Lkb1-Sik軸抑制肺腫瘤生長並控制分化

An Lkb1-Sik axis suppresses lung tumor growth and controls differentiation

• Murray CW, Brady JJ, Tsai MK, et al. An Lkb1-Sik axis suppresses lung tumor growth and controls differentiation. Cancer Discov 2019.
• Corresponding author:Monte M. Winslow Stanford University School of Medicine | 279 Campus Drive, Beckman Center B256, Stanford, CA 94305 Phone: 650-725-8696 | Fax: 650-725-1534 | E-mail: mwinslow@stanford.edu

The kinase, LKB1, is a critical tumor suppressor in sporadic and familial human cancers, yet the mechanisms by which it suppresses tumor growth remain poorly understood. To investigate the tumor-suppressive capacity of four canonical families of Lkb1 substrates in vivo, we employed CRISPR/Cas9-mediated combinatorial genome editing in a mouse model of oncogenic K-ras driven lung adenocarcinoma. We demonstrate that members of the salt-inducible kinase (Sik) family are critical for constraining tumor development.

在散發性和家族性人類癌症中LKB1激酶是一種關鍵的腫瘤抑制因子，但其抑制腫瘤生長的機制仍知之甚少。為了研究Lkb1底物的4個典型家族在體內的抑癌能力，我們採用CRISPR/ cas9介導的組合基因組編輯技術對K-ras癌基因驅動的肺腺癌小鼠模型進行了研究。我們證明，鹽誘導激酶(Sik)家族成員對抑制腫瘤的進展至關重要。

Histological and gene expression similarities between Lkb1- and Sik-deficient tumors suggest that Siks and Lkb1 operate within the same axis. Furthermore, a gene expression signature reflecting Sik deficiency is enriched in LKB1 mutant human lung adenocarcinomas and is regulated by LKB1 in human cancer cell lines. Together, these findings reveal a key Lkb1-Sik tumor-suppressive axis and underscore the need to redirect efforts to elucidate the mechanisms through which LKB1 mediates tumor suppression.

Lkb1和Sik缺陷的腫瘤組織學和基因表達的相似性表明Siks和Lkb1在同一軸上發揮。作用，此外，反映Sik缺陷的基因表達特徵在LKB1突變體人肺腺癌中豐富存在，且在人癌細胞系中受LKB1調控。總之，這些發現揭示了一個關鍵的LKB1- Sik腫瘤抑制軸，並強調有必要重新努力闡明LKB1介導腫瘤抑制的機制。

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