The pan-cancer analysis of the oncogenic role of FAM72A as a BRCA prognostic biomarker and immunotherapeutic target.

In this study, we first comprehensively investigated the expression profile, mutation status, and survival analysis of FAM72A as well as the correlation between FAM72A and DNA damage repair, methylation, and cell stemness analysis using bioinformatics techniques. In addition, we also analyzed the relationship between FAM72A and immune cell infiltration and pathway enrichment. The role of FAM72A in breast cancer (BC) was so conspicuous that we analyzed the prognostic significance and clinicopathological parameter's relevance of FAM72A in BC. We also validated biological functions by applying in vitro experiments. FAM72A was highly expressed in 26 types of a total of 31 cancers, while it expressed low levels in only five cancers. FAM72A expression was relative to clinical stages in nine cancers and has a significant difference in disease-free survival among 31 kinds of cancers. In addition, FAM72A has negatively correlated with cancer-associated fibroblast and endothelial cells in BC but positively correlated with follicular helper T cells. Univariate and multivariate cox regression analyses identified T, N, M, age, and FAM72A expression as independent influences on BC prognosis, so we created a nomogram to predict patient survival benefits. In in vitro experiments, we verified that downregulation of FAM72A not only inhibited cell proliferation, colony formation, cell migration, cell invasion, and G2/M cell cycle transition but also promoted apoptosis of breast invasive carcinoma cells. Our study discovered FAM72A as a clinically meaningful biomarker for prognostic predicting and a guiding target for immune treatment in BC.

Prognostic and Immunological Implications of FAM72A in Pan-Cancer and Functional Validations.

The family with sequence similarity 72 Member A (FAM72A) is overexpressed in several types of cancer. However, its contributions to tumorigenesis remain largely unknown. Based on The Cancer Genome Atlas (TCGA) database, FAM72A was upregulated across 33 types of cancer. Accordingly, high levels of FAM72A predicted inferior outcomes in half of the cancer types using survival analysis (the Kaplan-Meier curve and univariate Cox regression model). Receiver operating characteristic (ROC) analysis demonstrated that FAM72A showed high accuracy in distinguishing cancerous tissues from normal ones. FAM72A was correlated with immune and stromal scores and immune cell infiltrations in various tumors. Moreover, FAM72A was also associated with tumor mutation burden (TMB), microsatellite instability (MSI), and immune checkpoint genes. Immunophenoscore (IPS) further validated that the FAM72Alow tumor showed high immunogenicity and tended to respond to anti-PD1/PDL1/PDL2, anti-CTLA4 treatment, and combined immunotherapies. We also investigated the functional role of FAM72A in lung adenocarcinoma (LUAD). In vitro studies demonstrated that the ectopic expression of FAM72A accelerated the proliferation and migration of NSCLC cells, whereas silencing FAM72A showed the opposite effects on them. In short, FAM72A had prognostic potential and correlated with tumor immunogenicity in various tumors. Functional analysis indicated that FAM72A is an oncogene in LUAD.

Brain plasticity, cognitive functions and neural stem cells: a pivotal role for the brain-specific neural master gene |-SRGAP2-FAM72-|.

Due to an aging society with an increased dementia-induced threat to higher cognitive functions, it has become imperative to understand the molecular and cellular events controlling the memory and learning processes in the brain. Here, we suggest that the novel master gene pair |-SRGAP2-FAM72-| (SLIT-ROBO Rho GTPase activating the protein 2, family with sequence similarity to 72) reveals a new dogma for the regulation of neural stem cell (NSC) gene expression and is a distinctive player in the control of human brain plasticity. Insight into the specific regulation of the brain-specific neural master gene |-SRGAP2-FAM72-| may essentially contribute to novel therapeutic approaches to restore or improve higher cognitive functions.

All-or-(N)One - an epistemological characterization of the human tumorigenic neuronal paralogous FAM72 gene loci.

