甲状腺乳头状癌菌群失调及与肿瘤信号通路异常的相关性研究

喻爽, 丁彦强, 王雪洁, Siu Kin Ng, 曹思婷, 刘伟鑫, 郭朱明, 谢宇彬, 洪澍彬, 许丽霞, 李晓星, 李杰, 吕伟明, 彭穗, 李延兵, 沈祖尧, 于君, 肖海鹏

工程（英文） ›› 2023, Vol. 28 ›› Issue (9) : 179-192.

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工程（英文） ›› 2023, Vol. 28 ›› Issue (9) : 179-192. DOI: 10.1016/j.eng.2023.01.007
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甲状腺乳头状癌菌群失调及与肿瘤信号通路异常的相关性研究

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Intratumoral Bacteria Dysbiosis Is Associated with Human Papillary Thyroid Cancer and Correlated with Oncogenic Signaling Pathways

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摘要

研究表明微生态失调在多种肿瘤的发生发展中起至关重要的作用。然而，对于甲状腺肿瘤中细菌是否参与肿瘤的发生仍不清楚。本研究中，我们旨在探索甲状腺组织中的菌群特征及其对甲状腺乳头状癌（PTC）的作用。我们同时对 340 例PTC和甲状腺良性结节 （BTN） 患者的肿瘤组织及其邻近正常组织进行菌群分析和转录组测序。在PTC、BTN及其邻近无肿瘤组织中鉴定出明显不同的菌群特征。我们通过免疫组化染色、细菌原位杂交和电镜观察验证了甲状腺组织内细菌的存在。与BTN相比，我们发现在PTC中有17个菌属存在显著丰度差异，其中PTC中富集菌Rhodococcus、Neisseria、Streptococcus、Halomonas和Devosia存在促癌作用；以及丰度降低的Amycolatopsis则可能有抑癌作用。这些丰度存在明显差异的细菌可以鉴别PTC组织（PTC-T）与BTN组织（BTN-T），曲线下面积（AUC）为81.66%。微生物网络分析表明，PTC组织内细菌间的相互关联性高于BTN组织。同时，在合并桥本甲状腺炎组织的PTC中发现与免疫相关的菌属（Erwinia、Bacillus 和 Acinetobacter）明显富集。此外，我们联合转录组测序分析提示PTC富集菌与肿瘤相关信号通路的关键基因如BRAF、KRAS、IRAK4、CTNNB1、PIK3CA、MAP3K7 和 EGFR存在正相关性。总的来说，我们的研究结果表明，甲状腺肿瘤组织内存在菌群失调，并可能通过肿瘤相关信号通路参与PTC的发生。

Abstract

Emerging evidence suggests that microbial dysbiosis plays vital roles in many human cancers. However, knowledge of whether the microbial community in thyroid tumor is related to tumorigenesis remains elusive. In this study, we aimed to explore the microbial community in thyroid tissues and its contribution to papillary thyroid cancer (PTC). In parallel, we performed microbial profiling and transcriptome sequencing in the tumor and adjacent normal tissues of a large cohort of 340 PTC and benign thyroid nodule (BTN) patients. Distinct microbial signatures were identified in PTC, BTN, and their adjacent non-tumor tissues. Intra-thyroid tissue bacteria were verified by means of bacteria staining, fluorescence in situ hybridization, and immunoelectron microscopy. We found that 17 bacterial taxa were differentially abundant in PTC compared with BTN, which included enrichment in PTC of the pathobionts Rhodococcus, Neisseria, Streptococcus, Halomonas, and Devosia, and depletion of the beneficial bacteria Amycolatopsis. These differentially abundant bacteria could differentiate PTC tumor tissues (PTC-T) from BTN tissues (BTN-T) with an area under the curve (AUC) of 81.66%. Microbial network analysis showed increased correlation strengths among the bacterial taxa in PTC-T in comparison with BTN-T. Immune-function-corresponding bacteria (i.e., Erwinia, Bacillus, and Acinetobacter) were found to be enriched in PTC with Hashimoto’s thyroiditis. Moreover, our integrative analysis revealed that the PTC-enriched bacteria had a positive association with key PTC-oncogenic pathway-related genes, including BRAF, KRAS, IRAK4, CTNNB1, PIK3CA, MAP3K7, and EGFR. In conclusion, our results suggest that intratumor bacteria dysbiosis is associated with the thyroid tumorigenesis and oncogenic signaling pathways of PTC.

关键词

甲状腺乳头状癌 / 甲状腺良性结节 / 细菌 / 转录组 / 桥本甲状腺炎

Keywords

Papillary thyroid cancer / Benign thyroid nodule / Bacteria / Transcriptome / Hashimoto’s thyroiditis

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喻爽, 丁彦强, 王雪洁. 甲状腺乳头状癌菌群失调及与肿瘤信号通路异常的相关性研究. Engineering. 2023, 28(9): 179-192 https://doi.org/10.1016/j.eng.2023.01.007

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