Cardiac stem/progenitor cells (CPCs) have recently emerged as a potentially transformative regenerative medicine to repair the infarcted heart. However, the limited survival of donor cells is one of the major challenges for CPC therapy. Our recent research effort on preconditioning human CPCs (hCPCs) with cobalt protoporphyrin (CoPP) indicated that sulfiredoxin-1 (SRXN1) is upregulated upon preconditioning aldehyde dehydrogenase bright hCPCs (ALDH-hCPCs) with CoPP. Further studies demonstrated that overexpressing SRXN1 enhanced the survival capacity for ALDH-hCPCs. This was associated with the up-regulation of anti-apoptotic factors, including BCL2 and BCL-xL. Meanwhile, overexpressing SRXN1 decreased the ROS generation and mitochondrial membrane potential, concomitant with the up-regulated primary antioxidant systems, such as PRDX1, PRDX3, TXNRD1, Catalase and SOD2. It was also observed that overexpressing SRXN1 increased the migration, proliferation, and cardiac differentiation of ALDH-hCPCs. Interestingly, SRXN1 activated the ERK/NRF2 cell survival signaling pathway, which may be the underlying mechanism through which overexpressing SRXN1 lead to protection of hCPCs against oxidative stress-induced apoptosis. Taken together, these results provide a rationale for the exploration of SRXN1 as a novel molecular target that can be used to enhance the effectiveness of cardiac stem/progenitor cell therapy for ischemic heart disease.

Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer death worldwide. Hence, for a better understanding of tumor microenvironment and to seek for novel molecular targets for esophageal cancer, we performed related studies on two histopathological subtypes of esophageal cancer: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Bioinformatic analyses were conducted based on the RNA-seq, genomic mutation, and clinical data from TCGA and GEO cohorts. We clustered patients into high-immunity and low-immunity groups through the ssGSEA results. The ESTIMATE algorithm was used to evaluate the tumor microenvironment. Patients with high immunity in both ESCC and EAC had lower tumor purity and poor survival. Subsequently, CIBERSORT was performed to learn about the detailed difference of tumor-infiltrating lymphocytes (TILs) between high- and low-immunity patients. Specific increase of M2 macrophages and decrease of activated dendric cells can be observed in ESCC and EAC, respectively. The most enriched functions and pathways of high-immunity patients were immunoglobulin complex, MHC class II protein complex, and allograft rejection according to the GO terms and KEGG. Two prognostic immune-related multi-lncRNA risk models were constructed and validated by ROC curve and PCA in ESCC and EAC. High-risk patients in both subtypes had poor survival, advanced clinical characteristics, and higher drug susceptibility except cisplatin and sorafenib. In addition, the tumor mutation burden (TMB) was positively correlated with the risk level in the ESCC and EAC and showed distinct differences between the two subtypes. In summary, we comprehensively analyzed the tumor microenvironment for two subtypes of esophageal cancer, identified two multi-lncRNA signatures predictive for the prognosis, and explored the possibility of the signatures to forecast drug susceptibility as well as TMB for the first time. The findings may serve as a conceptual basis for innovative strategy of individualized immunotherapy for esophageal cancer.

Identifying effective donor cells is one of obstacles that limits cell therapy for heart disease. In this study, we sorted a subpopulation of human mesenchymal progenitor cells (hMPCs) from the right atrial appendage using the low mitochondrial membrane potential. Compared to the non-sorted cells, hMPCs hold the capacity for stemness and enrich mesenchymal stem cell markers. The hMPCs display better ability for survival, faster proliferation, less production of reactive oxygen species (ROS), and greater release of cytoprotective cytokines. The hMPCs exhibit decreased expression of senescence genes and increased expression of anti-apoptotic and antioxidant genes. Intramyocardial injection of hMPCs into the infarcted heart resulted in increased left ventricular ejection fraction and reduced cardiac remodeling and infarct size in the group of animals receiving hMPCs. Both in vitro and in vivo studies indicated hMPCs have the potential to differentiate into endothelial cells and smooth muscle cells. Immunohistochemistry staining showed that cell therapy with hMPCs enhances cardiac vascular regeneration and cardiac proliferation, and decreases cardiac cell apoptosis, which is associated with the increased secretion of cytoprotective and pro-angiogenic cytokines. Overall, we discovered a subpopulation of human mesenchymal progenitor cells via their low mitochondrial membrane potential, which might provide an alternative donor cell source for cellular therapy for ischemic heart disease.

PRSS8, a glycosylphosphatidylinositol-anchored epithelial extracellular membrane serine protease prostasin, is expressed in normal epithelia and is involved in terminal epithelial differentiation. Aberrantly expression of PRSS8 was observed in human prostate, breast and gastric cancers, and the reduction might be linked to promoter hypermethylation in vitro. However, the expression of PRSS8 in colorectal cancer and its significance in colorectal carcinogenesis and progression are largely unknown. In this study, the expression levels of PRSS8 were firstly determined in four human colorectal cancer cell lines and in 47 paired human colorectal cancer tissues (cancers and their adjacent non-cancer tissues) by real-time PCR, Western blotting and immunohistochemistry. We found that PRSS8 was significantly reduced in colorectal cancer tissues, compared to adjacent non-cancer tissues, and was in very low levels in the colorectal cancer cell lines. Interestingly, the reduced PRSS8 was associated with histopathological stages and differentiation: PRSS8 was lower in poor differentiated cancers and was higher in well differentiated cancers. In addition, the expression levels of PRSS8 were also determined in esophageal cancer, prostate cancer, breast cancer, liver cancer and lung cancer using tissue microarray (TMA) by immunohistochemical staining. Consistent with those in colorectal cancer, PRSS8 protein levels were reduced in all the five cancers and the reduction was associated with cancer differentiation. Further analysis revealed that the patients with lower expression of PRSS8 in esophageal cancer were likely to have a shorter survival time. Functional studies by gain- and loss-expression of PRSS8 showed that increased PRSS8 expression inhibited colon cancer cell proliferation, promoted apoptosis, attenuated cell migration and epithelial-mesenchymal transition (EMT). Mechanistic study showed tumor suppression of PRSS8 was linked to Wnt/beta-catenin signaling pathways. Moreover, PRSS8 interacted with Sphk1 to target S1P and affect EMT/metastasis. Lastly, PRSS8 inhibited colorectal cancer cell growth in tumor-bearing mice, and purified PRSS8 protein showed therapeutic effects in vitro and nude mice. Taken together, this study has identified PRSS8 as a tumor suppressor in colorectal cancer and acts as a key regulator in colorectal cancer formation, progression and outcomes. Therefore, PRSS8 could be a useful biomarker for monitoring colorectal carcinogenesis and progression, and also could have a therapeutic potential for cancers. Note: This abstract was not presented at the meeting. Citation Format: Yonghua Bao, Kai Li, Qian Wang, Yongchen Guo, Rongfei Han, Zhiguo Chen, Zexin Li, Jianguo Wang, Weixing Zhao, Wenliang Han, Jiaqi Wang, Huijuan Zhang, Pan He, Wancai Yang. Characterization of a novel tumor suppressor PRSS8 in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2044. doi:10.1158/1538-7445.AM2015-2044