Immunocompromised individuals exhibit an increased risk of malignancies attributable to impaired immune surveillance and increased susceptibility to oncogenic infections, resulting in distinct responses to immunotherapy. The intricacies of infection-related cancer risks and the feasibility and efficacy of immunotherapy in these patients remain inadequately understood. A comprehensive search of PubMed, Web of Science, EMBASE, Medline, and Cochrane Library was conducted up to Nov 10, 2024. A random-effects model was pre-specified as the primary analytical method to account for anticipated clinical and methodological heterogeneity among the included studies. Heterogeneity was quantified using the I2 statistic. Tumor mutational burdens (TMBs) were assessed for Spearman correlation with standardized incidence ratios (SIRs). This systematic review included 151 studies, comprising 74 in solid organ transplant (SOT), 15 in hematopoietic stem cell transplant (HSCT), and 62 in people living with HIV (PLHIV). The analysis encompassed 2,418,274 SOT recipients, 117,264 HSCT recipients, and 5,762,641 PLHIV, covering 17 infection-related cancers. Excluding nasopharyngeal cancer, 16 cancers showed higher SIRs in SOT recipients and PLHIV compared to the general population. A statistically significant correlation was observed between TMBs and SIRs in SOT recipients (Spearman’s ρ = 0.85, P = 0.002), with consistent findings across key subgroups (kidney [Spearman’s ρ = 0.92, P < 0.001], liver [Spearman’s ρ = 0.91 (P < 0.001)], heart and/or lung [Spearman’s ρ = 0.74, P = 0.023]), and PLHIV (Spearman’s ρ = 0.89, P = 0.002), whereas no significant association was detected in HSCT recipients (Spearman’s ρ = 0.15, P = 0.805). These findings suggest that TMBs from infections or immunosuppression may contribute to cancer risk, emphasizing the potential of immune checkpoint inhibitors despite rejection risks. Personalized cancer surveillance and tailored therapies are essential for immunosuppressed populations. PROSPERO protocol ID CRD42024594181.

BACKGROUND & AIMS:There is a gap in our understanding of mechanisms promoting hepatocellular carcinoma (HCC), and this limits our ability to provide targeted therapy interventions for HCC. In HCC samples, NAD-dependent deacetylase sirtuin 2 (SIRT2) levels are increased and associated with a significantly worse prognosis, but the role of SIRT2 in hepatocarcinogenesis remains controversial. METHODS:To assess the role of SIRT2 in hepatocarcinogenesis, we used a hepatocyte-specific knockout of SIRT2 and two plasmid overexpression HCC models: c-MET (MET)/β-catenin (CAT) and protein kinase B (AKT)/Nras. RNA sequencing of mouse liver tissue was performed, and mechanistic findings were confirmed using immunohistochemistry (IHC), quantitative polymerase chain reaction, Western blot, and Cell Counting Kit-8. RESULTS:Using the MET/CAT and AKT/Nras models, we found that SIRT2 is a significant mediator of liver tumorigenesis, with the knockout of SIRT2 delaying tumor growth. RNA sequencing of MET/CAT-driven tumor tissue showed an increase in growth arrest and DNA-damage-inducible protein gamma (GADD45γ) in SIRT2 knockout mice compared with wild-type. GADD45γ is a known tumor suppressor, but the regulation of GADD45γ by SIRT2 has not been shown. CCAAT/enhancer-binding protein beta (C/EBPβ) proteins are known to regulate GADD45γ expression, and we found that C/EBPβ expression was increased in SIRT2 knockout livers and HCC cells. Also, C/EBPβ knockdown reversed GADD45γ expression and growth suppression following SIRT2 inhibition. Finally, C/EBPβ or GADD45γ overexpression significantly suppressed MET/CAT-induced HCC development. CONCLUSIONS:SIRT2 is a potent tumor promotor in HCC that negatively regulates GADD45γ expression through C/EBPβ. The SIRT2-C/EBPβ-GADD45γ pathway elucidates a novel mechanism in HCC and establishes SIRT2 as a therapeutic target for patients with HCC.