FAM72 is a novel neuronal progenitor cell (NPC) self-renewal supporting protein expressed under physiological conditions at low levels in other tissues. Accumulating data indicate the potential pivotal tumourigenic effects of FAM72. Our in silico human genome-wide analysis (GWA) revealed that the FAM72 gene family consists of four human-specific paralogous members, all of which are located on chromosome (chr) 1. Unique asymmetric FAM72 segmental gene duplications are most likely to have occurred in conjunction with the paired genomic neighbour SRGAP2 (SLIT-ROBO Rho GTPase activating protein), as both genes have four paralogues in humans but only one vertebra-emerging orthologue in all other species. No species with two or three FAM72/SRGAP2 gene pairs could be identified, and the four exclusively human-defining ohnologues, with different mutation patterns in Homo neanderthalensis and Denisova hominin, may remain under epigenetic control through long non-coding (lnc) RNAs.

Expression and Function of FAM72A Gene in Multiple myelomaFAM72A.

AIMS: This study aims to comprehensively investigate the role of Family Member A with sequence similarity 72-A (FAM72A) in multiple myeloma. BACKGROUND: Multiple myeloma poses significant challenges. This study delves into FAM72A's impact on key cellular processes, shedding light on potential therapeutic targets and enhancing our understanding of multiple myeloma progression. OBJECTIVE: Investigate the impact of FAM72A on the proliferation, apoptosis, and bortezomib sensitivity of multiple myeloma cell line U266. METHODS: qRT-PCR analyzed FAM72A expression levels in bone marrow samples from 30 patients with multiple myeloma and 10 healthy donors at the Second Hospital of Shanxi Medical University. Cell lines overexpressing FAM72A were constructed, and Cell Counting Kit 8 (CCK-8) and flow cytometry were used to assess U266 cell proliferation, apoptosis, and sensitivity to bortezomib. Biological predictions for FAM72A were performed to find transcription factors binding to the FAM72A promoter region, verified using a luciferase assay. U266 cells were transfected with si-POU2F2 (POU class 2 homeobox 2), and the impact on cell proliferation was validated. Western blot analysis detected the expression of downstream proteins in the p53 signaling pathway. In vivo, experiments established a xenograft mouse model further to study the role of FAM72A in multiple myeloma. RESULTS: FAM72A was upregulated in multiple myeloma bone marrow tissues. Compared to the OE-NC group, the OE-FAM72A group showed increased Mouse Double Minute 2 homolog (MDM2) expression, decreased p53 expression, increased cell proliferation, and decreased apoptosis. POU2F2 was identified as the upstream transcription factor for FAM72A. Compared to the si-NC group, the si-POU2F2 group exhibited decreased MDM2 expression, increased p53 expression, slowed cell proliferation, and increased apoptosis. Silencing POU2F2 could reverse the pro-proliferative effect of over-expressing FAM72A in U266 cells. In vivo experiments in a xenograft mouse model further studied the role of FAM72A in multiple myeloma. CONCLUSION: Overexpression of FAM72A promotes U266 cell proliferation, inhibits apoptosis, and reduces sensitivity to bortezomib by regulating the POU2F2/FAM72A/p53 signaling pathway.

Pan-cancer analysis and experimental validation reveal FAM72D as a potential novel biomarker and therapeutic target in lung adenocarcinoma.

BACKGROUND: Cancers, particularly lung adenocarcinoma (LUAD), represent a major global health concern. However, the role of FAM72D in various cancers, including LUAD, remains poorly understood. METHODS: We utilized databases such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx) and online tools to investigate the correlation between FAM72D expression and its prognostic, diagnostic, and mutational significance, as well as its impact on immune cell infiltration across multiple cancers. Additionally, we developed LUAD cell lines overexpressing FAM72D to confirm its oncogenic role. RESULTS: FAM72D expression was elevated in cancerous tissues compared to noncancerous tissues, with diagnostic and prognostic implications in many cancers, including LUAD. Moreover, associations were identified between FAM72D expression and diverse immune subtypes, alongside factors such as microsatellite instability, neoantigens, and tumour mutational burden across pan-cancers. Additionally, FAM72D was associated with immune infiltration and various immune checkpoint-related genes in LUAD. In vitro experiments demonstrated that FAM72D promoted cell proliferation, colony formation, and migration, while inhibiting apoptosis in LUAD cells. CONCLUSIONS: Our study establishes associations between FAM72D expression and diagnosis, prognosis, and tumour immunity across multiple cancers, as well as its oncogenic effects in LUAD. FAM72D shows promise as a biomarker and therapeutic target in LUAD.

