Background: Recent studies have reported that Integrin alpha 2 (ITGA2) plays an essential role in tumor cell proliferation, invasion, metastasis, and angiogenesis. An abnormally expressed ITGA2 correlates with unfavorable prognoses in multiple types of cancer. However, the specific mechanism of how ITGA2 contributes to tumorigenesis remains unclear.Methods: The GEPIA web tool was used to find the clinical relevance of ITGA2 in cancer, and this significance was verified using Western blotting analysis of paired patient tissues and immunohistochemistry of the pancreatic cancer tissue. Functional assays, such as the MTS assay, colony formation assay, and transwell assay, were used to determine the biological role of ITGA2 in human cancer. The relationship between ITGA2 and programmed death-ligand 1 (PD-L1) was examined using Western blot analysis, RT-qPCR assay, and immunohistochemistry. The protein-protein interaction between ITGA2 and STAT3 was detected via co-immunoprecipitation.Results: Our study showed that ITGA2 was markedly overexpressed in several malignant tumor cells and clinical tissues. Blocking ITGA2 inhibited the proliferation and invasion ability of cancer cells significantly, whereas overexpressed ITGA2 increased the degree of those processes considerably. Additionally, the RNA-seq assay indicated that ITGA2 transcriptionally regulated the expression of PD-L1 in pancreatic cancer. We also demonstrated that ITGA2 interacted with STAT3 and up-regulated the phosphorylation of STAT3; this interaction might involve the mechanism of ITGA2 inducing PD-L1 expression in cancer cells. Our results suggest that ITGA2 plays a critical role in cancer cell progression and the regulation of PD-L1 by activating the STAT3 pathway.Conclusions: We identified a novel mechanism by which ITGA2 plays a critical role in modulating cancer immune response by transcriptionally increasing the expression of PD-L1 in cancer cells. Thus, targeting ITGA2 is an effective method to enhance the efficacy of checkpoint immunotherapy against cancer.

Rationale: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a dismal 5-year survival less than 10%. Most patients with PDAC exhibit poor response to single-agent immunotherapy. Multimodal therapies targeting mechanisms of resistance to immunotherapy are urgently needed. We found that the class IIa histone deacetylase (HDAC) member, HDAC5 is downregulated in multiple solid tumors and its level were associated with favorable prognosis in PDAC patients. Upregulated genes in patients harboring HDAC5 deletions were enriched in adaptive immune responses and lymphocyte-mediated immunity in The Cancer Genome Atlas (TCGA) pancreatic cancer dataset.

Ovarian cancer is one of the most malignant tumors of the female reproductive system, with high invasiveness. The disease is a severe threat to women's health. The ITGA2 gene, which codes for integrin subunit α2, is involved in the proliferation, invasion, and metastasis of cancer cells. Although previous studies have shown that ITGA2 increases in ovarian cancer, the specific molecular mechanism of how ITGA2 promotes ovarian cancer proliferation and metastasis is still unclear. In this study, we confirmed that ITGA2 was elevated in ovarian cancer, which led to poor prognosis and survival. Overexpressed ITGA2 promoted the proliferation of ovarian cancer cells. We also found that ITGA2 regulated the phosphorylation of forkhead box O1 (FoxO1) by mediating AKT phosphorylation, which provided a reasonable explanation for ITGA2's role in ovarian cancer's resistance to albumin paclitaxel. In summary, ITGA2 could be used as a new therapeutic target and prognostic indicator in ovarian cancer.

Background: Several studies were conducted to explore the prognostic value of modified Glasgow Prognostic Score (mGPS) in pancreatic cancer, which reported contradictory results. The purpose of this meta-analysis was to summarize and further investigate the correlation between mGPS and overall survival (OS) in pancreatic cancer. Methods: A systematic literature search was performed in PubMed, EMBASE, ISI Web of Science, Cochrane library databases and OVID to identify eligible studies published from Jan 1, 2011 to June 20, 2020. Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were used to detect the prognostic significance of mGPS in patients with pancreatic cancer. Results: A total of 222 non-repetitive studies were identified, and 20 related studies that explored the association between survival outcomes and mGPS in pancreatic cancer patients were finally enrolled in this meta-analysis. The results showed a significant correlation between high level of mGPS and poor OS (HR = 1.50, 95% CI 1.20–1.89, P < 0.0001). Similar results were observed in the subgroup analyses based on the treatment regimen and research region. Conclusions: Our study suggested the close association between poor prognosis and high level of mGPS, which will be helpful for future clinical applications in patients with pancreatic cancer.

NR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a dual lipid and protein phosphatase. Multiple mechanisms contributing to the regulation of PTEN levels have been identified thus far, including post‐translational modifications, epigenetic mechanisms, and transcriptional mechanisms. In the present study, we identified ubiquitin‐specific peptidase 22 (USP22) as a novel deubiquitination‐modifying enzyme of PTEN. Furthermore, by inducing deubiquitination and inhibiting the degradation of PTEN, USP22 could induce cyclin‐dependent kinase inhibitor 1A (CDKN1A, also symboled as p21) expression in pancreatic cancer. Besides, MDM2 proto‐oncogene (MDM2) inhibitor enhanced the antipancreatic cancer effects of USP22 overexpression. In addition to its regulation of MDM2‐tumor protein p53 (p53) signaling, we found that PTEN could induce p21 expression by interacting with ankyrin repeat and KH domain containing 1 (ANKHD1) and inhibiting ANKHD1 binding to the p21 promoter. Taken together, our results indicate that ANKHD1 and MDM2 might be novel therapeutic targets in pancreatic cancer.