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Increased expression of DNA repair genes in invasive human pancreatic cancer cells.

ABSTRACT: OBJECTIVE:Pancreatic cancer was the fourth leading cause of cancer death in the United States in 2010. Recurrence of disease after resection occurs because of neoplastic cell survival. To better understand these highly aggressive cells, gene expression microarrays were performed. METHODS:Using the established lines HPAC and PANC1 and a Matrigel assay, genome expression arrays were performed to analyze patterns between invasive and total cells. RESULTS:Significant increases in the expression of genes related to DNA repair were observed. A number of the same genes also demonstrated an increase in expression when comparing bulk cells to a putative tumor-initiating cell (TIC) population. The TIC population was isolated using the spheroid technique, and compared with bulk cells, spheroid cells functionally repair breaks in DNA faster after challenge with the drug gemcitabine. Finally, using Oncomine, we observed a significant increase in DNA copy number of BRCA1 and RAD51 in tissue isolated from metastatic pancreatic cancer compared with tissue isolated from the primary site. CONCLUSIONS:From these data, we conclude that the most invasive cells within a pancreatic tumor are able to thrive because of their increased genomic stability. These cells have also been linked to the TIC population in a tumor.

SUBMITTER: Mathews LA

PROVIDER: S-EPMC3116046 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Increased expression of DNA repair genes in invasive human pancreatic cancer cells.

Mathews Lesley A LA Cabarcas Stephanie M SM Hurt Elaine M EM Zhang Xiaohu X Jaffee Elizabeth M EM Farrar William L WL

Pancreas 20110701 5

<h4>Objective</h4>Pancreatic cancer was the fourth leading cause of cancer death in the United States in 2010. Recurrence of disease after resection occurs because of neoplastic cell survival. To better understand these highly aggressive cells, gene expression microarrays were performed.<h4>Methods</h4>Using the established lines HPAC and PANC1 and a Matrigel assay, genome expression arrays were performed to analyze patterns between invasive and total cells.<h4>Results</h4>Significant increases ...[more]

PMID: 21633318

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Project description:IntroductionMany studies have reported that human-induced pluripotent stem (hiPS)/embryonic stem (hES) cells have an exceptional ability to repair damaged DNA. Moreover, unlike differentiated cells, hES cells have features and mechanisms such as apoptosis-prone mitochondria, which prevent any changes in genetic information caused by DNA damage to be transmitted to their descendants. Type-A (dark) spermatogonia and cancer stem cells are thought to be dormant. However, hiPS/hES cells, the so-called stem cells used in regenerative medicine, generally have a high proliferative capacity. This suggests that in these cells, oxidative DNA damage associated with vigorous proliferation and DNA scission associated with replication occur frequently. Although pluripotency according to change of genomic structure is well studied, the change of DNA repair through reprogramming has not been well studied.MethodsWe analyzed the expression of DNA repair-related genes in hiPS cells using microarray and western blotting analyses and assessed changes in PARP activity through reprogramming.ResultsThrough reprogramming, hiPS cells were found to upregulate poly (ADP-ribose) polymerase (PARP) activity and genes regulating homologous recombination (HR). Simultaneously, the expression level of genes involved in non-homologous end joining (NHEJ) was not high, suggesting that at least at the gene expression level, frequently occurring DNA scission is preferentially dealt with via HR instead of NHEJ. Also, reflecting the high proliferative activity, genes related to mismatch repair (MMR) were upregulated through reprogramming. Conversely, error-prone polymerase was downregulated through reprogramming. These are also likely to be the mechanisms preventing changes in genetic information.ConclusionsHigh PARP activity and HR-related gene expression in hiPS cells were achieved through reprogramming and likely facilitate precise genome editing in these cells in exchange for a high possibility of cell death.

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Increased expression of DNA repair genes in invasive human pancreatic cancer cells.

Publications

Increased expression of DNA repair genes in invasive human pancreatic cancer cells.

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