FAM72 family proteins as poor prognostic markers in clear cell renal carcinoma.

Purpose: This study aimed to investigate the prognostic significance of the Family with Sequence Similarity 72 member (FAM72) gene family in clear cell renal carcinoma (ccRCC) using a bioinformatic approach. Patients and methods: To investigate the association between FAM72 and ccRCC, we utilized various databases and analysis tools, including TCGA, GEPIA, Metscape, cBioPortal, and MethSurv. We conducted an analysis of FAM72 expression levels in ccRCC tissues compared to normal kidney tissues and performed univariate and multivariate Cox analysis to determine the relationship between FAM72 expression and patient prognosis. Furthermore, we carried out Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) to identify enriched biological processes associated with FAM72 expression. Additionally, we analyzed immune cell infiltration and the level of methylation in ccRCC patients. Our bioinformatic analysis revealed that FAM72 expression levels were significantly higher in ccRCC tissues than in normal kidney tissues. High expression of FAM72 was associated with poor prognosis in ccRCC patients and was found to be an independent prognostic factor for ccRCC. GO and GSEA analyses indicated that FAM72 was enriched in biological processes related to mitosis, cell cycle, and DNA metabolism. Moreover, we found a significant correlation between FAM72 and immune cell infiltration and the level of methylation in ccRCC patients. Conclusion: Our findings suggest that FAM72 could serve as an unfavorable prognostic molecular marker for ccRCC. A comprehensive understanding of FAM72 could provide crucial insights into tumor progression and prognosis.

Family with Sequence Similarity 72 (FAM72) - A prospective biomarker for poor prognosis in patients with oral squamous cell carcinoma.

OBJECTIVE: To study the effect of FAM72 on the prognosis of patients with oral squamous cell carcinoma (OSCC) and to explore the relationship between FAM72 and OSCC. DESIGN: We used a vast array of databases and analytical vehicles to assess the relation between FAM72 and OSCC, including The Cancer Genome Atlas (TCGA), Metascape, and MethSurv. We made a preliminary verification of OSCC lines and tissues by real time quantitative polymerase chain reaction (RT-qPCR). RESULTS: FAM72 was higher in OSCC than in normal tissues. Analysis of univariate COX data indicated that elevated expression of FAM72A, FAM72B, and FAM72C in OSCC was related to poor overall survival. Moreover, FAM72B and FAM72C were independent of overall survival in multiple COX regression. FAM72A-D and its coexpressed genes in Metascape were analyzed by Gene Ontology (GO), they were enriched in cellular cycle, mitotic and DNA metabolism. Gene set enrichment analysis (GSEA) demonstrated an enrichment in pathways related to cell metabolism. Additionally, high FAM72 expression related to a worse prognosis in OSCC patients. FAM72A-D linked to the infiltration of tumor immune cell in OSCC patients. We found that methylation levels are likely linked to prognosis in OSCC patients. We used RT-qPCR to ascertain the differential FAM72B and FAM72C expression levels in cancer and paracancerous tissues of OSCC, human normal oral keratinocytes (HOK), and human tongue squamous cell carcinoma (Cal-33). CONCLUSION: Our findings indicate that FAM72B and FAM72C are potential molecular markers of poor prognosis in OSCC and may act as novel targets for OSCC treatment strategies.

FAM72A promotes glioma progression by regulating mitophagy through the Pink1/Parkin signaling pathway.

