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Sine Oculis Homeobox Homolog 1 Regulates Mitochondrial Apoptosis Pathway Via
Caspase-7 In Gastric Cancer Cells
#MMPMID28367243
Du P
; Zhao J
; Wang J
; Liu Y
; Ren H
; Patel R
; Hu C
; Zhang W
; Huang G
J Cancer
2017[]; 8
(4
): 636-645
PMID28367243
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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.
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