A Gene Expression Signature of Epithelial Tubulogenesis and a Role for ASPM in Pancreatic Tumor Progression

Wang, Wei–Yu; Hsu, Chung–Chi; Wang, Ting–Yun; Li, Chi–Rong; Hou, Ya–Chin; Chu, Jui–Mei; Lee, Chung–Ta; Liu, Ming–Sheng; Su, Jimmy; Jian, Kuan–Ying; Huang, Shu-Ching; Jiang, Shih–Sheng; Shan, Yan–Shen; Lin, Pin–Wen; Shen, Yin–Ying; Lee, Michael T.–L.; Chan, Tze–Sian; Chang, Chi-Jen; Chen, Chung–Hsing; Chang, I–Shou; Lee, Yen–Ling; Chen, Li Tzong; Tsai, Kelvin K.

doi:10.1053/j.gastro.2013.07.040

Cited by 85 publications

(104 citation statements)

References 30 publications

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“…Among the possible E2F1 target genes (Figure C), Aspm seemed particularly interesting to investigate further, as it is associated with stem cells in other tissues and is a suggested target gene for c‐MYC and KLF4 . In addition, E2F1 and ASPM share a functional association with cell cycle regulation .…”

Section: Resultsmentioning

confidence: 99%

Genome‐wide analysis of the oxyntic proliferative isthmus zone reveals ASPM as a possible gastric stem/progenitor cell marker over‐expressed in cancer

Vange

Bruland

Beisvåg

et al. 2015

The Journal of Pathology

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The oxyntic proliferative isthmus zone contains the main stem/progenitor cells that provide for physiological renewal of the distinct mature cell lineages in the oxyntic epithelium of the stomach. These cells are also proposed to be the potential cells‐of‐origin of gastric cancer, although little is known about their molecular characteristics and specific biological markers are lacking. In this study, we developed a method for serial section‐navigated laser microdissection to isolate cells from the proliferative isthmus zone of rat gastric oxyntic mucosa for genome‐wide microarray gene expression analysis. Enrichment analysis showed a distinct gene expression profile for the isthmus zone, with genes regulating intracellular processes such as the cell cycle and ribosomal activity. The profile was also related to stem cell transcriptional networks and stomach neoplasia. Genes expressed uniquely in the isthmus zone were associated with E2F transcription factor 1 (E2F1), which participates in the self‐renewal of stem cells and in gastric carcinogenesis. One of the unique genes was Aspm [Asp (abnormal spindle) homologue, microcephaly‐associated (Drosophila)]. Here we show ASPM in single scattered epithelial cells located in the proliferative isthmus zone of rat, mouse and human oxyntic mucosa, which do not seem to be actively dividing. The ASPM‐expressing cells are mainly mature cell marker‐deficient, except for a limited overlap with cells with neuroendocrine and tuft cell features. Further, both ASPM and E2F1 were expressed in human gastric cancer cell lines and increased and correlated in human gastric adenocarcinomas compared to non‐tumour mucosa, as shown by expression profile analyses and immunohistochemistry. The association between ASPM and the transcription factor E2F1 in gastric tissue is relevant, due to their common involvement in crucial cell fate‐regulatory mechanisms. Our results thus introduce ASPM as a novel possible oxyntic stem/progenitor cell marker that may be involved in both normal gastric physiology and gastric carcinogenesis. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Resultsmentioning

confidence: 99%

Genome‐wide analysis of the oxyntic proliferative isthmus zone reveals ASPM as a possible gastric stem/progenitor cell marker over‐expressed in cancer

Vange

Bruland

Beisvåg

et al. 2015

The Journal of Pathology

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“…Human pancreatic duct epithelial (HPDE) cells were obtained from Dr. Y.S. Shan (Institute of Clinical Medicine and Department of Surgery, College of Medicine, National Cheng Kung University, Tainan, Taiwan) [25]. Details of cell culture are described in Supplementary Appendix S1: Materials and Methods.…”

Section: Cell Culturementioning

confidence: 99%

Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6

Chiu

Lin

et al. 2015

Cancer Letters

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“…Mutations in human ASPM occur in familial microcephaly (Bond et al, 2002(Bond et al, , 2003Woods et al, 2005), and studies in model organisms have shown that ASPM is expressed by neural stem cells and promotes brain growth (Bond et al, 2002;Pulvers et al, 2010;Marinaro et al, 2011;Rujano et al, 2013). ASPM has also been implicated in the growth of diverse cancers, including medulloblastomas (VulcaniFreitas et al, 2011), gliomas (Horvath et al, 2006;Bikeye et al, 2010), hepatocellular carcinomas (Lin et al, 2008), ovarian cancers (Brüning-Richardson et al, 2011) and pancreatic cancers (Wang et al, 2013). Thus, loss of Aspm function is associated with growth failure, and aberrant ASPM is associated with excessive growth.…”

Section: Introductionmentioning

confidence: 99%

Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth

et al. 2015

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Alterations in genes that regulate brain size may contribute to both microcephaly and brain tumor formation. Here, we report that Aspm, a gene that is mutated in familial microcephaly, regulates postnatal neurogenesis in the cerebellum and supports the growth of medulloblastoma, the most common malignant pediatric brain tumor. Cerebellar granule neuron progenitors (CGNPs) express Aspm when maintained in a proliferative state by sonic hedgehog (Shh) signaling, and Aspm is expressed in Shh-driven medulloblastoma in mice. Genetic deletion of Aspm reduces cerebellar growth, while paradoxically increasing the mitotic rate of CGNPs. Aspm-deficient CGNPs show impaired mitotic progression, altered patterns of division orientation and differentiation, and increased DNA damage, which causes progenitor attrition through apoptosis. Deletion of Aspm in mice with Smo-induced medulloblastoma reduces tumor growth and increases DNA damage. Co-deletion of Aspm and either of the apoptosis regulators Bax or Trp53 (also known as p53) rescues the survival of neural progenitors and reduces the growth restriction imposed by Aspm deletion. Our data show that Aspm functions to regulate mitosis and to mitigate DNA damage during CGNP cell division, causes microcephaly through progenitor apoptosis when mutated, and sustains tumor growth in medulloblastoma.

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A Gene Expression Signature of Epithelial Tubulogenesis and a Role for ASPM in Pancreatic Tumor Progression

Cited by 85 publications

References 30 publications

Genome‐wide analysis of the oxyntic proliferative isthmus zone reveals ASPM as a possible gastric stem/progenitor cell marker over‐expressed in cancer

Genome‐wide analysis of the oxyntic proliferative isthmus zone reveals ASPM as a possible gastric stem/progenitor cell marker over‐expressed in cancer

Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6

Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth

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