Abstract
Multidrug resistance (MDR) is one of the most important contributors to the high mortality of cancer and remains a major concern. We previously found that zinc finger protein 32 (ZNF32), an important transcription factor associated with cancer in Homo sapiens, protects tumor cells against cell death induced by oxidative stress and other stimuli. We thus hypothesized that ZNF32 might enable the tolerance of cancer cells to anti-tumor drugs because higher ZNF32 expression has been found in cancer tissues and in drug-resistant lung adenocarcinoma (AC) cells. In this study, we found that ZNF32 is upregulated by Sp1 (specificity protein 1) in response to drug treatment and that ZNF32 promotes drug resistance and protects AC cells against cisplatin or gefitinib treatment. ZNF32 overexpression in AC cells conferred resistance to EGFR (epidermal growth factor receptor) inhibitors by enhancing MEK/ERK activation. Moreover, ZNF32 was found to directly bind to the TGF-βR2 (transforming growth factor-beta receptor 2) promoter to promote its expression, and ZNF32-induced resistance was mediated by enhancing TGF-βR2 expression and activating the TGF-βR2/SMAD2 pathway. In both a mouse model and ex vivo cultured patient samples, a high level of ZNF32 expression was closely associated with worse overall survival and cisplatin resistance. ZNF32 appears to be a potential inducer of drug resistance that could increase the expression of the drug resistance-associated gene TGF-βR2 and subsequently facilitate the induction of drug resistance during both conventional chemotherapy and novel target therapy. Thus, ZNF32-associated target therapy is a potential novel adjuvant therapy that might effectively prevent the occurrence of multidrug resistance (MDR) during chemotherapy and improve the survival of patients with AC.
Highlights
Lung cancer is one of the most lethal cancers throughout the world.[1]
High ZNF32 expression was observed in the AC tissues, whereas weaker ZNF32 expression was detected in the adjacent normal (AN) tissues (Figure 1a)
Higher ZNF32 expression was found in lung cancer cells (A549 and PC9 cells) compared with primary lung epithelial cells NHBE (Supplementary Figure S1A)
Summary
Lung cancer is one of the most lethal cancers throughout the world.[1]. Approximately 85% of lung cancers are non-small cell lung cancer (NSCLC),[2] and lung AC is the most common histological subtype of NSCLC, making up more than 50% of all NSCLCs.[3]. The overall survival of these patients is improved compared with that obtained with the best supportive care,[4] the therapeutic plateau has been reached, with a response rate of approximately 20% and a median survival of 8–10 months.[5] On the basis of the results of studies on the mechanism underlying the carcinogenesis and progression of NSCLC, EGFR became one of the landmark targets of NSCLC therapy. The effects of chemotherapy and target therapy on cancer cells are lost due to the emergence of drug resistance,[14,15,16] and resistance to anti-tumor therapy remains a major concern. The aim of the present study was to determine the role of ZNF32 in MDR in lung AC and to further identify the underlying mechanisms
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