Research Article: circStrn3 is involved in bone cancer pain regulation in a rat model

Date Published: May 12, 2020

Publisher: Oxford University Press

Author(s): Yiwen Zhang, Xiaoxia Zhang, Zumin Xing, Shuyi Tang, Hanwen Chen, Zhongqi Zhang, Jiyuan Li, Yalan Li.

http://doi.org/10.1093/abbs/gmaa018

Abstract

Bone cancer pain (BCP) is a common chronic pain that is caused by a primary or metastatic bone tumor. More detailed molecular mechanisms of BCP are warranted. In this study, we established a BCP rat model. The von Frey hair test, body weight, and hematoxylin and eosin staining were employed. We screened differentially expressed circRNAs (DECs) between the BCP group and sham group. The results revealed that 850 DECs were significantly up-regulated and 644 DECs were significantly down-regulated in the BCP group. Furthermore, we identified 1177 differentially expressed genes (DEGs) significantly up-regulated and 565 DEGs significantly down-regulated in the BCP group. Gene Ontology annotation of all 1742 DEGs revealed that biological regulation of metabolic processes, cellular processes, and binding were the top enriched terms. For Kyoto Encyclopedia of Genes and Genomes analysis, phagosome, HTLV-I infection, proteoglycans in cancer, and herpes simplex infection were significantly enriched in this study. In addition, we identified four selected circRNAs, chr6:72418120|72430205, chr20:7561057|7573740, chr18:69943105|69944476, and chr5:167516581|167558250, by quantitative real time PCR. chr6:72418120|72430205 (circStrn3) was selected for further study based on expression level and the circRNA–miRNA–mRNA network table. Western blot analysis suggested that knockdown of circStrn3 could effectively induce Walker 256 cell apoptosis. In summary, our study provided a more in-depth understanding of the molecular mechanisms of BCP.

Partial Text

Bone cancer pain (BCP) is a chronic pain caused by a primary or metastatic bone tumor. Clinically, the incidence of metastatic bone tumors is about 35–40 times higher than that of primary malignant bone tumors. Therefore, most malignant bone tumors are caused by bone metastasis from advanced cancer [1]. According to the World Health Organization, there are 10 million new cancer patients in the world annually and China has an annual increase of about 1.8 million [2]. The incidence of bone metastases in malignant tumors is 32.5% [3], of which more than 90% of bone metastases are derived from five tumor types, including breast cancer, prostate cancer, lung cancer, thyroid cancer, and kidney cancer [4–6]. When tumor cells, such as osteosarcoma cancer cells and breast cancer cells, invade into the bone, proliferation of tumors can lead to a variety of bone structural changes, including osteolysis, nonbone tissue formation, hypercalcemia, and inflammatory factor release [7]. These changes stimulate stromal cells to secrete the receptor RANKL, which promotes osteoclast proliferation and hypertrophy through the RANKL/RANK signaling pathway [8]. According to statistics, ~70% of patients with bone metastases have various degrees of chronic pain [9]. Although many drugs are available to treat BCP, such as antidepressants, anticonvulsants, and opioids, there may be various side effects such as nausea, dizziness, arrhythmia, and hyperalgesia, which lead to restrictions on the use of these drugs [10]. Meanwhile, there is still a lack of understanding of the mechanism of BCP and there are also limitations of existing clinical treatment measures. For example, ~50% of cancer patients are not effectively controlled in the symptoms of BCP [11,12]. Therefore, an in-depth study of the mechanism of BCP is absolutely critical.

BCP is the most common type of cancer pain and is also the most severe and difficult to control. It is often manifested as continuous background pain, breakthrough pain, and allodynia [35,36]. BCP pathogenesis may include inflammatory and neuropathic pain. However, it is not the same as inflammatory pain and/or neuropathic pain [8]. A previous study showed that plasticity changes in spinal dorsal horn neurons are important causes of cancer pain formation and maintenance [37]. However, detailed molecular mechanisms of these manifestations are still unclear.

Supplementary data is available at Acta Biochimica et Biophysica Sinica online.

This work was supported by the grants from the Medical Science and Technology Research Foundation of Guangdong Province (No. A2019045), the Scientific Research Foundation of Foshan City, Guangdong Province (No. 1920001000687), the 2018 Distinguished Youth Talent Fund Project of the First Medical Science Center of Foshan City, and the Key Specialist Project of Clinical Medicine of Foshan City (No. FSZDZK135049).

 

Source:

http://doi.org/10.1093/abbs/gmaa018

 

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