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Biomedical Journal of Scientific & Technical Research

August, 2019, Volume 20, 5, pp 15353-15355

Short Communication

Short Communication

Inactivation of JNK1/2 Promotes Lung Squamous Cell Carcinoma in Lkb1 Deficiency Mice

Ji Ying Song*

Author Affiliations

Department of Experimental Animal Pathology, The Netherlands Cancer Institute

Received: August 14, 2019 | Published: August 22, 2019

Corresponding author: Ji-Ying Song, Department of Experimental Animal Pathology The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

DOI: 10.26717/BJSTR.2019.20.003505

Short Communication

Lung cancer is the leading cause of cancer-associated mortality worldwide. In the last two decades, great efforts were made to search for effective treatments by identifying drug-targetable biomarkers based on multiple levels of genomic and epigenomic investigations. Histologically, lung cancer can be classified as two major subtypes, namely adenocarcinoma (ADC) and squamous cell carcinoma (SCC), together they account for more than 80% of cases. Although more than 50% of lung cancers showed a mix of the subtypes indicating a high degree of heterogeneity of these tumors [1,2], the ADC and SCC are shown to possess a distinct pattern of genomic abnormalities [3,4]. By mimicking genomic alterations of human cancer in mice, the whole process of tumorigenesis from initial to advanced stages can be dissected and studied in a spatial and temporal manner. Thereby it is possible to recapitulate, validate, and identify new targets for therapeutics. Importantly, the generated mouse models can be applied for testing new therapeutic strategy as well as drug resistance management.

Unlike previous Lung SCC (LSCC) models in which compound mutations and depletions were involved such as KrasG12D/ Lkb1loss, Sox2ox/ Lkb1loss, or Ptenloss/ Lkb1loss[5,7], Jian Liu et al. were able to show that Lkb1 deficiency by itself was sufficient to induce LSCC in 11-14 months after application of CCSPiCre in Lkb1f / f mice with a penetrance of 32.8% of LSCC and its initial lesions (Nature Communication, 10:1-16, 2019) [8]. Impressively the process of tumorigenesis was accelerated to 7-8 months when Jnk1d/d / Jnk2−/− was combined and a 100% penetrance of LSCC and its initial lesions was achieved!

In human, LSCC is initiated from epithelial hyperplasia and squamous cell metaplasia in bronchus/bronchiole, followed by dysplasia and carcinoma. Jian Liu et al. succeeded in mimicking this process and demonstrated sequential lesions of hyperplasia, squamous cell metaplasia, and SCC in the large airway of LKb1 deficiency mice. Importantly the lesions recapitulated the characteristics of human LSCC such as expression of ΔNp63/P63 and CK5 and had a high degree of a positive relationship with human LSCC in transcriptome profiling. Furthermore, in GSEA (Gene Set Enrichment Analysis) the authors identified the JNK1/2 phosphorylation-induced pathway that was the top enriched pathway and was negatively associated with the Lkb1 deficiency gene signature.

To address JNK1/2 as major suppressors for Lkb1-dependent LSCC initiation and progression, the authors conducted in vitro and in vivo investigations by ablating JNK1/2 in mLSCC cells and knocking JNK1/2 out in Lkb1 deficiency mice. The results thereby showed increased cell growth in vitro and acceleration of LSCC development with a full penetrance in vivo. In this context, they were able to associate Jnk1/2 knockout or inactivation with activation of ΔNp63 / p63 pathways that led to LSCC initiation and progress. Conversely, Jian Liu et al. utilized JNK1/2 activators such as Anisomycin for pharmaceutical activation of JNK1/2 in mice that resulted in a decrease of expression of ΔNp63 / p63 and consequently a lower incidence of LSCC. Thereby they elucidated a negative regulation of JNK1/2 on the Np63/p63 pathway involving in LSCC development. The negative relationship between JNK1/2 activation and P63 expression could be clinically relevant for prediction and treatment of LSCC patients when low JNK1/2 phosphorylation level is evident.

As shown by Jian Liu et al. and others [9], high inflammatory responses were present in mouse models of LSCC that resembled the human counterpart. Further investigations in the role of JNK1/2 and its regulation by cytokines will add more insight into the significance of the tumor microenvironment involving in tumor initiation and progress, which may provide new approaches towards LSCC management.

References

Short Communication

Inactivation of JNK1/2 Promotes Lung Squamous Cell Carcinoma in Lkb1 Deficiency Mice

Ji Ying Song*

Author Affiliations

Department of Experimental Animal Pathology, The Netherlands Cancer Institute

Received: August 14, 2019 | Published: August 22, 2019

Corresponding author: Ji-Ying Song, Department of Experimental Animal Pathology The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

DOI: 10.26717/BJSTR.2019.20.003505

Abstract

Lung cancer is the leading cause of cancer-associated mortality worldwide. In the last two decades, great efforts were made to search for effective treatments by identifying drug-targetable biomarkers based on multiple levels of genomic and epigenomic investigations. Histologically, lung cancer can be classified as two major subtypes, namely adenocarcinoma (ADC) and squamous cell carcinoma (SCC), together they account for more than 80% of cases. Although more than 50% of lung cancers showed a mix of the subtypes indicating a high degree of heterogeneity of these tumors [1,2], the ADC and SCC are shown to possess a distinct pattern of genomic abnormalities [3,4].