SEZ6L2 Is an Important Regulator of Drug-Resistant Cells and Tumor Spheroid Cells in Lung Adenocarcinoma.

Jang-Seok Lee,Bomyi Won,Hyonchol Jang,Sang Won Kang,Hee Yeon Kim,Yong-Nyun Kim

doi:10.3390/biomedicines8110500

Jang-Seok Lee, Bomyi Won + Show 4 more

Open Access

https://doi.org/10.3390/biomedicines8110500

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Journal: Biomedicines	Publication Date: Nov 13, 2020
Citations: 16	License type: CC BY 4.0

Affiliation: National Cancer Center, Ewha Womans University

Abstract

Many lung cancer deaths result from relapses in distant organs, such as the brain or bones, after standard chemotherapy. For cancer cells to spread to other organs, they must survive as circulating tumor cells (CTCs) in blood vessels. Thus, reducing distant recurrence after chemotherapy requires simultaneously inhibiting drug resistance and CTC survival. Here, we investigated the molecular pathways and genes that are commonly altered in drug-resistant lung cancer cells and lung tumor spheroid (TS) cells. First, RNA sequencing was performed in drug-resistant cells and TS cells originating from H460 and A549 lung cancer cells. Bioinformatic pathway analysis showed that cell cycle-related pathways were downregulated in drug-resistant cells, and cholesterol biosynthesis-related pathways were upregulated in TS cells. Seizure-related 6 homolog-like 2 (SEZ6L2) was selected as a gene that was commonly upregulated in both drug-resistant cells and TS cells, and that showed elevated expression in samples from lung adenocarcinoma patients. Second, the protein expression of SEZ6L2 was analyzed by flow cytometry. The proportions of SEZ6L2 positive cells among both drug-resistant cells and TS cells was increased. Finally, as SEZ6L2 is a transmembrane protein with an extracellular region, the function of SEZ6L2 was disrupted by treatment with an anti-SEZ6L2 antibody. Treatment with the anti-SEZ6L2 antibody reduced drug resistance and TS formation. Overall, our data showed that SEZ6L2 plays an important role in drug resistance and TS formation and may be a therapeutic target for reducing distant recurrence of lung adenocarcinoma.

Highlights

Lung cancer is the leading cause of cancer deaths worldwide [1]
We showed that inhibition of Seizure-related 6 homolog-like 2 (SEZ6L2) via treatment with an anti-SEZ6L2 antibody reduced drug resistance and tumor spheroid (TS) formation, suggesting that anti-SEZ6L2 antibody therapy may be an option for reducing tumor relapse after chemotherapy in lung adenocarcinoma (LUAD)
As cancer cells continue to die for a period after cessation of the anticancer drug treatment (Figure 1A, right), the culture medium was exchanged for fresh medium 3 days after treatment with the anticancer drugs, and the cells were cultured for an additional 3 days

Summary

Introduction

Lung cancer is the leading cause of cancer deaths worldwide [1]. 85% of lung cancer patients are diagnosed with non-small cell lung cancer (NSCLC), and the two major NSCLC subtypes are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma [2,3]. Many treatments have been developed for lung cancer, including surgery, chemotherapy, and radiation therapy. Despite improvements in lung cancer treatment, many patients with NSCLC experience recurrence after surgery or chemotherapy [4,5,6]. 65% of NSCLC patients will develop persistent disease or distant metastasis to the brain or bone after surgery and postoperative adjuvant therapy [7,9,10]

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