Lung cancer has become a global health problem due to high morbidity and high mortality (20). Lung adenocarcinoma (ADC) is a histological type of non-small cell lung cancer that is becoming a major component of lung cancer (20–22). Despite significant advances in cancer treatment in recent years, 5-year survival rate of ADC is still not satisfactory (23, 24). With the advent of precision medicine concepts, molecular biomarkers and molecular drug targets have become hotspots in cancer research, thus targeted treatment of certain targets has enabled tumor patients to get different degrees of treatment benefits. For example, lung cancer patients with EGFR mutations can benefit from the treatment of TKIs, such as Gefitinib and Erlotinib (25). Other potential biomarkers are mainly oncogene-driven mutations, including ALK translocation and ROS1 gene rearrangement (26, 27). Therefore, there is an urgent need to identify and validate clinically relevant and effective prognostic markers for lung ADC to complement existing molecular biomarkers and further guide treatment decisions.
Uroplakin 2 (UPK2) is a highly specific marker of bladder transitional cell carcinoma. As early as 1999, it was found that UPK2 mRNA was detected in blood samples from two patients with metastatic bladder cancer who did not receive chemotherapy and 1/8 of patients with metastatic bladder cancer who received chemotherapy, but it was not detected in 50 patients with non-metastatic bladder cancer or in normal control group, indicating that detection of peripheral blood UPK2 was associated with metastatic spread of bladder cancer cells (28). UPK2 specificity and sensitivity testing may be potential means of detecting bladder cancer metastasis, staging, and monitoring chemotherapy response. Lotan et al. (29) have tested 11 immunohistochemical markers at the primary sites of various micropapillary carcinomas, and found that urinary tract protein (UPs) can also be used as the best marker for identifying urinary mesothelial IMC. Li et al. (30) have found that UPK2 is expressed in 63% of plasma cell samples, significantly higher than UPK3 (6%), and they further indicate that UPK2 is a valuable marker and should be included in immunohistochemical markers to facilitate the differential diagnosis of tumors with plasmacytoid features. Further studies by Matuszewski et al. (31) have found that with the development of bladder cancer, the concentration of UPK2 in the urine is decreased, which further confirms the diagnostic value of UPK2 concentration in plasma and urine for bladder cancer. Based on clinical diagnostic needs, Tian et al. (32) have evaluated the expression of UPK2 by bladder tissue microarray and find that UPK2 is highly specific (100%). It can therefore be used as a marker to identify urothelial lineage tumors and to help distinguish between bladder and prostate cancers, or used in combination with GATA3 as potential markers for metastatic breast cancer.
Hoang et al. have found that the positive rate of UPK2, GATA3 and p40 antibody combined testing was 94.2% (97/103) in invasive urothelial carcinomas, indicating combination of these three antibodies has a high sensitivity to the differential diagnosis of invasive urothelial carcinoma. But the combination testing of UPK2, GATA3 and p40 is negative in lung adenocarcinoma, colon adenocarcinoma and renal cell carcinoma (33). However, so far, there is still no report on the expression and role of UPK2 in patients with ADC recurrence.
In this study, we first verified the expression level of UPK2, and found that the expression of this gene was significantly increased in patients with ADC recurrence and the prognosis of patients with high expression of UPK2 was poor. These different prognostic trends are consistent with previous studies in different types of cancers, suggesting that the differential expression of UPK2 in patients with ADC recurrence may have clinical implications. Enrichment analysis showed that the function of this gene was mainly related to post-translational modification of proteins. Thereafter, we collected blood samples from 105 patients with ADC, 35 of whom were patients with ADC recurrence, and the other 70 patients with no recurrence. RT-qPCR showed that the expression of UPK2 mRNA in the blood of relapsed patients was significantly higher than that of patients without recurrence, indicating that the difference in UPK2 expression was closely related to the recurrence of ADC and UPK2 was expected to be a biomarker for recurrence of ADC patients. In future studies, we will examine the expression of UPK2 in ADC patients with different genders, stages, and lymph node metastasis, and further clarify the clinicopathological correlation of UPK2 expression in order to provide a promising new strategy for targeted therapy of ADC.