Background: There is growing evidence that aberrant expression of FAM72A contributes to biological dysfunction, especially mitochondrial dysfunction. However, its role in most tumors remains unclear, especially in glioma. Methods: Herein, a high-throughput sequencing approach was used here to identify FAM72A as the target molecule. Next, we detected the protein and mRNA expression levels of FAM72A in normal brain tissue (NBT) as well as different grades of glioma tissue. CCK-8, colony formation, Transwell assays, and Western blotting, were all used to determine the molecular effects of FAM72A on glioma cells. Results: FAM72A was significantly upregulated in glioma, was significantly correlated with WHO grade and was associated with poor clinical outcomes. In functional assays, FAM72A was shown to promote glioma cell growth. Subsequent mechanistic studies indicated that FAM72A promoted glioma progression by regulating mitophagy through the Pink1/Parkin signaling pathway. In addition, FAM72A promoted mitophagy and maintained Pink1 stability through the Pink1/Parkin signaling pathway. Finally, FAM72A promoted tumor immune escape by upregulating PD-L1 expression. Conclusion: All of these data indicate that FAM72A confers an aggressive phenotype and poor prognosis on gliomas. Targeting FAM72A might represent a new therapeutic strategy for glioma.

Fam72a functions as a cell-cycle-controlled gene during proliferation and antagonizes apoptosis through reprogramming PP2A substrates.

The cell cycle is key to life. After decades of research, it is unclear whether any parts of this process have yet to be identified. Fam72a is a poorly characterized gene and is evolutionarily conserved across multicellular organisms. Here, we have found that Fam72a is a cell-cycle-regulated gene that is transcriptionally and post-transcriptionally regulated by FoxM1 and APC/C, respectively. Functionally, Fam72a directly binds to tubulin and both the Aα and B56 subunits of PP2A-B56 to modulate tubulin and Mcl1 phosphorylation, which in turn affects the progression of the cell cycle and signaling of apoptosis. Moreover, Fam72a is involved in early responses to chemotherapy, and it efficiently antagonizes various anticancer compounds such as CDK and Bcl2 inhibitors. Thus, Fam72a switches the tumor-suppressive PP2A to be oncogenic by reprogramming its substrates. These findings identify a regulatory axis of PP2A and a protein member in the cell cycle and tumorigenesis regulatory network in human cells.

Integrated systemic analysis of FAM72A to identify its clinical relevance, biological function, and relationship to drug sensitivity in hepatocellular carcinoma.

Background: The family with sequence similarity 72 member A (FAM72A) protein has been identified as an effector of multiple pathological processes in many cancers. The value of FAM72A in HCC remains largely unknown. Methods: Data from TCGA-LIHC, ICGC-LIRI-JP, IMvigor210, cBioPortal, GeneMANIA, and TIMER were processed and visualized to explore the association between FAM72A and the prognosis, stemness phenotype, mutational burden, immune cell infiltration, and drug sensitivity in HCC patients. Potential pathways were also revealed. Furthermore, we experimentally verified the results in vivo and in vitro using immunohistochemistry, western blotting, and CCK-8 assays. Results: First, FAM72A mRNA expression was significantly upregulated in HCC. High FAM72A expression was independently associated with a poor prognosis. Experimental validation confirmed that FAM72A was remarkably overexpressed in HCC patients and mice. Moreover, FAM72A knockdown suppressed HCC cell proliferation. In addition, the frequency of TP53 mutations was significantly higher in the high FAM72A expression group. Subsequently, the enrichment analysis revealed that FAM72A was closely related to immune processes and mTOR pathways. Silencing FAM72A increased the expression levels of mTOR in HCC cell lines. The FAM72A-mTOR pathway was strongly associated with a poor prognosis for patients with HCC. Patients with high FAM72A expression levels might be more resistant to sorafenib. Furthermore, the expression of FAM72A and mTOR was significantly associated with the abundance of some tumor-infiltrating immune cells, especially CD4+ T cells. Finally, patients with high levels of FAM72A and mTOR were more sensitive to immunotherapy. Conclusions: FAM72A, a member of the FAM72 family, might be a prognostic and immunotherapeutic target for HCC patients.

Identifying Immune Cell Infiltration and Effective Diagnostic Biomarkers in Lung Adenocarcinoma by Comprehensive Bioinformatics Analysis and In Vitro Study.

