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MicroRNA-330 Directs Downregulation of the GABABR2 in the Pathogenesis of Pancreatic Cancer Pain

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Abstract

Pancreatic cancer is one of the most aggressive and deadly malignancies with a very poor prognosis. Pancreatic cancer-induced visceral pain is very common and is generally presented among the initial symptoms in patients; such pain is strongly associated with poor quality of life, impaired functional activity, and decreased survival. However, the principal neurobiological mechanisms of pain caused by pancreatic cancer have not been fully elucidated. Accumulating studies have shown that miRNAs play a major role in chronic pain by suppressing key molecules involved in nociception. In the present study, we report that microRNA (miR)-330 is highly expressed in the spinal dorsal horn (SDH) of nude mice with pancreatic cancer pain. Mimicking pancreatic carcinoma-induced SDH miR-330 upregulation by microinjection of miR-330 mimic into the SDH significantly induced abdominal mechanical allodynia in normal nude mice. Additionally, we found that the expression of GABABR2 was significantly decreased in the SDH of nude mice with pancreatic cancer pain and was regulated directly by miR-330 both in vitro and in vivo. Furthermore, inhibition of miR-330 rescued the expression of GABABR2 and alleviated pancreatic carcinoma-induced abdominal pain hypersensitivity in nude mice with pancreatic carcinoma. These results show that miR-330 participates in the genesis of pancreatic carcinoma-induced pain hypersensitivity by inhibiting GABABR2 expression in the SDH and might be a potential therapeutic target for pancreatic cancer pain.

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Funding

This research was financially supported by the National Natural Science Foundation of the People’s Republic of China (31371084, 81870864), Joint fund for research, and development of high-level hospital (2017LHJJ10).

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  1. Mei Zhu and Liqin Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology and Intensive Care, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, China

    Mei Zhu, Jiao Zhu, Huihong Xu, Kai Wei, Qianbo Chen, Xuerong Miao & Zhijie Lu

  2. Department of Anesthesiology, 905th Hospital of PLAN, Shanghai, China

    Liqin Wang

  3. Department of Anesthesiology, Fujian Provincial Hospital, Fujian Provincial Clinical Medical College, Fujian Medical University, Fuzhou, 350001, Fujian, China

    Xiaodan Wu

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  1. Mei Zhu
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  3. Jiao Zhu
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  5. Kai Wei
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Contributions

Zhijie Lu participated in conceiving the project, designing experiments, and executing experiments. Xuerong Miao and Xiaodan Wu designed the projected. Mei Zhu, Liqin Wang, Jiao Zhu, Huihong Xu, Kai Wei, and Qianbo Chen performed animal model establishment, cultured cells, molecular, and behavioral experiments. Mei Zhu and Liqin Wang analyzed the data. Xuerong Miao and Mei Zhu wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xiaodan Wu, Xuerong Miao or Zhijie Lu.

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Zhu, M., Wang, L., Zhu, J. et al. MicroRNA-330 Directs Downregulation of the GABABR2 in the Pathogenesis of Pancreatic Cancer Pain. J Mol Neurosci 70, 1541–1551 (2020). https://doi.org/10.1007/s12031-020-01607-7

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