterizes a subpopulation of cells with cancer stem cell (CSC) properties in several malignancies. To clarify whether ALDH can be used as a marker of cervical cancer stem cells (CCSCs), ALDHhigh and ALDHlow cells were sorted from 4 cervical cancer cell lines and 5 primary tumor xenografts and examined for CSC characteristics. Here, we demonstrate that cervical cancer cells with high ALDH activity fulfill the functional criteria for CSCs: (1) ALDHhigh cells, unlike ALDHlow cells, are highly tumorigenic in vivo; (2) ALDHhigh cells can give rise to both ALDHhigh and ALDHlow cells in vitro and in vivo, thereby establishing a cellular hierarchy; and (3) ALDHhigh cells have enhanced self-renewal and differentiation potentials. Additionally, ALDHhigh cervical cancer cells are more resistant to cisplatin treatment than ALDHlow cells. Finally, expression of the stem cell self-renewal-associated transcription factors OCT4, NANOG, KLF4 and BMI1 is elevated in ALDHhigh cervical cancer cells. Taken together, our data indicated that high ALDH activity may represent both a functional marker for CCSCs and a target for novel cervical cancer therapies. Source

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