3月3日,，國際著名學術(shù)期刊《The Journal of Clinical
Investigation》在線發(fā)表了健康科學研究所胡國宏研究組與山東大學齊魯醫(yī)院楊其峰研究組合作完成的題為“DLC1-dependent
parathyroid hormone - like hormone inhibition suppresses breast
cancer bone metastasis”的最新研究成果,。論文首次報道了DLC1（deleted in liver cancer
1）通過抑制SMAD3 連接區(qū)域的磷酸化,，降低TGFβ誘導的PTHLH表達水平,，最終阻礙乳腺癌的骨轉(zhuǎn)移進程,。
乳腺癌是對女性健康構(gòu)成很大威脅的一種惡性疾病,。而乳腺癌向重要器官如骨,、肺,、腦,、肝等的轉(zhuǎn)移是乳腺癌致死的主要原因。臨床上的數(shù)據(jù)顯示大約70%的晚期乳腺癌病人會發(fā)生骨轉(zhuǎn)移,。乳腺癌發(fā)生骨轉(zhuǎn)移可能會給病人帶來疼痛,、骨折和高鈣血等癥狀，這使得病人生活質(zhì)量非常之低,。以前的研究表明在乳腺癌骨轉(zhuǎn)移過程中破骨細胞發(fā)揮著關(guān)鍵性的作用,，臨床上用于治療乳腺癌骨轉(zhuǎn)移的兩類藥物Bisphosphonates和RANKL抗體（比如Denosumab）主要機制即是抑制破骨細胞活性，具體而言,，前者能引發(fā)破骨細胞發(fā)生細胞凋亡,，后者通過競爭性結(jié)合RANKL而阻礙破骨細胞的成熟。兩種藥物能在一定程度上緩解病人的癥狀但對患者的生存率影響不大,，因此開發(fā)出更有效的阻止乳腺癌骨轉(zhuǎn)移的藥物迫在眉睫,。
健康科學研究所博士研究生王宇峰等在胡國宏研究員的指導下，與齊魯醫(yī)院合作,，利用具有不同骨轉(zhuǎn)移能力的乳腺癌細胞亞系作為模型,，結(jié)合小動物活體成像的檢測發(fā)現(xiàn)DLC1在乳腺癌骨轉(zhuǎn)移過程中起著關(guān)鍵性的負調(diào)控作用。他們的研究證明,，DLC1功能的行使依賴于它失活RHO-ROCK通路,，繼而抑制TGFβ誘導的SMAD3
linker
region磷酸化,。DLC1對后者的抑制降低了TGFβ誘導的PTHLH的轉(zhuǎn)錄和分泌，從而減少骨轉(zhuǎn)移微環(huán)境中的成熟破骨細胞,，最終阻礙了乳腺癌的破骨性轉(zhuǎn)移,。同時他們用一種已通過FDA審批的ROCK抑制劑Fasudil治療乳腺癌骨轉(zhuǎn)移，結(jié)果顯示Fasudil能有效阻遏骨轉(zhuǎn)移的進程,，這暗示這種藥物或許具有進行臨床試驗的價值,。該研究首次證明DLC1-RHO信號通路在調(diào)控乳腺癌骨轉(zhuǎn)移微環(huán)境中的重要作用，也為臨床上治療乳腺癌骨轉(zhuǎn)移提供了新思路,。
該項工作獲得國家科技部973項目,、國家自然科學基金委及中國科學院項目的經(jīng)費資助。
DLC1 inhibits bone metastasis by blocking TGFβ-induced PTHLH
production
Breast cancer is one of the major causes of cancer-related deaths
worldwide, mainly due to outgrowth of cancer cells in vital organs
including the bone, lungs, liver and brain. The majority of
patients with advanced breast cancer will develop bone metastases
and suffer from severe pains and eventually deaths. Current
treatments for bone metastasis have limited efficacy and,
therefore, there is an urgent need to identify functional molecules
in cancer cell bone colonization as new therapeutic targets.
Recently, the research group at Dr.Guohong Hu’s laboratory from
the Institute of Health Sciences defined a novel actor to regulate
breast cancer bone metastasis. This actor, deleted in liver cancer
1 (DLC1), is an important regulator of TGFβ response. DLC1
suppresses bone metastasis by inactivating Rho GTPases, while
Rho-ROCK signaling mediates SMAD3 linker region phosphorylation and
TGFβ-induced expression of parathyroid hormone-like hormone
(PTHLH), leading to osteoclast maturation for osteolytic
colonization. Pharmacological inhibition of Rho-ROCK effectively
reduces PTHLH production and breast cancer bone metastasis. These
findings define a stroma-dependent paradigm of Rho signaling in
cancer bone metastasis and support the application of Rho-ROCK
inhibitors as therapy against breast cancer bone metastasis.
This study entitled “DLC1-dependent parathyroid hormone–like
hormone inhibition suppresses breast cancer bone metastasis” was
published online in The Journal of Clinical Investigation on Mar 3,
2014. This work was funded by the Ministry of Science and
Technology of China, National Natural Science Foundation of China
and Chinese Academy of Sciences.