Background Many studies have shown that abnormal circular RNA (circRNA) expression is associated with the malignant progression of breast cancer (BC), but the role of circ_0000732 in BC progression remains unclear. Methods The expression of circ_0000732, microRNA (miR)-1253 and collagen XI alpha 1 (COL11A1) was measured by quantitative real-time PCR. Cell proliferation, migration, invasion and stemness were assessed by cell counting kit 8 assay, Edu assay, transwell assay and sphere formation assay. Western blot analysis was used to determine protein expression. Dual-luciferase reporter assay was performed to assess the interaction between miR-1253 and circ_0000732 or COL11A1. The effect of circ_0000732 on BC tumor growth was confirmed by animal experiments. Results Circ_0000732 was overexpressed in BC tissues and cells, and its knockdown suppressed BC cell proliferation, metastasis and stemness. MiR-1253 could be sponged by circ_0000732, and anti-miR-1253 overturned the effects of circ_0000732 knockdown on BC cell progression. COL11A1 was targeted by miR-1253, and miR-1253 inhibited BC cell progression by targeting COL11A1. Circ_0000732 could sponge miR-1253 to upregulate COL11A1. Also, interference of circ_0000732 decreased BC tumor growth by miR-1253/COL11A1 pathway. Conclusion Our data showed that circ_0000732 might be a potential target for BC treatment, which could enhance BC malignant phenotype through miR-1253/COL11A1 axis.

The mechanistic target of rapamycin-mLST8-raptor complex (mTORC1) functions as a central regulator of cell growth and metabolism in response to changes in nutrient signals such as amino acids. SAMTOR is an S-adenosylmethionine (SAM) sensor, which regulates the mTORC1 activity through its interaction with the GTPase-activating protein activity toward Rags-1 (GATOR1)-KPTN, ITFG2, C12orf66 and SZT2-containing regulator (KICSTOR) complex. In this work, we report the crystal structures of Drosophila melanogaster SAMTOR in apo form and in complex with SAM. SAMTOR comprises an N-terminal helical domain and a C-terminal SAM-dependent methyl-transferase (MTase) domain. The MTase domain contains the SAM-binding site and the potential GATOR1-KICSTOR-binding site. The helical domain functions as a molecular switch, which undergoes conformational change upon SAM binding and thereby modulates the interaction of SAMTOR with GATOR1-KICSTOR. The functional roles of the key residues and the helical domain are validated by functional assays. Our structural and functional data together reveal the molecular mechanism of the SAM sensing of SAMTOR and its functional role in mTORC1 signaling.

HOXB13, a homeodomain transcription factor, critically regulates androgen receptor (AR) activities and androgen-dependent prostate cancer (PCa) growth. However, its functions in AR-independent contexts remain elusive. Here we report HOXB13 interaction with histone deacetylase HDAC3, which is disrupted by the HOXB13 G84E mutation that has been associated with early-onset PCa. Independently of AR, HOXB13 recruits HDAC3 to lipogenic enhancers to catalyze histone deacetylation and suppress lipogenic regulators such as fatty acid synthase. Analysis of human tissues reveals that the HOXB13 gene is hypermethylated and downregulated in approximately 30% of metastatic castration-resistant PCa. HOXB13 loss or G84E mutation leads to lipid accumulation in PCa cells, thereby promoting cell motility and xenograft tumor metastasis, which is mitigated by pharmaceutical inhibition of fatty acid synthase. In summary, we present evidence that HOXB13 recruits HDAC3 to suppress de novo lipogenesis and inhibit tumor metastasis and that lipogenic pathway inhibitors may be useful to treat HOXB13-low PCa.

Hepatocellular carcinoma (HCC) is a very deadly disease. HCC initiation and progression involve multiple genetic events, including the activation of proto-oncogenes and disruption of the function of specific tumor suppressor genes. Activation of oncogenes stimulates cell growth and survival, while loss-of-function mutations of tumor suppressor genes result in unrestrained cell growth. In this review, we summarize the new findings that identified novel proto-oncogenes and tumor suppressors in HCC over the past five years. These findings may inspire the development of novel therapeutic strategies to improve the outcome of HCC patients.

