Abstract
Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.
Highlights
Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood
We further identified the stress response pathway MKK7-JNK1/2 as downstream effectors of Lkb[1] in suppressing ΔNp63 signaling during LSCC development
LSCCs were found in Lkb1d/d mice, as early as, 11 months old in addition to AD (Fig. 1a and Supplementary Fig. 2a–b; Table 1 and Supplementary Data 1−2)
Summary
Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb[1], and demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC. Mutations in one single gene lead to lung adenocarcinomas (ADs), as shown by Trp[53] deficiency, Pten ablation, KrasG12D or EgfrL858R activation and Sox[2] overexpression (Sox2OX)[10,12,13,14]. LSCC can be initiated by a single gene mutation remains outstanding and the underlying mechanism of LSCC formation and progression remains unclear[4,15]
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