Pseudogenes have long been marked as "false" genes, which are similar with real genes but have no apparent function. The 3'UTR is well-known to regulate gene expression post-transcriptionally. Our recent evidence, however, indicates novel functional roles of pseudogene CYP4Z2P 3'UTR (Z2P-UTR). We found that ectopic expression of Z2P-UTR in breast cancer cells significantly increased the expression of VEGF-A without affecting cell proliferation in vitro. Meanwhile, conditioned medium (CM) from Z2P-UTR overexpression cells enhanced proliferation, migration and tube formation of HUVEC, and promoted angiogenesis in ex vivo models. Also, CM increased the expression of VEGFR2 in HUVEC. Our data suggest that Z2P-UTR can promote breast cancer angiogenesis partly via paracrine pathway of VEGF-A/VEGFR2.

Patients with estrogen receptor α (ERα)-positive breast cancer can be treated with endocrine therapy using anti-estrogens such as tamoxifen; nonetheless, patients often develop resistance limiting the success of breast cancer treatment. The potential mechanisms remain elusive. In detail, many miRNAs have been associated with breast cancer tamoxifen resistance, but no studies have addressed the role of miRNA-mediated competitive endogenous RNAs network (ceRNET) in tamoxifen resistance. The ceRNET between CYP4Z1 and pseudogene CYP4Z2P has been revealed to promote breast cancer angiogenesis. However, its function in tamoxifen resistance remains unclear. Here we report CYP4Z1 and CYP4Z2P were downregulated in MCF-7 cells compared with tamoxifen-resistant MCF-7-TamR cells. Enforced upregulation of CYP4Z1- or CYP4Z2P-3'UTR level renders MCF-7 Cells resistant to tamoxifen. We find that overexpression of CYP4Z1- or CYP4Z2P-3'UTR enhances the transcriptional activity of ERα through the activation of ERα phosphorylation. Furthermore, we find that CYP4Z1- and CYP4Z2P-3'UTRs increase ERα activity dependent on cyclin-dependent kinase 3 (CDK3). Reporter gene and western blot assays revealed that CYP4Z1- and CYP4Z2P-3'UTRs act as CDK3 ceRNAs. More importantly, the blocking of CYP4Z1- and CYP4Z2P-3'UTRs reversed tamoxifen resistance in MCF-7-TamR cells. Our data demonstrates that the ceRNET between CYP4Z1 and pseudogene CYP4Z2P acts as a sub-ceRNET to promote CDK3 expression in ER-positive breast cancer and is a potential therapeutic target for treatment of tamoxifen-resistant breast cancer.

Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. PD-L1 could promote the expression of stemness markers (OCT4 and Nanog) in breast cancer stem cells. However, the mechanisms by which PD-L1 regulates the stemness of breast cancer cells and PD-L1 is regulated in breast cancer cells are still unclear.

The expression of CYP4Z1 and the pseudogene CYP4Z2P has been shown to be specifically increased in breast cancer by our group and others. Additionally, we previously revealed the roles of the competitive endogenous RNA (ceRNA) network mediated by these genes (ceRNET_CC) in breast cancer angiogenesis, apoptosis, and tamoxifen resistance. However, the roles of ceRNET_CC in regulating the stemness of breast cancer cells and the mechanisms through which ceRNET_CC is regulated remain unclear.

Competing endogenous RNAs (ceRNAs) network has been correlated with the initiation and development of cancer. Here, we identify CDH5, HOXD1, and HOXD10 as putative STARD13 ceRNAs and they display concordant patterns with STARD13 in different metastatic potential breast cancer cell lines and tissues. Notably, 3'UTRs of these genes suppress breast cancer metastasis via inhibiting epithelial-mesenchymal transition (EMT) in vitro and in vivo, which are activated through the crosstalk between STARD13 and its ceRNAs in 3'UTR- and miRNA-dependent manners. In addition, Kaplan-Meier survival analysis reveals that mRNA level of STARD13 and its ceRNAs is remarkably associated with survival of breast cancer patients. These results suggest that 3'UTRs of CDH5, HOXD1, and HOXD10 inhibit breast cancer metastasis via serving as STARD13 ceRNAs.

Iron is an essential trace element for the human body, and its deficiency or excess can induce a variety of biological processes. Plenty of evidences have shown that iron metabolism is closely related to the occurrence and development of tumors. In addition, iron plays an important role in cell death, which is very important for the development of potential strategies for tumor treatment. Here, we reviewed the latest research about iron metabolism disorders in various types of tumors, the functions and properties of iron in ferroptosis and ferritinophagy, and new opportunities for iron-based on treatment methods for tumors, providing more information regarding the prevention and treatment of tumors.