Hepatocellular carcinoma (HCC) is a highly lethal and complex malignancy strongly influenced by the surrounding tumor microenvironment. The HCC microenvironment comprises hepatic stellate cells (HSCs), tumor-associated macrophages (TAMs), stromal and endothelial cells, and the underlying extracellular matrix (ECM). Emerging evidence demonstrates that epigenetic regulation plays a crucial role in altering numerous components of the HCC tumor microenvironment. In this review, we summarize the current understanding of the mechanisms of epigenetic regulation of the microenvironment in HCC. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation, histone regulation, and non-coding RNAs mediated regulation) in HSCs, TAMs, and ECM, and how they contribute to HCC development, so as to gain new insights into the treatment of HCC via regulating epigenetic regulation in the tumor microenvironment.

Forkhead box protein A1 (FOXA1) is essential for androgen-dependent prostate cancer (PCa) growth. However, how FOXA1 levels are regulated remains elusive and its therapeutic targeting proven challenging. Here, we report FOXA1 as a nonhistone substrate of enhancer of zeste homolog 2 (EZH2), which methylates FOXA1 at lysine-295. This methylation is recognized by WD40 repeat protein BUB3, which subsequently recruits ubiquitin-specific protease 7 (USP7) to remove ubiquitination and enhance FOXA1 protein stability. They functionally converge in regulating cell cycle genes and promoting PCa growth. FOXA1 is a major therapeutic target of the inhibitors of EZH2 methyltransferase activities in PCa. FOXA1-driven PCa growth can be effectively mitigated by EZH2 enzymatic inhibitors, either alone or in combination with USP7 inhibitors. Together, our study reports EZH2-catalyzed methylation as a key mechanism to FOXA1 protein stability, which may be leveraged to enhance therapeutic targeting of PCa using enzymatic EZH2 inhibitors.

Background Splicing factor poly(rC)-binding protein 1 (PCBP1) is a novel tumor suppressor that is downregulated in many cancers thereby regulates tumor formation and metastasis. However, to date, little information has been available on the molecular mechanisms by which PCBP1 evokes apoptosis. Results Here, we explored the molecular mechanism by which PCBP1 triggers apoptosis in human cervical cancer cells. We testified that overexpression of PCBP1 greatly repressed proliferation of HeLa cells in time-dependent manner. It also induced a significant increase in G2 / M phase arrest and apoptosis. Furthermore, it was shown that overexpression of PCBP1 caused p73 splicing, and thus efficiently downregulated the ratio of Bax / Bcl-2, the release of cytochrome c and the expression of caspase-3. Conclusion Our results revealed that PCBP1 played a vital role in cycle arrest, apoptosis induction, and p73 splicing in human cervical carcinoma cells and targeting PCBP1 may be a promising approach in cervical cancer therapy.

Transforming growth factor beta (TGF-beta) is part of the transforming growth factor beta superfamily which is involved in many physiological processes and closely related to the carcinogenesis. Here, we discuss the TGF-beta structure, function, and its canonical Smads signaling pathway. Importantly, TGF-beta has been proved that it plays both tumor suppressor as well as an activator role in tumor progression. In an early stage, TGF-beta inhibits cell proliferation and is involved in cell apoptosis. In an advanced tumor, TGF-beta signaling pathway induces tumor invasion and metastasis through promoting angiogenesis, epithelial-mesenchymal transition, and immune escape. Furthermore, we are centered on updated research results into the inhibitors as drugs which have been studied in preclinical or clinical trials in tumor carcinogenesis to prevent the TGF-beta synthesis and block its signaling pathways such as antibodies, antisense molecules, and small-molecule tyrosine kinase inhibitors. Thus, it is highlighting the crucial role of TGF-beta in tumor therapy and may provide opportunities for the new antitumor strategies in patients with cancer.

