Lung cancer is very malignant due to high morbidity and mortality. More than 1 million suffers die from lung cancer yearly, and about 85% of them die because of NSCLC, seriously endangering human life and health. Traditional treatments for NSCLC include surgery, radiotherapy, chemotherapy, and combination chemotherapy with radiotherapy and chemotherapy (Signal Transduction and Targeted Therapy 3, Article number: 28 (2018)). With the continuous improvement of technology, molecularly targeted therapy is gradually accepted. Despite this, the 5-year survival rate is still low (15%), so further research on the occurrence, development, and mechanism of lung cancer is the current focus. Here, we examined the XB130 expression in the pathological tissues of NSCLC and its relationship with OS and PFS, and suggested that it promoted the lung cancer cell proliferation via the PI3K/AKT pathway. These findings provide new ideas and directions for inhibiting tumor proliferation and evaluating disease prognosis, progression in the future.As reported, XB130 is involved not only in cell proliferation, survival, invasion[9, 13, 14] but also in signal transduction. Controlled by Rac and cytoskeleton, XB130 activates c-Src and PI3K/AKT pathway, which in turn regulates cytoskeleton. These signaling pathways are critical for the lung cancer progression[16, 17]. As an adapter protein, XB130 is crucial for signal transduction, cancer cell proliferation, survival, and tumorigenesis. It binds the F-actin network of lamellipodia and enhances the cancer cell motility and invasiveness. XB130 is phosphorylated by Src and other tyrosine kinases, and its interaction with Src results in the SRE transactivation of AP-1. XB130 also has a YxxM motif, a kinase binding to the p85a subunit of PI3K, through which the AKT is subsequently activated by its SH2 domain. Down-regulating XB130 can affect various molecules downstream of AKT. XB130 inhibition also decreases the expression levels of multiple genes involved in cell proliferation and/or survival. The effects of XB130 in lung cancer are mediated by AKT, which is an important signaling molecule for tumorigenesis and development. PI3K/AKT stimulates cancer cell proliferation, suppresses apoptosis and increases cell invasion and metastasis by directly phosphorylating multiple transcription factors. PI3K/AKT activation is prevalent in human malignancies, and its inhibition is important for the prevention and treatment of malignant tumors. AKT is a central mediator for the inhibition and induction of apoptosis-sensitive chemotherapeutic drugs. More and more experiments have shown that inhibition of Akt expression, especially activation of Akt (p-Akt), can block the PI3K/Akt classical signaling pathway to improve the treatment effect. Here, the XB130 expression was significantly related to AKT expression, and XB130 may affect patient prognosis through AKT. High XB130 level is significantly related to cell proliferation, angiogenesis, and poor prognosis in a variety of tumor patients[8-12]. However, there have been few studies about the clinical value of XB130 in cancers including NSCLC. To study the relationship between XB130 expression and prognosis of gastric cancer, 411 patients were selected as subjects. They found that both mRNA and protein of XB130 were detected in normal gastric tissues. The OS was significantly shorter in subjects having high XB130 compared with those having low XB130. The XB130 expression predicts the sensitivity of tumors to several clinical drugs. 5-fluorouracil (5-FU), cisplatin, and irinotecan inhibited the activity of wild-type and XB130-knockout gastric cancer cells in a concentration-dependent manner, with cisplatin, irinotecan and 5-FU being more sensitive to XB130-knockout and wild-type cells, respectively. In 5-FU treatment, the survival rate was higher in subjects having high XB130 level when comparing to those having low level, suggesting that the reduction in XB130 protein level is a prognostic factor for gastric cancer patients with short survival time, high recurrence rate, and chemotherapy response. To elucidate the prognostic role of XB130 in pancreatic ductal adenocarcinoma (PDAC), a retrospective analysis of 76 PDAC subjects who underwent continuous surgical resection was performed. The expression of XB130 in paraffin-embedded tumor sections was detected by immunohistochemistry and the correlation between XB130 expression and clinicopathological indicators was assessed. They found that XB130 was significantly up-regulated in PDAC relative to normal pancreatic tissue; enhanced XB130 level was associated with lymphatic metastasis, tumor nodular metastasis (TNM) stage, and tumor grade; the survival rate was significantly lower in patients having high XB130 level when comparing to those having low XB130 level; high XB130 level, tumor scale, long-distance metastasis, TNM stage, and lymph node metastasis were considered to be independent risk factors that affect prognosis by univariate analysis of the Cox proportional hazard model; multivariate analysis demonstrated that high XB130 level and long-distance metastasis were significant risk factors. Taken together, XB130 is believed to be a potential pathological indicator for predicting PDAC patient prognosis. In NSCLC, our study showed the similar results. In summary, the expression of XB130 was significantly related to the tumor differentiation degree, lymphatic metastasis, T staging, and AKT expression. High XB130 expression, high AKT expression, and lymphatic metastasis were independent prognostic factors for NSCLC. XB130 may be an important clinical prognostic marker. XB130 might regulate the survival and prognosis of NSCLC by affecting the AKT signaling pathway. We believe that XB130 might become a promising therapeutic drug target for NSCLC treatment, and inhibition of XB130 expression may become one of the methods for treating tumors.