Currently, an effective targeted therapy for pancreatitis is lacking. Hereditary pancreatitis (HP) is a heritable, autosomal-dominant disorder with recurrent acute pancreatitis (AP) progressing to chronic pancreatitis (CP) and a markedly increased risk of pancreatic cancer. In 1996, mutations in PRSS1 were linked to the development of HP. Here, we developed a mouse model by inserting a full-length human PRSS1^R122H gene, the most commonly mutated gene in human HP, into mice. Expression of PRSS1^R122H protein in the pancreas markedly increased stress signaling pathways and exacerbated AP. After the attack of AP, all PRSS1^R122H mice had disease progression to CP, with similar histologic features as those observed in human HP. By comparing PRSS1^R122H mice with PRSS1^WT mice, as well as enzymatically inactivated Dead-PRSS1^R122H mice, we unraveled that increased trypsin activity is the mechanism for R122H mutation to sensitize mice to the development of pancreatitis. We further discovered that trypsin inhibition, in combination with anticoagulation therapy, synergistically prevented progression to CP in PRSS1^R122H mice. These animal models help us better understand the complex nature of this disease and provide powerful tools for developing and testing novel therapeutics for human pancreatitis.

Gastric cancer (GC) is a leading cause of cancer-induced mortality, with poor prognosis with metastasis. The mechanism of gastric carcinoma lymph node metastasis remains unknown due to traditional bulk-leveled approaches masking the roles of subpopulations. To answer questions concerning metastasis from the gastric carcinoma intratumoural perspective, we performed single-cell level analysis on three gastric cancer patients with primary cancer and paired metastatic lymph node cancer tissues using single-cell RNA-seq (scRNA-seq). The results showed distinct carcinoma profiles from each patient, and diverse microenvironmental subsets were shared across different patients. Clustering data showed significant intratumoural heterogeneity. The results also revealed a subgroup of cells bridging the metastatic group and primary group, implying the transition state of cancer during the metastatic process. In the present study, we obtained a more comprehensive picture of gastric cancer lymph node metastasis, and we discovered some GC lymph node metastasis marker genes (ERBB2, CLDN11 and CDK12), as well as potential gastric cancer evolution-driving genes (FOS and JUN), which provide a basis for the treatment of GC.

Mutations in the trypsinogen gene (PRSS1) cause human hereditary pancreatitis. However, it is not clear how mutant forms of PRSS1 contribute to disease development. We studied the effects of expressing mutant forms of human PRSS1 in mice. We expressed forms of PRSS1 with and without the mutation encoding R122H (PRSS1^R122H) specifically in pancreatic acinar cells under control of a full-length pancreatic elastase gene promoter. Mice that did not express these transgenes were used as controls. Mice were given injections of caerulein to induce acute pancreatitis or injections of lipopolysaccharide to induce chronic pancreatitis. Other groups of mice were fed ethanol or placed on a high-fat diet to induce pancreatitis. Pancreata were collected and analyzed by histology, immunoblots, real-time polymerase chain reaction, and immunohistochemistry. Trypsin enzymatic activity and chymotrypsin enzymatic activity were measured in pancreatic homogenates. Blood was collected and serum amylase activity was measured. Pancreata from mice expressing transgenes encoding PRSS1 or PRSS1^R122H had focal areas of inflammation; these lesions were more prominent in mice that express PRSS1^R122H. Pancreata from mice that express PRSS1 or PRSS1^R122H had increased levels of heat shock protein 70 and nuclear factor (erythroid-derived 2)-like 2, and reduced levels of chymotrypsin C compared with control mice. Increased expression of PRSS1 or PRSS1^R122H increased focal damage in pancreatic tissues and increased the severity of acute pancreatitis after caerulein injection. Administration of lipopolysaccharide exacerbated inflammation in mice that express PRSS1^R122H compared to mice that express PRSS1 or control mice. Mice that express PRSS1^R122H developed more severe pancreatitis after ethanol feeding or a high-fat diet than mice that express PRSS1 or control mice. Pancreata from mice that express PRSS1^R122H had more DNA damage, apoptosis, and collagen deposition and increased trypsin activity and infiltration by inflammatory cells than mice that express PRSS1 or control mice. Expression of a transgene encoding PRSS1^R122H in mice promoted inflammation and increased the severity of pancreatitis compared with mice that express PRSS1 or control mice. These mice might be used as a model for human hereditary pancreatitis and can be studied to determine mechanisms of induction of pancreatitis by lipopolysaccharide, ethanol, or a high-fat diet.

As a significant public health problem with high morbidity and mortality worldwide, tumor is one of the major diseases endangering human life. Moreover, metastasis is the most important contributor to the death of tumor patients. Epithelial-mesenchymal transition (EMT) is an essential biological process in developing primary tumors to metastasis. It underlies tumor progression and metastasis by inducing a series of alterations in tumor cells that confer the ability to move and migrate. Tumor-associated macrophages (TAMs) are one of the primary infiltrating immune cells in the tumor microenvironment, and they play an indispensable role in the EMT process of tumor cells by interacting with tumor cells. With the increasing clarity of the relationship between TAMs and EMT and tumor metastasis, targeting TAMs and EMT processes is emerging as a promising target for developing new cancer therapies. Therefore, this paper reviews the recent research progress of tumor-associated macrophages in tumor epithelial-mesenchymal transition and briefly discusses the current anti-tumor therapies targeting TAMs and EMT processes.

Drug resistance is a major cause of cancer‑associated mortality. Epirubicin‑based chemotherapy initially benefits patients with metastatic or advanced gastric cancer; however, tumor recurrence can occur following several courses of treatment. Mitochondrial ribosomal protein L33 (MRPL33)‑long (L) and MRPL33‑short (S), isoforms of MRPL33 that arise from AS, have been reported to regulate cell growth and apoptosis in cancer; however, few studies have evaluated the roles of MRPL33‑L and MRPL33‑S in gastric cancer. In the present study, MRPL33‑L was demonstrated to be significantly more abundant in gastric tumor tissues than the MRPL33‑S isoform. MRPL33‑S promoted chemosensitivity to epirubicin in gastric cancer as demonstrated by a chemoresponse assay; chemosensitivity was suppressed in response to MRPL33‑L. Gene microarray analysis was performed to investigate the underlying mechanisms. Bioinformatic analysis revealed that overexpression of MRPL33‑L and MRPL33‑S served critical roles in transcription, signal transduction and apoptosis. In particular, the phosphoinositide 3‑kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway was markedly regulated. A total of 36 target genes, including PIK3 regulatory subunit α, AKT2, cAMP response element‑binding protein (CREB) 1, forkhead box 3, glycogen synthase kinase 3β and mammalian target of rapamycin, which are involved in the PI3K/AKT signaling pathway, were selected for further investigation via protein‑protein interaction network and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Furthermore, western blot analysis indicated that MRPL33‑S promoted the chemoresponse to epirubicin by deactivating PI3K/AKT/CREB signaling and inducing apoptosis, while MRPL33‑L had the opposite effects. In conclusion, the results of the present study revealed that isoforms S and L of MRPL33, which arise from alternative splicing, exhibited opposing roles in the chemoresponse to epirubicin in gastric cancer via the PI3K/AKT signaling pathway. These findings may contribute to the development of potential therapeutic strategies for the resensitization of patients with gastric cancer to epirubicin treatment.