Lung cancer is one of the major diseases that cause cancer-related death. Among them, LAC is the most common pathological type, and it has gradually increased in recent years . Studies have shown that some gene mutations and protein expression abnormalities are closely related to the occurrence and development of LAC, and some molecular targeted drugs have been used in clinical practice [3, 18, 19]. STIP1 is a is an adaptor protein that combines heat shock protein 70 and heat shock protein 90 to modulate biological effects such as transcription, translation, and protein folding, and promotes the growth of tumor cells [12, 20, 21]. According to a recentmeta-analysis, the high expression of STIP1 was related to lymph node metastasis, advanced TNM stage and shorter survival of patients compared with that of tumor tissues with low STIP1 expression, which was expected to be a molecular marker of malignancy or provide new ideas for the development of targeted drugs . However, the malignant tumors included in themeta-analysis have only ovarian cancer, liver cancer, gastric cancer, thyroid cancer, and colon cancer. This also reflects the current lack of research on the expression pattern of STIP1 in LAC. In our study, we investigated the association and prognostic significance of STIP1 and Hsp90 with LAC clinical features by methods of molecular biology and biostatistics.
We first used the Western blot method to determine the expression patterns of STIP1 and Hsp90 in A549 and 16HBE cells and found that the expressions of STIP1 and Hsp90 in A549 cells were higher than that in 16HBE cells. Some studies have observed that the expression of STIP1 is increased in other tumor cells and tissues, and suggests that STIP1 expression plays a role in the occurrence, invasion and metastasis of malignant tumors [23, 24]. We found that the expressions of STIP1 and Hsp90 in LAC tissues were higher than that in adjacent normal lung tissues. These results from our study suggest that STIP1 and Hsp90 may play an importantrole in the occurrence and development of LAC, and the synergistic increase of the two may be risk factor for LAC. Hsp90 has been found to be highly expressed in the serum and tissues of lung cancer patients and up-regulation of Hsp90 is related to the occurrence, development and outcome of lung cancer . We found that the expression of STIP1 was associated with poor differentiation, lymph node metastasis and advanced stage of LAC and that the expression of Hsp90 was related to lymph node metastasis and advanced stage of LAC. Lymph node metastasis and poor differentiation are the malignant biological characteristics of tumors and are often used to determine the treatment of tumors and to predict the prognosis of tumors [26–28]. Previous studies suggest that STIP1 is elevated in patients with lymph node metastasis and advanced clinical stages, and indicate that STIP1 expression may serve as a potentially valuable biomarker for cancer [11, 12, 20–22, 24]. As a chaperone, Hsp90 can activate signals of some cancer-related proteins, kinases and transcriptional regulatory proteins, which lead to the proliferation of tumor cells and promote the development, migration and metastasis of tumors . However, inhibition of Hsp90 expression has shown inhibition of lung cancer cell proliferation, migration and metastasis, which involves complex signaling pathways including induction of apoptosis, inhibition of vascular endothelial growth factor (VEGF) and EGFR pathways [15, 16, 29, 30]. Combining our findings with previous studies, we hypothesized that the high expression of STIP1 and Hsp90 may promote the progression and invasion of LAC cells, thus speeding the development of LAC.
STIP1 has been shown to act as an adaptor which can guide Hsp90 to Hsp70 in cytoplasm to form a customer protein complex and ultimately regulate its molecular chaperone activity, which play complex roles in RNA splicing, signal transcription, protein folding, signal transduction and cell cycle regulation [10, 31]. Overexpression of STIP1 in cancer cells is associated with regulation of the JAK2-STAT3 signaling pathway. The interaction of STIP1 and HSP90 promotes maturation of the JAK2 protein and forms a scaffold complex that transduces JAK2-STAT3 signaling. However, inhibiting the expression of STIP1 can block the interaction between STIP1-Hsp90 and showed an antitumor effect. From our study, we deduce that STIP1 and Hsp90 have synergistic effects in the occurrence and development of LAC, and the common increase in both may play a role in the progress of LAC. During our follow-up, 64 out of 73 patients were followed up with complete survival data. We found that patients with expressions of STIP1 and Hsp90 had a shorter survival than those without expressions, which means that STIP1 and Hsp90 are prognostic risk factors for LAC. A meta-analysis points out that cancerpatients with high STIP1 expression often have shorter overall survival (hazard ratio = 2.15) compared with those with lower STIP1 expression . A clinical pathology analysis suggests that STIP1 expression is significantly associated with tumor size, lymph node metastasis, and TNM stage, and patients with higher STIP1 expression have a shorter overall survival . Our analysis suggested that TNM staging, STIP1 and Hsp90 were included in the regression equation, indicating that advanced TNM staging, STIP1 and Hsp90 are risk factors for shortening the survival of patients with LAC.A study of ovarian cancer suggests that patients with STIP1 expression have worse survival (high STIP1 = 76 months; low STIP1 = 112 months) . And, high expression of STIP1 is associated with the poor prognosis of breast cancer patients and HER-2 positive expression . The expression of Hsp90 in lung cancer tissue has been found to beincreased and thesurvival is shorter inpatients with high expression than in those with low expression . And, the high expression of Hsp90 in lung cancer promotes the metastasis and proliferation of lung cancer [34–36]. However, inhibition of Hsp90 expression has been found to block proliferation, migration and metastasis of lung cancer cells .