Maddi Engelhaupt

Introduction. Squamous cell lung cancer (SqCLC) comprises 90% of all non-small cell lung cancers (NSCLC)¹. Of which, only 15% survive more than 5 years¹. This poor prognosis contributes to lung cancer being the leading cause of death worldwide². High mortality of SqCLC may be attributed to limited prevention and detection, late diagnosis, and lack of treatment that targets SqCLC at the molecular level^1-4. Additionally, tumors of SqCLC are often unresectable due to their central location in the bronchi⁴. Therefore, new therapies are critical for survival of these patients. There is evidence that Sry-related HMG box 2 (SOX2) is overexpressed in 70-80% of SqCLC cases¹. Considering its role in maintaining cancer stem cell function, SOX2 has been examined as a target for SqCLC treatment⁵. Methods. Western blot and qPCR were used to compare FGFR1-amplified lung cancer cell lines⁶. SOX2 overexpression was modeled via the addition of human SOX2 lentivirus to cell lines⁶. Tumors from an orthotopic lung cancer model were stained with HE and immunofluorescence to visualize epithelial to mesenchymal transition (EMT)⁶. Patients with SqCLC were staged, and tumor specimens were analyzed for SOX2 and miR-590-5p expression⁷. RT-qPCR was used to analyze SOX2 expression during PRRX1A/B overexpression vs knockdown in human NSCLC cell lines⁵.  Results. SOX2 overexpression results in increased cell proliferation, migration, invasion, and EMT⁶. As SOX2 expression increases, lymph node metastasis and cancer stage also increase while overall survival decreases^{6, 7}. The mechanism of SOX2-induced EMT involves fibroblast growth factor 2 (FGF2) binding fibroblast growth factor receptor 1 (FGFR1) causing downstream phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2)⁶. Activated ERK1/2 facilitates a downstream phosphorylation cascade that results in SOX2 overexpression⁶. SOX2 is then stabilized by binding of a paired-related homeobox 1 isoform (PRRX1A) via a TGF-beta/TGF-beta receptor pathway⁵. Inhibition of upstream regulators, FGFR1 or ERK1/2, does not prevent EMT or metastasis when SOX2 is overexpressed⁶. Downregulation of SOX2 via a miR-590-5p mimic does prevent EMT and metastasis, and high miR-590-5p expression is present in tumors of patients with lower cancer stages and absent lymph node metastasis⁷. Additionally, knockdown of PRRX1A/B results in tumor size reduction due to subsequent SOX2 instability⁵. Conclusions. SOX2 is upregulated in SqCLC and is essential for EMT, tumor growth and metastasis^{6, 8, 9}. Inhibition of SOX2 directly via specific miRNAs or by harnessing the anti-SOX2 effects of cancer associated fibroblasts, shows potential to reverse premalignant metaplasias, halt tumor progression and metastasis, and promote tumor regression^{7, 9}.

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6. Wang K, Ji W, Yu Y, et al. FGFR1-ERK1/2-SOX2 axis promotes cell proliferation, epithelial-mesenchymal transition, and metastasis in FGFR1-amplified lung cancer. Oncogene. Sep 2018;37(39):5340-5354. doi:10.1038/s41388- 018-0311-3
7. Chang Z. Downregulation of SOX2 may be targeted by miR-590-5p and inhibits epithelial-to-mesenchymal transition in non-small-cell lung cancer. Exp Ther Med. Aug 2019;18(2):1189-1195. doi:10.3892/etm.2019.7642
8. Aruga N, Kijima H, Masuda R, et al. Epithelial-mesenchymal Transition (EMT) is Correlated with Patient’s Prognosis of Lung Squamous Cell Carcinoma. Tokai J Exp Clin Med. Apr 20 2018;43(1):5-13.
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