肺癌是最常見的肺原發(fā)性惡性腫瘤,，絕大多數(shù)肺癌起源于支氣管粘膜上皮,，故亦稱支氣管肺癌。近50多年來,，世界各國特別是工業(yè)發(fā)達國家,，肺癌的發(fā)病率和病死率均迅速上升，肺癌目前是全世界癌癥死因的第一名,。
早期研究已證實肺癌起源于支氣管粘膜上皮,，局限于基底膜內(nèi)者稱為原位癌癌腫，可向支氣管腔內(nèi)或/和臨近的肺組織生長,，并可通過淋巴血行或經(jīng)支氣管轉(zhuǎn)移擴散,。近來研究人員發(fā)現(xiàn)基底干細胞能導(dǎo)致肺鱗癌的發(fā)生發(fā)展,，但其具體分子機制尚未完全明了。
最近,，一項刊登在The Journal of Pathology的研究揭示：β-連環(huán)蛋白（β-catenin）調(diào)控氣管基底膜細胞的分化,，參與了肺鱗癌的發(fā)生發(fā)展過程。
研究者發(fā)現(xiàn)氣管基底膜細胞中β-連環(huán)蛋白表達的上調(diào)與肺鱗癌的嚴(yán)重程度,、上皮細胞的增殖以及細胞間黏附的減少有正相關(guān)性,。科學(xué)家通過抑制β-連環(huán)蛋白發(fā)現(xiàn)：在表達角蛋白-14（Keratin14）的基底膜細胞中,，抑制β-連環(huán)蛋白會導(dǎo)致正常氣道修復(fù)減緩,，而當(dāng)β-連環(huán)蛋白信號通路被特異性激活時，基底膜細胞的增殖速度,、分化以及上皮-間質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transitions, EMT)都會大大增加,。
體外實驗中，研究人員對正常人氣管基底膜上皮細胞用藥物特異性激活β-catenin,，結(jié)果也發(fā)現(xiàn)細胞的增殖,、分化和早期上皮-間質(zhì)轉(zhuǎn)化加快等類似現(xiàn)象。
總之該項研究表明,，氣管基底膜細胞中β-連環(huán)蛋白的表達與基底膜細胞的分化,、肺鱗癌的發(fā)生發(fā)展有著緊密聯(lián)系，或許可以成為新的治療肺癌的靶標(biāo),。(生物谷 Bioon.com)
doi:10.1002/path.3962
PMC:
PMID:
β-Catenin determines upper airway progenitor cell fate and preinvasive squamous lung cancer progression by modulating epithelial-mesenchymal transition.
Giangreco A, Lu L, Vickers C, Teixeira VH, Groot KR, Butler CR, Ilieva EV, George PJ, Nicholson AG, Sage EK, Watt FM, Janes SM.
Human lung cancers, including squamous cell carcinoma (SCC) are a leading cause of death and, whilst evidence suggests that basal stem cells drive SCC initiation and progression, the mechanisms regulating these processes remain unknown. In this study we show that β-catenin signalling regulates basal progenitor cell fate and subsequent SCC progression. In a cohort of preinvasive SCCs we established that elevated basal cell β-catenin signalling is positively associated with increased disease severity, epithelial proliferation and reduced intercellular adhesiveness. We demonstrate that transgene-mediated β-catenin inhibition within keratin 14-expressing basal cells delayed normal airway repair while basal cell-specific β-catenin activation increased cell proliferation, directed differentiation and promoted elements of early epithelial-mesenchymal transition (EMT), including increased Snail transcription and reduced E-cadherin expression. These observations are recapitulated in normal human bronchial epithelial cells in vitro following both pharmacological β-catenin activation and E-cadherin inhibition, and mirrored our findings in preinvasive SCCs. Overall, the data show that airway basal cell β-catenin determines cell fate and its mis-expression is associated with the development of human lung cancer.