BACKGROUND & AIMS: We investigated whether ABL protooncogene 1, non-receptor tyrosine kinase (ABL1) is involved in development of hepatocellular carcinoma (HCC). METHODS: We analyzed clinical and gene expression data from The Cancer Genome Atlas. Albumin-Cre (Hep(WT)) mice and mice with hepatocyte-specific disruption of Abl1 (Hep(Abl-/-) mice) were given hydrodynamic injections of plasmids encoding the Sleeping Beauty transposase and transposons with the MET gene and a catenin beta 1 gene with an N-terminal truncation, which induces development of liver tumors. Some mice were then gavaged with the ABL1 inhibitor nilotinib or vehicle (control) daily for 4 weeks. We knocked down ABL1 with short hairpin RNAs in Hep3B and Huh7 HCC cells and analyzed their proliferation and growth as xenograft tumors in mice. We performed RNA sequencing and gene set enrichment analysis of tumors. We knocked down or overexpressed NOTCH1 and MYC in HCC cells and analyzed proliferation. We measured levels of phosphorylated ABL1, MYC, and NOTCH1 by immunohistochemical analysis of an HCC tissue microarray. RESULTS: HCC tissues had higher levels of ABL1 than non-tumor liver tissues, which correlated with shorter survival times of patients. Hep(WT) mice with the MET and catenin beta 1 transposons developed liver tumors and survived a median 64 days; Hep(Abl-/-) mice with these transposons developed tumors that were 50% smaller and survived a median 81 days. Knockdown of ABL1 in human HCC cells reduced proliferation, growth as xenograft tumors in mice, and expression of MYC, which reduced expression of NOTCH1. Knockdown of NOTCH1 or MYC in HCC cells significantly reduced cell growth. NOTCH1 or MYC overexpression in human HCC cells promoted proliferation and rescued the phenotype caused by ABL1 knockdown. The level of phosphorylated (activated) ABL1 correlated with levels of MYC and NOTCH1 in human HCC specimens. Nilotinib decreased expression of MYC and NOTCH1 in HCC cell lines, reduced the growth of xenograft tumors in mice, and slowed growth of liver tumors in mice with MET and catenin beta 1 transposons, reducing tumor levels of MYC and NOTCH1. CONCLUSIONS: HCC samples have increased levels of ABL1 compared with nontumor liver tissues, and increased levels of ABL1 correlate with shorter survival times of patients. Loss or inhibition of ABL1 reduces proliferation of HCC cells and slows growth of liver tumors in mice. Inhibitors of ABL1 might be used for treatment of HCC.

Transforming growth factor β (TGF‐β) is part of the transforming growth factor β superfamily which is involved in many physiological processes and closely related to the carcinogenesis. Here, we discuss the TGF‐β structure, function, and its canonical Smads signaling pathway. Importantly, TGF‐β has been proved that it plays both tumor suppressor as well as an activator role in tumor progression. In an early stage, TGF‐β inhibits cell proliferation and is involved in cell apoptosis. In an advanced tumor, TGF‐β signaling pathway induces tumor invasion and metastasis through promoting angiogenesis, epithelial–mesenchymal transition, and immune escape. Furthermore, we are centered on updated research results into the inhibitors as drugs which have been studied in preclinical or clinical trials in tumor carcinogenesis to prevent the TGF‐β synthesis and block its signaling pathways such as antibodies, antisense molecules, and small‐molecule tyrosine kinase inhibitors. Thus, it is highlighting the crucial role of TGF‐β in tumor therapy and may provide opportunities for the new antitumor strategies in patients with cancer.

