Abstract
BackgroundAccumulating evidence shows that Parkinson’s disease is negatively associated with colon cancer risk, indicating that Parkinson’s disease family proteins may be involved in the initiation of colon cancer. Here, we aimed to identify a Parkinson’s disease-related gene involved in colon cancer, elucidate the underlying mechanisms, and test whether it can be used as a target for cancer therapy.MethodsWe first screened colon cancer and normal tissues for differential expression of Parkinson’s disease-associated genes and identified ATP13A2, which encodes cation-transporting ATPase 13A2, as a putative marker for colon cancer. We next correlated ATP13A2 expression with colon cancer prognosis. We performed a series of ATP13A2 knockdown and overexpression studies in vitro to identify the contribution of ATP13A2 in the stemness and invasive capacity of colon cancer cells. Additionally, autophagy flux assay were determined to explore the mechanism of ATP13A2 induced stemness. Finally, we knocked down ATP13A2 in mice using siRNA to determine whether it can be used as target for colon cancer treatment.ResultsColon cancer patients with high ATP13A2 expression exhibit shorter overall survival than those with low ATP13A2. Functionally, ATP13A2 acts as a novel stimulator of stem-like traits. Furthermore, knockdown of ATP13A2 in HCT116 resulted in decreased levels of cellular autophagy. Additionally, bafilomycin A1, an autophagy inhibitor, reversed the ATP13A2-induced stemness of colon cancer cells. Lastly treatment with ATP13A2 siRNA reduced the volume of colon cancer xenografts in mice.ConclusionsThe PD-associated gene ATP13A2 is involved in colon cancer stemness through regulation of autophagy. Furthermore, ATP13A2 is a novel prognostic biomarker for colon cancer and is a potential target for colon cancer therapy.
Highlights
Accumulating evidence shows that Parkinson’s disease is negatively associated with colon cancer risk, indicating that Parkinson’s disease family proteins may be involved in the initiation of colon cancer
We found that the mRNA levels of ATPase 13A2 (ATP13A2) and PARK7 were significantly higher in colon cancer tissue than in normal tissue (Fig. 1a)
We have revealed that PARK7 is associated with colon cancer invasion and progression [14, 15], but the role of ATP13A2 in colon cancer initiation and progression remains unknown
Summary
Accumulating evidence shows that Parkinson’s disease is negatively associated with colon cancer risk, indicating that Parkinson’s disease family proteins may be involved in the initiation of colon cancer. Colon cancer is one of the most prevalent cancers worldwide and causes 551,269 deaths each year [1] Accumulating evidence supports the hypothesis that colorectal cancer stem cells (CSC), which exhibit stemness (i.e., self-renewal and pluripotency), have the ability to initiate and sustain tumor growth, metastasis, and resistance to therapy [2]. When faced with endogenous or exogenous stress, tumor cells maintain their stemness and self-renew through autophagic degradation of misfolded proteins and aging organelles [4, 5] identifying novel factors that target autophagy-mediated stemness of colon cancer cells has been proposed as a therapeutic strategy for colon cancer. Given the inverse correlation between Parkinson’s disease and colon cancer risks, some of these genes may be involved in the initiation of colon cancer. Our previous research suggested that Parkinson’s disease family proteins, such as PARK15 and PARK7, are associated with tumorigenesis of nonsmall cell lung cancer [11], the Parkinson’s disease-associated proteins that are involved in the initiation of colon cancer have not yet been determined
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