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Krüppel-Like Factor 10 Expression as a Prognostic Indicator for Pancreatic
Adenocarcinoma
Vincent H.S. Chang, Pei-Yi Chu, Shu-Ling Peng, Tsui-Lien Mao, Yan-Shen Shan, Ching-Fang Hsu,
Chun-Yu Lin, Kelvin K.C. Tsai, Winston C.Y. Yu, And Hui-Ju Ch’ang
The American Journal of Pathology, Vol. 181, No. 2, August 2012
Presenter: Ming Jung Lin
Date/Time: 2012/10/25 16:10~17:00
Commentator: Shan, Yan-Shen, MD, PhD
Location: Room 601, Med College Building
Background:
Despite substantial development in the diagnosis and treatment of pancreatic adenocarcinoma, it remains a
disease with high morbidity and mortality. Therefore, novel molecular markers that help with early diagnosis
and prognosis and with the development of therapeutic targets are urgently needed to help pancreatic cancer
patients. Deregulation of transforming growth factor (TGF-ß) function is a common feature of pancreatic
cancer, rendering these cancers unresponsive to TGF-ß stimulated growth inhibition. The mechanisms
underlying the effects of TGF-ß on pancreatic cancer progression are currently poorly understood.
Krüppel-like factor 10 (KLF10) is an important transcription factor involved in mediating TGF-ß signaling.
Further studies on the regulation by TGF-ß of Klf10 transcription have revealed that increased intracellular
levels of KLF10 mimic the anti-proliferative and apoptotic effects of TGF-ß on epithelial cell growth,
suggesting that Klf10 is an important factor mediating TGF-ß signaling.
Objective/Hypothesis:
To evaluate the correlation between KLF10 expression and the clinical and pathologic features of
pancreatic cancer.
Result:
The authors perform cancer profiling assay to demonstrate Klf10 mRNA expression status in tissues of
different organ and compare the expression in normal part and tumor part of each organ. Klf10 was
generally down-regulated in tumors when compared with normal counterparts in pancreas, kidney, and colon.
KLF10 expression was inversely correlated with pancreatic cancer stage from IHC staining of pancreatic
cancer tissue specimens. Multivariable analysis revealed that, in addition to the presence of distant
metastasis at diagnosis, KLF10 was another independent prognostic factor related to progression-free and
overall survival. Several studies have revealed DNA methyltransferase 1 (DNMT1) specifically silenced
several tumor suppress genes which lead to cancer progression. Therefore, the authors used
methylation-specific PCR to examine Klf10 promoter in pancreas cancer cell line (Panc-1), and they found 3
probable sites of methylation, -495 to -197, +656 to +859, -1145 to -854. Over-expression of DNMT1 was
observed in advanced pancreatic cancer. To investigate whether the down-regulation of Klf10 in tumor
progression is regulated by DNMT1, the authors used DNMT inhibitor and siRNA to deplet DNMT gene.
They found that only deplete DNMT1 was paralleled by increasing level of Klf10 protein.
Conclusion:
The loss of KLF10 expression in advanced pancreatic cancer is correlated with altered methylation status,
which seems to be regulated by DNMT1. This paper suggests that KLF10 is a potential clinical predictor for
progression of pancreatic cancer.
References:
1.
Ellenrieder V: TGFbeta regulated gene expression by Smads and Sp1/KLF-like transcription factors in cancer. Anticancer Res
2008, 28:1531–1539