B-cell-specific Moloney murine leukemia virus integration site 1 knockdown impairs adriamycin resistance of gastric cancer cells

Gastric cancer (GC) remains an important global cancer. In 2018, there were about 1.8 million new cases, and by 2040, there will be some 1.3 million deaths [1]. It is the fifth most commonly diagnosed cancer and the third leading cause of cancer-related death, with rates in men twice as high as in women [2]. Surgery and chemotherapy are usual therapies for patients with GC, but the prognosis is not promising owing to tumor metastasis and chemotherapy resistance, with a poor 5-year overall survival rate of less than 15% [3]. For stage IV GC, the 5-year survival rate is even lower, which is only 4% [4].

The molecular mechanisms of GC are complex and not fully understood, but several key pathways have been identified as playing a role in the development and progression of the disease. Some of the most well-known mechanisms include activation of the PI3K/Akt/mTOR pathway; inactivation of the tumor suppressor genes TP53 and APC (adenomatous polyposis coli); aberrant expression of transcription factors, such as c-Myc, Twist1, and Snail; microsatellite instability; and epithelial-mesenchymal transition (EMT) [5], [6], [7]. Drug resistance is a major challenge in the treatment of GC, and the molecular mechanisms underlying this phenomenon are also complicated. The reconstruction of some of the conditions mentioned in GC development, such as PI3K/Akt/mTOR reactivation and reinforced EMT, overexpression of drug efflux pumps, and mutations in genes targeted by chemotherapy drugs are well-known important factors [8], [9], [10], [11]. In addition, STAT3- and SOX family transcription factor-mediated pathways have also been proven to be key signals in chemoresistance of GC [12], [13]. Adriamycin (ADR), also known as doxorubicin, is a chemotherapy drug commonly used to treat various types of cancer. However, some cancer cells have developed resistance to ADR, including GC, making treatment less effective. It can be bound with P-gp, a well-known multidrug membrane transporter, and transferred out of the cells. To overcome ADR resistance, combination therapy with other chemotherapy drugs or targeted therapies may be used. Cancer stem cells (CSCs) have self-renewal potential and are capable of giving rise to more cancer cells, thus also leading to recurrence of GC [10]. It is already known that targeting CSCs is a potential method to reverse therapy resistance [14]. Therefore, drug resistance mediated by CSCs warrants further exploration.

Polycomb group (PcG) gene has a key role in gene expression through chromatin modification in stem cell biology, multicellular development, and cancer [15]. As a member of the PcG transcriptional inhibitor family, B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) was first found by van Lohuizen et al. [16]. Aberrant expression of BMI-1 in various types of human cancers has been reported [17]. Overexpression of BMI-1 is associated with low survival rates of multiple human cancers, including GC, through plenty of signaling pathways in stimulating invasion, proliferation, malignancy, and distant metastasis [17], [18]. It has been found that down-regulation of BMI-1 can inhibit EMT and the invasion of cancer cells, and knocking out BMI-1 could reduce the invasiveness of pancreatic CSCs and its liver metastasis in nude mice [19], [20], [21], [22]. More and more evidence indicates that BMI-1 was related to the progression and chemoresistance of GC [23], [24]. However, little research has been conducted on the role of BMI-1 in gastric cancer stem cell (GCSC) resistance. In this study, we aimed to investigate the biological function of BMI-1 in GC cells and its role in drug resistance of GCSCs.

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