Correlation analysis of clock genes and MEN2 medullary thyroid carcinoma.

Ya Kui Mou; Chao Ren; Yu Mei LI; Guo Hua YU; Gui Bin Zheng; Hong Song; Cong Xian LU; Ru Xian Tian; Xin Cheng Song

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Correlation analysis of clock genes and MEN2 medullary thyroid carcinoma.

Author: Ya Kui MOU ¹ ; Chao REN ² ; Yu Mei LI ³ ; Guo Hua YU ⁴ ; Gui Bin ZHENG ⁵ ; Hong SONG ⁶ ; Cong Xian LU ⁶ ; Ru Xian TIAN ⁶ ; Xin Cheng SONG ⁷
Author Information

1. Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai 264000, China State Key Laboratory of Oncology in South China, Guangzhou 510000, China.
2. Taishan Scholar Laboratory, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China Department of Neurology, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China.
3. Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai 264000, China Taishan Scholar Laboratory, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China.
4. Department of Pathology, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China.
5. Taishan Scholar Laboratory, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China Department of Thyroid Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China.
6. Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China.
7. Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai 264000, China Taishan Scholar Laboratory, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China.
Publication Type:Journal Article
MeSH: ARNTL Transcription Factors/genetics*; CLOCK Proteins/genetics*; Calcitonin; Carcinoma, Neuroendocrine/genetics*; Dexamethasone; Humans; Lipopolysaccharides; Lymphatic Metastasis; Multiple Endocrine Neoplasia Type 2a/genetics*; Thyroid Neoplasms/surgery*
From: Chinese Journal of Otorhinolaryngology Head and Neck Surgery 2022;57(9):1079-1086
CountryChina
Language:Chinese
Abstract: Objective: To investigate the correlation between CLOCK and BMAL1 genes and MEN2 medullary thyroid carcinoma (MTC). Methods: Thirteen cases with MEN2 MTC and thirteen cases with non-MEN2 MTC were selected who were treated in the Yantai Yuhuangding Hospital between January 2013 and September 2021. Clinical indicators such as blood calcitonin level, tumor diameter and metastatic lymph node of patients were collected. The expression differences of CLOCK and BMAL1 between MEN2 MTC and para-carcinoma tissue as well as between MEN2 MTC and non-MEN2 MTC were detected by immunohistochemistry and qPCR. The correlation between lymph node metastasis and CLOCK or BMAL1 expression was analyzed. Protein-protein interaction (PPI) network analysis combined with qPCR and correlation analysis was used to explore the expression regulation relationship between RET and circadian clock genes. The rhythm disorder of MEN2 cells was verified by lipopolysaccharide cell stimulation experiment after dexamethasone rhythm synchronization. Results: MEN2 MTC exhibited typical RET gene mutation. The mean blood calcitonin level, the tumor diameter and the number of metastatic lymph nodes of patients with MEN2 MTC were higher than those of patients with non-MEN2 MTC (t value was 2.76, 2.53, 2.26, all P<0.05). Immunohistochemical results showed that the expression levels of CLOCK and BMAL1 in MEN2 MTC were higher than those in non-MEN2 MTC, while negatively expressed in para-cancerous thyroid follicle. qPCR displayed that the expression of CLOCK gene in cancer tissues was higher than that in non-MEN2 MTC and para-cancerous tissues (t value was 2.68 and 2.86, all P<0.05); the expression of BMAL1 gene in MEN2 MTC was higher than that in non-MEN2 MTC and para-cancerous tissues (t value was 2.21 and 2.35, all P<0.05). Correlation analysis showed that the expression levels of CLOCK and BMAL1 genes were positively correlated with the number of lymph node metastases in patients with MEN2 MTC (r=0.65, P<0.001; r=0.52, P=0.005). PPI network analysis indicated that the expression of CLOCK gene was positively correlated with the abnormal expression of RET gene (r=0.96, P<0.001). With lipopolysaccharide to stimulate cultured cells in vitro after dexamethasone rhythm synchronization, the expressions of CLOCK and BMAL1 in MEN2 MTC cells (0.47±0.22 and 2.60±1.48) at 12 hours of synchronization were significantly lower than those in para-cancerous tissues (1.70±1.62 and 8.23±2.52), the difference was statistically significant(t=5.04, P=0.007; t=3.34, P=0.029). Conclusion: CLOCK and BMAL1 are correlated with the occurrence and development of MEN2 MTC, and may be potential targets for the development of new therapeutic strategies for MEN2 MTC.