Prostate cancer (CaP) is the second most common cancer in men worldwide in 2012, and radiation therapy is one of the most common definitive treatment options for localized CaP. However, radioresistance is a major challenge for the current radiotherapy, accumulating evidences suggest microRNAs (miRNAs), as an important regulator in cellular ionizing radiation (IR) responses, are closely correlated with radiosensitivity in many cancers. Here, we identified microRNA‐16‐5p(miR‐16‐5p) is significantly upregulated in CaP LNCaP cells following IR and can enhance radiosensitivity through modulating Cyclin D1/E1–pRb–E2F1 pathway. To identify the expression profile of miRNAs in CaP cells exposed to IR, we performed human miRNA probe hybridization chip analysis and miR‐16‐5p was found to be significantly overexpressed in all treatment groups that irradiated with different doses of X‐rays and heavy ions ( 12 C 6+ ). Furthermore, overexpression of miR‐16‐5p suppressed cell proliferation, reduced cell viability, and induced cell cycle arrest at G0/G1 phase, resulting in enhanced radiosensitivity in LNCaP cells. Additionally, miR‐16‐5p specifically targeted the Cyclin D1/E1–3′‐UTR in LNCaP cells and affected the expression of Cyclin D1/E1 in both mRNA and protein levels. Taken together, miR‐16‐5p enhanced radiosensitivity of CaP cells, the mechanism may be through modulating Cyclin D1/Cyclin E1/pRb/E2F1 pathway to cause cell cycle arrest at G0/G1 phase. These findings provided new insight into the correlation between miR‐16‐5p, cell cycle arrest, and radiosensitivity in CaP, revealed a previously unrecognized function of miR‐16‐5p–Cyclin D1/E1–pRb–E2F1 regulation in response to IR and may offer an alternative therapy to improve the efficiency of conventional radiotherapy.

Hepatocellular carcinoma (HCC) is the fifth most common primary cancer and second largest cause of cancer‐related death worldwide. The first‐line oral chemotherapeutic agent sorafenib only increases survival in patients with advanced HCC by less than 3 months. Most patients with advanced HCC have shown limited response rates and survival benefits with sorafenib. Although sorafenib is an inhibitor of multiple kinases, including serine/threonine‐protein kinase c‐Raf, serine/threonine‐protein kinase B‐Raf, vascular endothelial growth factor receptor (VEGFR)‐1, VEGFR‐2, VEGFR‐3, and platelet‐derived growth factor receptor β, HCC cells are able to escape from sorafenib treatment using other pathways that the drug insufficiently inhibits. The aim of this study was to identify and target survival and proliferation pathways that enable HCC to escape the antitumor activity of sorafenib. We found that insulin‐like growth factor 1 receptor (IGF1R) remains activated in HCC cells treated with sorafenib. Knockdown of IGF1R sensitizes HCC cells to sorafenib treatment and decreases protein kinase B (AKT) activation. Overexpression of constitutively activated AKT reverses the effect of knockdown of IGF1R in sensitizing HCC cells to treatment with sorafenib. Further, we found that ceritinib, a drug approved by the U.S. Food and Drug Administration for treatment of non‐small cell lung cancer, effectively inhibits the IGF1R/AKT pathway and enhances the inhibitory efficacy of sorafenib in human HCC cell growth and survival in vitro , in a xenograft mouse model and in the c‐Met/β‐catenin‐driven HCC mouse model. Conclusion : Our study provides a biochemical basis for evaluation of a new combination treatment that includes IGF1R inhibitors, such as ceritinib and sorafenib, in patients with HCC. ( Hepatology Communications 2018;2:732‐746)

In acute myelogenous leukemia (AML), the bone marrow microenvironment provides growth and survival signals that may confer resistance to chemotherapy. Granulocyte colony-stimulating factor (G-CSF) potently inhibits lymphopoiesis by targeting stromal cells that comprise the lymphoid niche in the bone marrow; nonetheless, its healing effects in AML are unknown. In this current study, we demonstrated that G-CSF significantly inhibits the CXCR4 expressionin a time-dependent manner, and antagonized SDF-1 alpha-induced migration of AML cells. Furthermore, G-CSF effectively mobilized regulatory T cells into the circulation and inhibits the SDF-1 alpha in in vivo xenograft models. These findings indicate that G-CSF is useful as an effective ingredient in antileukemia activity.

