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CASC9 potentiates gemcitabine resistance in pancreatic cancer by reciprocally activating NRF2 and the NF-κB signaling pathway

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Abstract

Gemcitabine resistance is a frequently occurring and intractable obstacle in pancreatic cancer treatment. However, the underlying mechanisms require further investigation. Adaptive regulation of oxidative stress and aberrant activation of the NF-κB signaling pathway are associated with resistance to chemotherapy. Here, we found that gemcitabine upregulated the expression of CASC9 in a dose-dependent manner, partially via induction of reactive oxygen species, whereas inhibition of CASC9 expression enhanced gemcitabine-induced oxidative stress and apoptosis in pancreatic cancer cells. Furthermore, suppression of CASC9 level inhibited the expression of NRF2 and the downstream genes NQO1 and HO-1, and vice versa, indicating that CASC9 forms a positive feedback loop with NRF2 signaling and modulates the level of oxidative stress. Silencing CASC9 attenuated NF-κB pathway activation in pancreatic cancer cells and synergistically enhanced the cytotoxic effect of gemcitabine chemotherapy in vivo. In conclusion, our findings suggest that CASC9 plays a key role in driving resistance to gemcitabine through a reciprocal loop with the NRF2-antioxidant signaling pathway and by activating NF-κB signaling. Our study reveals potential targets that can effectively reverse resistance to gemcitabine chemotherapy.

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Data availability

The datasets presented in the current study are available from the corresponding author on reasonable request.

Abbreviations

CASC9:

LncRNA cancer susceptibility candidate 9

GEM:

Gemcitabine

NF-κB:

Nuclear factor-kappa B

LncRNAs:

Long noncoding RNAs

NAC:

N-acetyl-L-cysteine

EMSA:

Electrophoretic mobility shift assay

HO-1:

Heme oxygenase-1

NQO1:

NAD(P)H quinone oxidoreductase 1

NRF2:

Nuclear factor erythroid 2-related factor 2

ROS:

Reactive oxygen species

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Funding

The study was supported by the National Natural Science Foundation of China (grant number: 81803030), and National Natural Science Foundation of China (grant number: 82172570).

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Author notes

  1. Zhengle Zhang, Longjiang Chen, and Chuanbing Zhao contributed equally to the work.

Authors and Affiliations

  1. Department of Pancreatic Surgery, Renmin Hospital, Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei Province, China

    Zhengle Zhang, Longjiang Chen, Chuanbing Zhao, Qiong Gong, Zhigang Tang, Hanjun Li & Jing Tao

Authors
  1. Zhengle Zhang
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  2. Longjiang Chen
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  3. Chuanbing Zhao
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  4. Qiong Gong
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  5. Zhigang Tang
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  6. Hanjun Li
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  7. Jing Tao
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Contributions

Hanjun Li and Jing Tao were responsible for the experimental concept and research supervision. Zhengle Zhang, Longjiang Chen, and Chuanbing Zhao carried out the main research, analyzed the data, and wrote the paper. Qiong Gong participated in data analysis. Zhigang Tang performed revising the manuscript. All authors reviewed and approved the final version of manuscript.

Corresponding authors

Correspondence to Hanjun Li or Jing Tao.

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The study was approved by the ethical review board of Renmin Hospital of Wuhan University (Wuhan, China).

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Zhang, Z., Chen, L., Zhao, C. et al. CASC9 potentiates gemcitabine resistance in pancreatic cancer by reciprocally activating NRF2 and the NF-κB signaling pathway. Cell Biol Toxicol 39, 1549–1560 (2023). https://doi.org/10.1007/s10565-022-09746-w

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