Abstract
NIMA-related kinase 7 (NEK7) is a serine/threonine kinase involved in cell cycle progression via mitotic spindle formation and cytokinesis. It has been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer, and colorectal cancer. Moreover, NEK7 regulated the NLRP3 inflammasome to activate Caspase-1, resulting in cell pyroptosis. In the present study, we investigated whether NEK7 is involved in cell pyroptosis of hepatocellular carcinoma (HCC). Interestingly, we found that NEK7 was significantly related to expression of pyroptosis marker GSDMD in HCC. We found that NEK7 expression was significantly correlated with GSDMD expression in bioinformatics analysis, and NEK7 expression was significantly co-expressed with GSDMD in our HCC specimens. Cell viability, migration, and invasion capacity of HCC cell lines were inhibited, and the tumor growth in the xenograft mouse model was also suppressed following knockdown of NEK7 expression. Mechanistic studies revealed that knockdown of NEK7 in HCC cells significantly upregulated the expression of pyroptosis markers such as NLRP3, Caspase-1, and GSDMD. Coculture of HCC cells stimulated hepatic stellate cell activation by increasing p-ERK1/2 and α-SMA. Knockdown of NEK7 impaired the stimulation of HCC cells. Therefore, downregulation of NEK7 inhibited cancer–stromal interaction by triggering cancer cell pyroptosis. Taken together, this study highlights the functional role of NEK7-regulated pyroptosis in tumor progression and cancer–stromal interaction of HCC, suggesting NEK7 as a potential target for a new therapeutic strategy of HCC treatment.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second most common cause of cancer deaths worldwide [1], with a 5-year overall survival rate of 12% and a median survival of 23 months for Chinese hepatocellular carcinoma (HCC) patients [2]
By analyzing UALCAN [26], we found that expressions of NIMA-related kinase 7 (NEK7) and Gasdermin D (GSDMD) were significantly upregulated in tumor tissues compared to tumoradjacent normal tissues of liver hepatocellular carcinoma (Figure 1A)
Based on the bioinformatic analysis of the datasets from The Cancer Genome Atlas (TCGA, https:// www.cancer.gov/tcga) database [27], we found that NEK7 expression was highly correlated with expression levels of Kras and GSDMD in HCC tumor tissues (Figures 1F, G and S1B)
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second most common cause of cancer deaths worldwide [1], with a 5-year overall survival rate of 12% and a median survival of 23 months for Chinese HCC patients [2]. Early-stage HCC may be treated with surgical resection and systemic therapy. Treatment is associated with high overall relapse rates, and curative resection is not feasible after tumor progressed [3]. More >70% of patients with HCC are diagnosed at the late stage [4, 5]. As curative resection and chemotherapy are not feasible, it is urgent to explore nonsurgical therapeutic approaches for new biomarkers and effective therapeutic strategies [6]. NIMA-related kinases (NEKs) of NEK1 to NEK11 are serine/ threonine kinases that drive cell-cycle dynamics by modulating mitotic spindle formation and cytokinesis [7]. The biological role of NEK7 was not limited to cell proliferation capacity; involvement of NEK7 in tumorigenesis and metastasis was proved [9–12]
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