J Cancer 2017; 8(4):636-645. doi:10.7150/jca.16018

Research Paper

Sine Oculis Homeobox Homolog 1 Regulates Mitochondrial Apoptosis Pathway Via Caspase-7 In Gastric Cancer Cells

Peizhun Du1*, Jing Zhao1*, Jing Wang2*, Yongchao Liu3, Hong Ren4, Rajan Patel5, Cheng'en Hu1, Wenhong Zhang2✉, Guangjian Huang1✉

1. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China;
2. Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China;
3. Department of Surgical Intensive Care Unit, Shanghai Tenth People's Hospital, Shanghai, China;
4. Department of Breast Surgery, Huashan Hospital, Fudan University, Shanghai, China.
5. General Internal Medicine, Shady Grove Adventist Hospital, Maryland, America.
* These authors contributed equally to this work.

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Du P, Zhao J, Wang J, Liu Y, Ren H, Patel R, Hu C, Zhang W, Huang G. Sine Oculis Homeobox Homolog 1 Regulates Mitochondrial Apoptosis Pathway Via Caspase-7 In Gastric Cancer Cells. J Cancer 2017; 8(4):636-645. doi:10.7150/jca.16018. Available from http://www.jcancer.org/v08p0636.htm

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Sine oculis homeobox homolog 1 (Six1) is crucial in normal organ development. Recently, Six1 is reported to display aberrant expression in various cancers and plays important roles in cancer development. However, the regulatory mechanism of Six1 in gastric cancer is largely unknown. In the current study, we found that Six1 was increased in gastric cancer tissues, and its upregulation significantly associated with lymph node metastasis (p=0.042) and poor differentiation (p=0.039). Next, we took advantage of public available microarray data to assess Six1 prognostic value with online K-M Plotter software in gastric cancer, which demonstrated that patients with higher Six1 expression had shorter survival time (p=0.02). To explore the underlying mechanism of Six1, we silenced its upregulation in gastric cells to detect cellular functions. Our results indicated that knock-down Six1 could decrease colony formation number and rendered cells sensitive to 5- Fluorouracil drug treatment. The flow cytometry analyses showed that Six1 silence could promote apoptosis but had little effect on cell cycle transition. Along this clue, we tested mitochondrial membrane potential with JC-1 assay, which suggested that Six1 inhibition could trigger mitochondrial apoptosis. Our subsequent results revealed that Six1 knock-down could reduce the level of anti-apoptotic protein Bcl-2, and caspase-7 but not caspase-3 was involved to execute the mitochondrial apoptosis pathway. Taken together, we find Six1 has oncogenic role in gastric cancer development, and silenced Six1 expression can promote mitochondrial apoptosis by repressing Bcl-2 and activating executor caspase-7. These findings suggest that Six1 may become a valuable prognostic and therapeutic target in gastric cancer.

Keywords: Six1, Gastric cancer, Mitochondrial apoptosis, Caspase-7, Bcl-2