Oncogenic ADAM28 induces gemcitabine resistance and predicts a poor prognosis in pancreatic cancer

Abstract

BACKGROUNDPancreatic cancer is a major cause of cancer-related death, with a 5-year overall survival rate being below 5%. The main causes of poor prognosis in pancreatic cancer include easy metastasis, high recurrence rate, and robust drug resistance. Gemcitabine is a first-line drug for patients with unresectable pancreatic cancer. However, due to drug resistance, the clinical effect is not satisfactory. ADAM28 is reported as a tumor promoter in some cancers, but its role in pancreatic cancer and gemcitabine chemoresistance in pancreatic cancer has not been elucidated.AIMTo identify if ADAM28 can act as an important target to reverse the gemcitabine drug resistance in pancreatic cancer.METHODSRNA-sequence analysis was applied to explore the potential targets involved in the gemcitabine of pancreatic cancer. SW1990 pancreatic cancer cells were treated with an increased dose of gemcitabine, and the mRNA levels of ADAM28 were evaluated by RT-PCR. The protein and mRNA levels of ADAM28 were confirmed in the gemcitabine resistant and parallel SW1990 cells. The ADAM28 expression was also assessed in TCGA and GEO databases, and the results were confirmed in the collected tumor and adjacent normal tissues. The overall survival (OS) rate and relapse-free survival (RFS) rate of pancreatic cancer patients with high ADAM28 level and low ADAM28 level in TCGA were evaluated with Kaplan-Meier Plotter. Furthermore, the OS rate was calculated in pancreatic cancer patients with high tumor mutation burden (TMB) and low TMB. CCK-8 assay was used to examine the effect of ADAM28 on the viability of SW1990 cells. The ADAM28 and its co-expressed genes were analyzed in the cBioPortal for cancer genomics and subjected to GSEA pathway analysis. The correlations of ADAM28 with GSTP1, ABCC1, GSTM4, and BCL2 were analyzed based on TCGA data on pancreatic cancer.RESULTSRNA-sequence analysis identified that ADAM28 was overexpressed in gemcitabine-resistant cells, and gemcitabine treatment could induce the expression of ADAM28. The mRNA and protein levels of ADAM28 were elevated in gemcitabine-resistant SW1990 cells compared with parallel cells. Also, the expression of ADAM28 was upregulated in pancreatic tumor tissues against normal pancreatic tissues. Notably, ADAM28 was highly expressed in the classical type than in the basal tumor type. Furthermore, the high expression of ADAM28 was associated with low OS and RFS rates. Interestingly, the high levels of ADAM28 was associated with a significantly lower OS rate in the high TMB patients, but not in the low TMB patients. Moreover, overexpression of ADAM28 could reduce the cell viability inhibition by gemcitabine, and knockdown of ADAM28 could enhance the proliferation inhibition by gemcitabine. The GSEA analysis showed that ADAM28 was related to the regulation of drug metabolism, and ADAM28 was significantly positively correlated with GSTP1, ABCC1, GSTM4, and BCL2.CONCLUSIONThis study demonstrates that ADAM28 is overexpressed in pancreatic cancer, and closely involved in the regulation of gemcita...

ADAM28: Another ambivalent protease in cancer

“…ADAM28 is overexpressed by carcinoma cells in multiple cancer types: breast cancer [9,12,13], renal cell carcinoma [58], non-small cell lung carcinoma (NSCLC) [59,60], leukemia [49,61], prostate cancer [29], chondrosarcoma [62], bladder cancer [63], pancreatic cancer [64] and head and neck carcinoma [65]. In experimental in vitro models, ADAM28 expression is induced by the protein kinase src in v-src-transformed epithelial cells and in various human carcinoma cells including PC-9 and MDA-MB231 cells [66].…”

“…Besides, ADAM28 expression is higher in tumors from patients displaying asbestos-related lung cancer than in tumors from patients with non-asbestos related lung cancer suggesting that ADAM28 is a potential oncogene in this cancer and could be a biomarker for asbestos-related lung cancer [69]. In pancreatic cancer, ADAM28 contributes to gemcitabine resistance and is a factor of poor prognosis in terms of overall survival (OS) and relapse-free survival (RFS) since patients with high ADAM28 expression exhibit a worse OS and RFS [64]. Many studies report the contribution of ADAM28 to development and progression of various cancers and some consider ADAM28 as a potential therapeutic target [3,4,70,71].…”

DDIT4 Novel Mutations in Pancreatic Cancer

“…The UTR mutation of DDIT4 is involved in autophagy of pancreatic cancer cells by regulating the expression of DDIT4, and it may be a potential biomarker for chemotherapy resistance and poor prognosis. The overexpression of ADAM28 in pancreatic cancer is closely related to the regulation of gemcitabine resistance, so it is a new prognostic biomarker in pancreatic cancer [ 31 ]. High expression of miR-155-5p is directly associated with chemotherapy resistance and poor prognosis in PDAC patients treated with gemcitabine [ 32 ].…”

Wogonoside inhibits TNF receptor-associated factor 6 (TRAF6) mediated-tumor microenvironment and prognosis of pancreatic cancer

“…However, in 2020, there were approximately 57,600 newly diagnosed patients and 47,050 deaths in the United States (2). Considering the 5-year survival rate of PC was less than 5%, PC is considered one of the worst prognostic malignant cancers (3). Low early diagnosis rates, high cancer recurrence, metastasis rates, and energetic drug resistance are all responsible for the poor prognosis of PC (3,4).…”