Abstract
Lung adenocarcinoma is often discovered as metastatic disease with very poor prognosis. However, much remains unknown about the mechanisms of lung adenocarcinoma tumor progression. In this study we showed that knockdown of BUB1B/BUBR1, a critical mitotic checkpoint protein, significantly inhibited anchorage-independent growth of lung adenocarcinoma cell lines. In allograft and tail vein mouse model studies, BUB1B suppression inhibited primary tumor growth and reduced metastasis to the lung and lymph nodes, resulting in prolonged survival in both tumor prevention and tumor intervention settings. Mechanistic studies revealed that BUB1B knockdown sensitized cells to anoikis. The N-terminal region and GLEBS domain of BUB1B were required for its functions in both anchorage-independent growth and anoikis resistance, whereas the kinase domain was less critical. Overexpression of BUB1B is associated with disease progression and poor survival in human lung adenocarcinoma patients. Collectively, these data reveal a novel function for BUB1B in mediating anchorage-independent survival and growth, thereby facilitating lung adenocarcinoma dissemination during metastasis. Thus, targeting BUB1B could provide potential therapeutic benefit in suppressing metastasis and prolonging survival in lung adenocarcinoma patients.
Highlights
Lung cancer is the leading cause of cancer-related mortality worldwide, resulting in more than a million deaths per year [1]
We further examined the effect of BUB1B knockdown in multiple human lung adenocarcinoma cell lines (Table S1)
Very few human lung adenocarcinoma cell lines with wild-type TP53 were capable of AIG, three cell lines that were permissive were more sensitive to BUB1B knockdown compared to those harboring TP53 alterations (Figure 1G)
Summary
Lung cancer is the leading cause of cancer-related mortality worldwide, resulting in more than a million deaths per year [1]. Identification of driver mutations that frequently occur in subsets of lung adenocarcinoma has brought significant advances in molecular diagnostics and targeted therapies for this disease. About half of lung adenocarcinoma harbors no known oncogenic drivers [2, 3]. While lung adenocarcinoma is often discovered as locally advanced or metastatic disease with an average 5-year survival rate of ~15% [4], the mechanisms mediating tumor progression and metastasis remain largely uncharacterized. A recent mapping of somatic alterations to cancer hallmarks illuminates many gaps in the understanding of the somatic underpinnings of lung adenocarcinoma [5]. Knowledge of additional genomic changes in lung adenocarcinoma, especially those involved in tumor metastasis, is needed to further guide diagnosis and treatment
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