Lynch syndrome is one of the most common hereditary cancer syndromes and is characterized by the development of many cancers, such as colorectal cancer (CRC), endometrial cancer, ovarian cancer, stomach cancer and many other cancers. Lynch syndrome is caused by pathogenic germline variants in one of four DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or by an EPCAM deletion. The MLH1 variant is correlated with the highest risk of CRC, while the MSH2 variant is correlated with the highest risk of other cancers. CRC is the most common cancer type that develops in individuals with Lynch syndrome, followed by endometrial cancer. Recent advances have been made to help us further understand the molecular pathogenesis of this disease and help improve diagnostic testing efficiency and surveillance strategies. Moreover, recent advances in immunotherapy provided by clinical trials also provide clinicians with more chances to better treat Lynch syndrome. This study aims to review many advances in the molecular genetics, clinical features, diagnosis, surveillance and treatment of Lynch syndrome.

Background: In recent years, there have been many studies on the relationship between DLGAP5 and different types of cancers, yet there is no pan-cancer analysis of DLGAP5. Therefore, this study aims to analyze the roles of DLGAP5 in human tumors. Methods: Firstly, we evaluated the expression level of DLGAP5 in 33 types of tumors throughout the datasets of TCGA (Cancer Genome Atlas) and GEO (Gene Expression Synthesis). Secondly, we used the GEPIA2 and Kaplan-Meier plotter to conduct Survival prognosis analysis. Additionally, cBioPortal web was utilized to analyze the genetic alteration of DLGAP5, after which we selected hepatocellular carcinoma (HCC) cell lines to define the function of DLGAP5. Last but not least, we performed immune infiltration analysis and DLGAP5-related gene enrichment analysis. Results: DLGAP5 is highly expressed in most type of cancers, and there is a significant correlation between the expression of DLGAP5 and the prognosis of cancer patients. We have observed that DLGAP5 promotes the proliferation and invasion of hepatocellular carcinoma (HCC) cell lines. We also found that DLGAP5 expression was related with the CD8⁺ T-cell infiltration status in kidney renal clear cell carcinoma, uveal melanoma, and thymoma, and cancer-associated fibroblast infiltration was observed in breast invasive carcinoma, kidney renal papillary cell carcinoma and testicular germ cell tumors. In addition, enrichment analysis revealed that cell cycle- and oocyte meiosis-associated functions were involved in the functional mechanism of DLGAP5. Conclusions: Taken together, our unpresented pan-cancer analysis of DLGAP5 provides a relatively integrative understanding of the oncogenic role of DLGAP5 in various tumors. DLGAP5 may prompt HCC cellular proliferation, invasion and metastasis. All of these provides solid basement and will promote more advanced understanding the role of DLGAP5 in tumorigenesis and development from the perspective of clinical tumor samples and cells.

The incidence and mortality of papillary thyroid cancer (PTC) have steadily increased. Although conventional therapies are very effective toward differentiated PTC patients, very limited therapeutic options are applicable to those patients with distant metastases. Therefore, better understanding of the molecular biology of metastatic PTC helps identify novel targets and facilitates the development of new therapies. In this study, we first found that testicular orphan receptor 4 (TR4) was significantly increased in PTC tumors spreading to lymph nodes compared to the paired primary tumors. Experimental evidence suggested that TR4 drove PTC progression via promoting its cell invasion and cell migration. Mechanistically, TR4 transcriptionally regulated the expression level of circ-filamin A (FLNA), which competed with matrix metalloproteinase 9 (MMP9) for microRNA (miR)-149-5p binding and led to an increased protein level of MMP9. Interruption assays with various gene manipulations verified that the TR4/circ-FLNA/miR-149-5p/MMP9 signaling axis played a central role in cell invasion and cell migration of PTC cells. Moreover, a xenografted mouse model also confirmed that the TR4/circ-FLNA signal promoted PTC tumor growth. Overall, our study pinpoints the oncogenic role of TR4 in PTC development, and the targeting of TR4/circ-FLNA/miR-149-5p/MMP9 signaling may be an alternative option for metastatic PTC patients.

Due to the abnormal vasculation and proliferation, the tumor microenvironment is hypoxic, lacking nutrients, and under high interstitial pressure. Compared to oxygen and nutrients, the effect of pressure on cancer biology remains poorly studied. Here we constructed αROR1-CAR T cells and co-cultured with A549 cells with and without elevated pressure. We then measured apoptosis and cell death by flow cytometry and luciferase activity. We also measured cytokine (IL-2, IFN-γ, and TNF-α) release by ELISA. The results show that pressure-preconditioned A549 cells are much resistant to αROR1-CAR T cell-mediated cytotoxicity. Pressure preconditioning does not appear to affect the expression of αROR1-CAR or cytokine production. However, pressure preconditioning upregulates PD-L1 expression in A549 cells and decreases cytokine release from αROR1-CAR T cells. In addition, Pembrolizumab and Cemiplimab that block PD-1::PD-L1 interaction increase the cytokine production in αROR1-CAR T cells, increase the apoptotic cell death in A549 cells, and improve the αROR1-CAR T-mediated cytotoxicity. In xenograft mice, pressure preconditioning increases tumorigenesis of A549 cells, which can be blocked by a combined therapy using Pembrolizumab and αROR1-CAR T cells. Together, our studies suggest that elevated pressure in the tumor microenvironment could blunt the T cell therapy by upregulating PD-L1 expression, which could be overcome by combining CAR T therapy with immune checkpoint inhibitors.

Hepatocellular carcinoma (HCC) is a malignant tumor with a high degree of malignancy and a poor prognosis. Androgen receptor (AR) has been reported to play important roles in the regulation of the progression of HCC, but the underlying mechanisms of how AR regulates HCC initiation, progression, metastasis, and chemotherapy resistance still need further study. Our study found that AR could act as a tumor suppression gene to suppress HCC cells invasion and migration capacities via miR-122-5p/RABL6 signaling, and the mechanism study further confirmed that miR-122-5p could suppress the expression of RABL6 to influence HCC cells progression by directly targeting the 3’UTR of the mRNA of RABL6. The preclinical study using an in vivo mouse model with orthotopic xenografts of HCC cells confirmed the in vitro data, and the clinical data gotten from online databases based on TCGA samples also confirmed the linkage of AR/miR-122-5p/RABL6 signaling to the HCC progression. Together, these findings suggest that AR could suppress HCC invasion and migration capacities via miR-122-5p/RABL6 signaling, and targeting this newly explored signaling may help us find new therapeutic targets for better treatment of HCC.

Pseudomyxoma peritonei (PMP) is a rare disease characterized by extensive peritoneal implantation and mass secretion of mucus after primary mucinous tumors of the appendix or other organ ruptures. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is currently the preferred treatment, with excellent efficacy and safety, and is associated with breakthrough progress in long-term disease control and prolonged survival. However, the high recurrence rate of PMP is the key challenge in its treatment, which limits the clinical application of multiple rounds of CRS-HIPEC and does not benefit from conventional systemic chemotherapy. Therefore, the development of alternative therapies for patients with refractory or relapsing PMP is critical. The literature related to PMP research progress and treatment was searched in the Web of Science, PubMed, and Google Scholar databases, and a literature review was conducted. The overview of the biological research, treatment status, potential therapeutic strategies, current research limitations, and future directions associated with PMP are presented, focuses on CRS-HIPEC therapy and alternative or combination therapy strategies, and emphasizes the clinical transformation prospects of potential therapeutic strategies such as mucolytic agents and targeted therapy. It provides a theoretical reference for the treatment of PMP and the main directions for future research.