Family with sequence similarity 72B (FAM72B) has been characterized in the regulation of neuronal development. Nevertheless, the prognostic value of FAM72B expression and its function in the immune microenvironment of lung adenocarcinoma (LUAD) currently remains elusive. In this study, by adopting bioinformatics methodology and experimental verification, we found that FAM72B was upregulated in lung cancer tissues and cell lines, and a higher FAM72B level predicted an unfavorable clinical outcome in LUAD patients. The knockdown of FAM72B significantly inhibited cell proliferation, cell migration, and induced cell apoptosis in LUAD. The receiver operating characteristic curve suggested that FAM72B had a high predictive accuracy for the outcomes of LUAD. Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analyses confirmed that FAM72B-related genes were involved in cell proliferation and immune-response signaling pathway. Moreover, upregulated FAM72B expression was significantly associated with immune cell infiltration in the LUAD tumor microenvironment. Meanwhile, a potential ceRNA network was constructed to identify the lncRNA-AL360270.2/TMPO-AS1/AC125807.2/has-let-7a/7b/7c/7e/7f/FAM72B regulatory axis that regulates FAM72B overexpression in LUAD and is associated with a poor prognosis. We also confirmed that AL360270.2, TMPO-AS1, and AC125807.2 were significantly upregulated in LUAD cell lines than in human bronchial epithelial cells. In conclusion, FAM72B may serve as a novel biomarker in predicting the clinical prognosis and immune status for lung adenocarcinoma.

FAM72 serves as a biomarker of poor prognosis in human lung adenocarcinoma.

FAM72A-D promote the self-renewal of neural progenitor cells. There is accumulating evidence that FAM72 promotes tumorigenicity. However, its effects in lung adenocarcinoma (LUAD) have not been determined. Thus, we evaluated the prognostic value of FAM72A-D in LUAD using bioinformatics approaches. In particular, we evaluated the relationship between FAM72 and LUAD using a wide range of databases and analysis tools, including TCGA, GEO, GEPIA, Metascape, cBioPortal, and MethSurv. Compared with its expression in normal lung tissues, FAM72 expression was significantly increased in LUAD tissues. A univariate Cox analysis showed that high FAM72 expression levels were correlated with a poor OS in LUAD. Additionally, FAM72 expression was independently associated with OS through a multivariate Cox analysis. GO and GSEA revealed enrichment in mitotic nuclear division and cell cycle. Moreover, high FAM72 expression was associated with poor survival. An analysis of immune infiltration showed that FAM72 is correlated with immune cell infiltration. Finally, we found that the methylation level was associated with prognosis in patients with LUAD. In summary, these results indicate that FAM72 is a potential molecular marker for poor prognosis in LUAD and provide additional insight for the development of therapies and prognostic markers.

Serum exosomal long noncoding RNAs lnc-FAM72D-3 and lnc-EPC1-4 as diagnostic biomarkers for hepatocellular carcinoma.

Long noncoding RNAs (lncRNAs), such as LINC00462, HOTAIR, and MALAT1, are significantly upregulated in hepatocellular carcinoma (HCC) tissues. However, lncRNA expression in the serum of HCC patients is still unclear. To identify candidate lncRNAs for HCC diagnosis, we purified exosomal total RNA from the serum of healthy volunteers (controls) and hepatitis, cirrhosis, and HCC patients. To assess the function of lncRNAs, small interfering RNAs and overexpression vectors were designed and cell viability and cell apoptosis assays conducted. The exosomes of the control group had a larger number of lncRNAs with a high amount of alternative splicing compared to hepatic disease patients. qPCR assays showed that lnc-FAM72D-3, lnc-GPR89B-15, lncZEB2-19, and lnc-EPC1-4 are differentially expressed in HCC. Furthermore, the expression level of lnc-EPC1-4 correlated with age. While the expression levels of lnc-GPR89B-15 and lnc-EPC1-4 correlated with serum alpha-fetoprotein level. lnc-FAM72D-3 knockdown decreased cell viability and promoted cell apoptosis, indicating that lnc-FAM72D-3 functions as an oncogene in HCC. In contrast, lnc-EPC1-4 overexpression inhibited cell proliferation and induced cell apoptosis, indicating that it functions as a tumor suppressor gene. Collectively, these findings show that lnc-FAM72D-3 and lnc-EPC1-4 play a novel role that might contribute to hepatocarcinogenesis and identify potential candidate biomarkers for HCC diagnosis.