Tissue-resident memory T (Trm) cells are enriched at the sites of previous infection and required for enhanced protective immunity. However, the emergence of Trm cells and their roles in providing protection are unclear in the field of Helicobacter pylori (H. pylori) vaccinology. Here, our results suggest that conventional vaccine strategies are unable to establish a measurable antigen (Ag)-specific memory cell pool in stomach; in comparison, gastric subserous injection of mice with micro-dose of Alum-based H. pylori vaccine can induce a pool of local CD4+ Trm cells. Regional recruitment of Ag-specific CD4+ T cells depends on the engagement of Ag and adjuvant-induced inflammation. Prior subcutaneous vaccination enhanced this recruitment. A stable pool of Ag-specific CD4+ T cells can be detected for 240 days. Two weeks of FTY720 administration in immune mice suggests that these cells do not experience the recirculation. Immunohistochemistry results show that close to the vaccination site, abundant CD4+T cells locate on epithelial niches, independent of lymphocyte cluster. Paradigmatically, Ag-specific CD4+ T cells with a phenotype of CD69+CD103- are preferential on lymphocytes isolated from epithelium. Upon Helicobacter infection, CD4+ Trm cells orchestrate a swift recall response with the recruitment of circulating antigen-specific Th1/Th17 cells to trigger a tissue-wide pathogen clearance. This study investigates the vaccine-induced gastric CD4+ Trm cells in a mice model, and highlights the need for designing a vaccine strategy against H. pylori by establishing the protective CD4+ Trm cells.

The relapse of breast cancer could be due to the existence of breast cancer stem cells (BCSCs). Other and our researches have indicated the suppressive roles of miR-375 in various tumors, however, its roles in breast cancer stemness remain confusing. Here, we constructed breast cancer cells with miR-375 stable overexpression via lentivirus infection. Flow cytometry, Western blot, mammosphere formation, cell colony formation and CCK8 as well as in vivo assays were performed to identify the role of miR-375 in the stemness of breast cancer cells. Luciferase reporter, RNA-Fluorescence in situ hybridization (RNA-FISH) and RNA-binding protein immunoprecipitation (RIP) assays were utilized to elucidate the mechanism whereby miR-375 exerts its effects. It was found that miR-375 not only reduced the stemness, but also decreased adriamycin resistance of breast cancer cells. These results were characterized by the decrease of BCSC rate, mammosphere-forming and tumor-initiating ability, and IC50 value of adriamycin, and weakened by JAK2 re-expression. This work indicates that miR-375 suppresses the stemness of breast cancer cells through targeting JAK2.

Gastric cancer stem cells (CSCs) are the main causes of metastasis and drug resistance. We previously indicated that miR-375 can inhibit Helicobacter pylori-induced gastric carcinogenesis; here, we aim to explore the effects and mechanisms of miR-375 on gastric cancer (GC) cell stemness.

Targeting cancer stem cells is critical for suppressing cancer progression and recurrence. Finding novel markers or related pathways could help eradicate or diagnose cancer in clinic.

Transcription factor Yin Yang 1 (YY1) is upregulated in multiple tumors and plays essential roles in tumor proliferation and metastasis. However, the function of YY1 in breast cancer stemness remains unclear. Herein, we found that YY1 expression was negatively correlated with the overall survival and relapse-free survival of breast cancer patients and positively correlated with the expression of stemness markers in breast cancer. Overexpression of YY1 increased the expression of stemness markers, elevated CD44+CD24- cell sub-population, and enhanced the capacity of cell spheroid formation and tumor-initiation. In contrast, YY1 knockdown exhibited the opposite effects. Mechanistically, YY1 decreased microRNA-873-5p (miR-873-5p) level by recruiting histone deacetylase 4 (HDAC4) and HDAC9 to miR-873-5p promoter and thus increasing the deacetylation level of miR-873-5p promoter. Sequentially, YY1 activated the downstream PI3K/AKT and ERK1/2 pathways, which have been confirmed to be suppressed by miR-873-5p in our recent work. Moreover, the suppressed effect of YY1/miR-873-5p axis on the stemness of breast cancer cells was partially dependent on PI3K/AKT and ERK1/2 pathways. Finally, it was found that the YY1/miR-873-5p axis is involved in the chemoresistance of breast cancer cells. Our study defines a novel YY1/miR-873-5p axis responsible for the stemness of breast cancer cells.