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. 2020 May 26:2020:3181596.
doi: 10.1155/2020/3181596. eCollection 2020.

HEATR1 Deficiency Promotes Chemoresistance via Upregulating ZNF185 and Downregulating SMAD4 in Pancreatic Cancer

Yuan Fang  1 , Xu Han  1 , Jianang Li  1 , Tiantao Kuang  1 , Wenhui Lou  1
Affiliations

HEATR1 Deficiency Promotes Chemoresistance via Upregulating ZNF185 and Downregulating SMAD4 in Pancreatic Cancer

Yuan Fang et al. J Oncol. .

Abstract

Objective: To discover the correlated gene with HEATR1 in regulating chemoresistance of gemcitabine.

Methods: Gene chip analysis was performed to find out differential genes between HEATR1-KD and control groups. The top 20 genes were subjected to high-content screening, and functional assay was implemented. Gene expression profiling was carried out to find the downstream target. Immunohistochemistry and survival analysis were performed.

Results: ZNF185 fold change (4.5285) was the most significant between the HEATR1-KD and control groups. Knocking down ZNF185 could promote the chemosensitivity, apoptosis, and proliferative inhibition, with SMAD4 significantly upregulated. Patients with high HEATR1 and SMAD4 or low ZNF185 exhibited better survival.

Conclusion: HEATR1, ZNF185, and SMAD4 could affect the chemosensitivity of gemcitabine and may be the indicators of gemcitabine selection in the chemotherapy of pancreatic cancer.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
HEATR1 promotes the chemosensitivity to gemcitabine in pancreatic cell lines. (a) HEATR1 knockdown in PANC-1. (b) Increased chemoresistance of PANC-1 to gemcitabine after HEATR1 knockdown. (c) Apoptotic percentage decreased after HEATR1 knockdown when treated with gemcitabine. (d) Proliferation increased on day 5 dramatically after HEATR1 knockdown when treated with gemcitabine.
Figure 2
Figure 2
Gene chip analysis of differentially expressed genes and HCS screening after HEATR1 knockdown. (a) Differential expression fold change (4.5285) of ZNF185 was the most significant in the selected 30 genes between the HEATR1-KD and control groups in gene chips. (b) Quantitative PCR of the selected 30 genes. (c) In HCS screening, knocking down ZNF185 in the pancreatic cancer cells could promote the chemosensitivity of gemcitabine; confirmation of chemosensitive function of ZNF185 by observing the increased apoptotic percentage (d) and proliferative inhibition (e) when HEATR1 and ZNF185 were both knocked down. (f) After knocking down ZNF185, the pancreatic cancer cells in the S phase and the G2/M phase increased, while the cells in the G1 phase decreased.
Figure 3
Figure 3
Expression of SMAD4 increased in the ZNF185 knockdown pancreatic cancer cells. (a) qRT-PCR of ZNF185 and (b) SMAD4 when ZNF185 was knocked down. (c) Western blots of ZNF185 and SMAD4 when ZNF185 was knocked down.
Figure 4
Figure 4
Expression status in pancreatic ductal adenocarcinoma. Representative images of expression of HEATR1 in cancer (a) and normal (b) tissues. Representative images of expression of ZNF185 in cancer (c) and normal (d) tissues. Representative images of expression of SMAD4 in cancer (e) and normal (f) tissues.
Figure 5
Figure 5
Expression of HEATR1, ZNF185, and SMAD4 in the pancreatic cancer tissues and correlation with the survival. (a) Univariate analysis of HEATR1 expression and OS. (b) Univariate analysis of ZNF185 expression and OS. (c) Univariate analysis of SMAD4 expression and OS.
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