Conditional ERK3 overexpression cooperates with PTEN deletion to promote lung adenocarcinoma formation in mice

Abstract

ERK3, officially known as mitogen-activated protein kinase 6 (MAPK6), is a poorly studied mitogen-activated protein kinase (MAPK). Recent studies have revealed the upregulation of ERK3 expression in cancer and suggest an important role for ERK3 in promoting cancer cell growth and invasion in some cancers, in particular lung cancer. However, it is unknown whether ERK3 plays a role in spontaneous tumorigenesis in vivo. To determine the role of ERK3 in lung tumorigenesis, we created a conditional ERK3 transgenic mouse line in which ERK3 transgene expression is controlled by Cre recombinase. By crossing these transgenic mice with a mouse line harboring a lung tissue-specific Cre recombinase transgene driven by a club cell secretory protein gene promoter (CCSP-iCre), we have found that conditional ERK3 overexpression cooperates with phosphatase and tensin homolog (PTEN) deletion to induce the formation of lung adenocarcinomas (LUADs). Mechanistically, ERK3 overexpression stimulates activating phosphorylations of erb-b2 receptor tyrosine kinases 2 and 3 (ERBB2 and ERBB3) by upregulating Sp1 transcription factor (SP1)-mediated gene transcription of neuregulin 1 (NRG1), a potent ligand for ERBB2/ERBB3. Our study has revealed a bona fide tumorpromoting role for ERK3 using genetically engineered mouse models. Together with previous findings showing the roles of ERK3 in cultured cells and in a xenograft lung tumor model, our findings corroborate that ERK3 acts as an oncoprotein in promoting LUAD development and progression.

Role of the Atypical MAPK ERK3 in Cancer Growth and Progression

“…These findings suggest that ERK3 itself may not be able to transform normal epithelial cells but is capable of promoting tumor growth once cells are transformed and/or tumorigenic following the loss-of-function mutation of tumor suppressor genes (e.g., PTEN) or gain-of-function mutation(s) of oncogenes such as KRAS G12 mutations. In line with the cooperative role for ERK3 overexpression and PTEN deletion in promoting tumor growth in vivo [41], ERK3 was shown to activate AKT via phosphorylating S473, thereby promoting xenograft tumor growth of both lung cancer cells and breast cancer cells (Figure 2) [44]. The role of ERK3 in promoting tumor cell growth can be explained, at least partially, by its functions in regulating cell cycle progression.…”

“…ERK3 overexpression alone had little effect on lung epithelial cell growth (cell proliferation and apoptosis) and conditional deletion of PTEN tumor suppressor induced hyperplasia of lung epithelium. However, ERK3 overexpression, in combination with PTEN deletion, increased cell proliferation, decreased cell apoptosis and promoted lung tumor formation [41]. These findings suggest that ERK3 itself may not be able to transform normal epithelial cells but is capable of promoting tumor growth once cells are transformed and/or tumorigenic following the loss-of-function mutation of tumor suppressor genes (e.g., PTEN) or gain-of-function mutation(s) of oncogenes such as KRAS G12 mutations.…”

“…ERK3 protein also has heightened expression in actinic keratosis and cutaneous squamous cell carcinoma compared with normal skin tissue [40]. Additionally, in human lung adenocarcinoma, ERK3 mRNA expression is inversely correlated with PTEN protein expression [41].…”

“…Intriguingly, ERK3 expression level is upregulated in LUAD regardless of KRAS mutation status [44]. The idea that the role of ERK3 in cell growth is affected by other molecular alterations is supported by multiple lines of research, including a transgenic mouse study in which ERK3 was conditionally overexpressed in lungs [41]. ERK3 overexpression alone had little effect on lung epithelial cell growth (cell proliferation and apoptosis) and conditional deletion of PTEN tumor suppressor induced hyperplasia of lung epithelium.…”

Deguelin Attenuates Non-Small-Cell Lung Cancer Cell Metastasis by Upregulating PTEN/KLF4/EMT Signaling Pathway

“…The activation of tumor suppressor genes and oncogenes, including phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and Krüppel-like factor 4 (KLF4), plays a key role in regulating the occurrence and development of tumors. PTEN is a tumor suppressor gene that is closely related to tumorigenesis, and its functional defect exists widely in many kinds of tumors [ 14 – 16 ]. KLF4 plays a dual role in both oncogenes and tumor suppressor genes, and its expression is tissue or cell specific [ 17 – 20 ].…”