牙龈卟啉单胞菌LPS促乳腺癌发展的分子机制研究

Breast cancer is the most common cancer among women in China. Epidemiology studies indicate that periodontitis is associated with increased risk of breast cancer, but the mechanisms are unknown. Previous studies in our group have found that Porphyromonas gingivalis, the chief pathogen of periodontitis, can be detected in the human breast cancer tissue; this pathogen can travel to and settle down in breast tissue via the circulation system; heat-killed P. gingivalis and lipopolysaccharide, one of the major virulence factors of P. gingivalis, promotes breast cancer cells growth in vitro; and LPS promotes the cancer growth and mice death in vivo. But, the molecular mechanism of how P. gingivalis and LPS promote the growth of breast cancer cells is unknown. The current project plans to use RNA-seq technique to screen the key genes and pathways that LPS regulates cancer cells, and the TLR4 pathway will be focused on; to explore the effect and detailed mechanisms of LPS on breast cancer cell growth by using RNA interference technique, LPS antagonist and P. gingivalis LPS knockout strain; to create a periodontitis-breast cancer animal model, and finally confirm the mechanisms in vivo. This project will provide the first hand information about the internal association between periodontitis and breast cancer at molecular level, besides, it supports the idea that controlling oral diseases helps to reduce the risk of systemic diseases.

乳腺癌是我国女性发病率第一的癌症。流行病学调查显示牙周炎可增加乳腺癌风险，而其机制尚不明确。本课题组前期研究发现：乳腺肿瘤内可检出牙周炎主要致病菌牙龈卟啉单胞菌（Pg），该菌可以通过血液循环到达并定植于乳腺组织，Pg和其主要毒力因子脂多糖（LPS）均可促进乳腺癌细胞的增殖，同时原位注射LPS可促进小鼠肿瘤生长而导致小鼠死亡。但Pg及LPS促进乳腺癌发展的相关机制不清。本研究拟用转录组学测序技术寻找Pg的LPS促癌细胞生长的关键基因和通路，并将重点筛查TLR4相关的通路；通过使用RNA干扰技术、LPS拮抗剂、Pg的LPS敲除株，从多角度研究LPS对癌细胞生长的影响及其相关机制；同时建立牙周炎伴乳腺癌动物模型，进一步从体内进行验证。本课题从分子生物学的角度揭示牙周炎与乳腺癌的内在联系，为通过治疗口腔疾病而实现一定程度上降低全身疾病的风险提供理论依据。

乳腺癌是我国女性发病率第一的癌症。流行病学调查显示牙周炎可增加乳腺癌风险，而其机制尚不明确。牙龈卟啉单胞菌（Pg）是引发牙周炎的主要致病菌之一，而脂多糖（LPS）是其重要毒力因子。目前，Pg及LPS促进乳腺癌发展的相关机制不清。本研究将探索Pg-LPS对小鼠乳腺癌细胞4T1的增殖，迁移和侵袭能力的影响，并同时建立小鼠乳腺癌模型进一步探究Pg-LPS促乳腺癌发展的分子调控机制，从多角度研究LPS对癌细胞生长的影响及其相关机制。研究发现：Pg-LPS能够促进乳腺癌细胞的增殖、迁移，以及上调TLR4-MyD88-NF-κB基因通路的表达。 动物实验结果表明，Pg-LPS能够显著促进小鼠乳腺癌的生长并同时加速小鼠的死亡。其中，经含0.8ug/ml的Pg-LPS培养基培养24h的4T1效果最明显。研究揭示牙周炎中Pg-LPS与乳腺癌的内在联系，为通过治疗口腔疾病而实现一定程度上降低全身疾病的风险提供理论依据。