Abstract
PurposeCD147 is a tumor-associated antigen that plays a key regulatory role in tumor invasion and distant metastasis. However, the exact role of CD147 phosphorylation, which is deregulated during cancer progression, is unknown. Here, the effects of CD147 phosphorylation on the malignant behavior of hepatocellular carcinoma (HCC) cells and its possible underlying mechanisms are explored.MethodsAn in situ Duolink-proximity ligation assay (PLA) was used to detect CD147 phosphorylation. Tandem mass spectrometry was employed to identify the phosphorylation sites of CD147. The effects of CD147 phosphorylation on the malignant behavior of HCC cells were evaluated using scratch wound healing assays, transwell invasion assays and cell cycle assays. The genes regulated by CD147 phosphorylation were detected by RNA sequencing.ResultsWe identified phosphorylated serine-246 in the C terminus of CD147 in primary HCC tissues, whereas serine to alanine substitution mutation analysis suggested that CD147 is phosphorylated mainly at serine-252 in HCC-derived Huh-7 cells. Recovery expression of S246A/S252A mutants in CD147 knockout cells revealed significantly increased migration and invasion capacities compared to wildtype CD147 expressing cells. Cyclophilin A (CyPA) treatment decreased the phosphorylation level of CD147, whereas NIMA-related kinase 6 (NEK6) increased the CD147 phosphorylation level. Moreover, the CD147 phosphorylation level was found to be dramatically decreased in HCC tissues in patients with distant metastases, and a low phosphorylation level of CD147 was found to be associated with a high serum AFP level, recurrence and a poor overall survival.ConclusionsFrom our data we conclude that hypo-phosphorylated CD147 promotes the migration and invasion of HCC cells and correlates with an unfavorable prognosis in HCC patients, indicating that targeting the aberrantly hypo-phosphorylated form of CD147 may be instrumental for the development of novel therapeutic modalities directed against HCC metastasis.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies and one of the most frequent causes of cancerrelated death in the world [1]
We found that the phosphorylation level of CD147 was dramatically decreased in hepatocellular carcinoma (HCC) with distant metastases and that low CD147 phosphorylation levels were associated with high serum AFP levels, disease recurrence and a poor overall survival, suggesting that the aberrantly hypo-phosphorylated form of CD147 may serve as a valuable biomarker for prognosis assessment and the development of novel therapeutic modalities directed against HCC metastasis
As mass spectrometry-based global phosphoproteome analysis has revealed that CD147 can be phosphorylated at Ser246 and/or Ser252 in various human tissues and cell lines, we first examined whether CD147 is phosphorylated in HCC tissues and cell lines
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies and one of the most frequent causes of cancerrelated death in the world [1]. Despite significant improvements in both diagnostic and therapeutic modalities, metastasis is still a major contributor of treatment failure and death [2,3,4]. Failures to combat HCC invasion and metastasis have become major obstacles to improvements in the survival and quality of life of HCC patients [9]. CD147 has been found to be overexpressed in a broad range of human malignant tumors including HCC [11] and has been implicated in various aspects of tumor progression, in particular HCC metastasis [12]. We and others have previously shown that CD147 can promote the migration, invasion, proliferation and survival of tumor cells [13,14,15,16,17]. Overexpression of CD147 in tumor cells as well as in serum has been recognized as an unfavourable prognostic factor [18, 19]
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