As influenza A viruses remain a major threat to human health worldwide, the discovery of broadly neutralizing monoclonal antibodies that recognize conserved epitopes would facilitate the development of antibody-based therapeutic strategies. Here we report that a VH4-4-encoded human mAb named 3E1 could neutralize H1 and H5 subtype viruses in vitro and protect mice against the H1N1 and H5N6 viruses by inhibiting the low pH-induced conformational rearrangement of haemagglutinin (HA), hence blocking membrane fusion. The crystal structures of 3E1 Fab in complex with HA of two H1N1 strains reveal that 3E1, with both heavy and light chains, binds to a conserved epitope of the HA stem region, comprising parts of the fusion peptide, the F subdomain and the outermost β-strand preceding helix A. Altogether, these data suggest the potential of 3E1 as a therapeutic drug against H1 and H5 subtype viruses.

Understanding the molecular mechanisms of liver regeneration is essential to improve the survival rate of patients after surgical resection of large amounts of liver tissue. Focal adhesion kinase (FAK) regulates different cellular functions, including cell survival, proliferation and cell migration. The role of FAK in liver regeneration remains unknown. In this study, we found that Fak is activated and induced during liver regeneration after two-thirds partial hepatectomy (PHx). We used mice with liver-specific deletion of Fak and investigated the role of Fak in liver regeneration in 2/3 PHx model (removal of 2/3 of the liver). We found that specific deletion of Fak accelerates liver regeneration. Fak deletion enhances hepatocyte proliferation prior to day 3 post-PHx but attenuates hepatocyte proliferation 3 days after PHx. Moreover, we demonstrated that the deletion of Fak in liver transiently increases EGFR activation by regulating the TNFα/HB-EGF axis during liver regeneration. Furthermore, we found more apoptosis in Fak-deficient mouse livers compared to WT mouse livers after PHx.CONCLUSION:Our data suggest that Fak is involved in the process of liver regeneration, and inhibition of FAK may be a promising strategy to accelerate liver regeneration in recipients after liver transplantation.

Frequent alteration of upstream proto-oncogenes and tumor suppressor genes activates mechanistic target of rapamycin (mTOR) and causes cancer. However, the downstream effectors of mTOR remain largely elusive. Here we report that brain-expressed X-linked 2 (BEX2) is a novel downstream effector of mTOR. Elevated BEX2 in Tsc2(-/-) mouse embryonic fibroblasts, Pten(-/-) mouse embryonic fibroblasts, Tsc2-deficient rat uterine leiomyoma cells, and brains of neuronal specific Tsc1 knockout mice were abolished by mTOR inhibitor rapamycin. Furthermore, BEX2 was also increased in the liver of a hepatic specific Pten knock-out mouse and the kidneys of Tsc2 heterozygous deletion mice, and a patient with tuberous sclerosis complex (TSC). mTOR up-regulation of BEX2 was mediated in parallel by both STAT3 and NF-kappa B. BEX2 was involved in mTOR up-regulation of VEGF production and angiogenesis. Depletion of BEX2 blunted the tumorigenesis of cells with activated mTOR. Therefore, enhanced STAT3/NF-kappa B-BEX2-VEGF signaling pathway contributes to hyperactive mTOR-induced tumorigenesis. BEX2 may be targeted for the treatment of the cancers with aberrantly activated mTOR signaling pathway.

Autologous implantation of bone mesenchymal stem cells (BMSCs) has achieved promising clinical efficacy for the treatment of early-stage osteonecrosis of the femoral head (ONFH). However, the underlying mechanisms are not completely elucidated. Here, we investigated the effect of BMSCs on the early ONFH in vitro and in vivo. In co-cultured system, primary BMSCs enhanced the activity and inhibited the apoptosis of primary OB. The concentrations of VEGF and BMP-2 in the co-cultured medium were significantly higher than those without co-culture. Importantly, BMSCs implantation increased OB, capillaries and VEGF and BMP-2 expressions of the necrotic areas of femoral head in the ONFH rabbits. In conclusion, our results indicated that BMSCs treated the early ONFH possibly through increasing OB and capillaries, as well as VEGF and BMP-2 expression in the femoral head. These results provided possible mechanisms for the treatment of early-stage ONFH with BMSCs transplantation.