Ficolin-3 induces apoptosis and suppresses malignant property of hepatocellular carcinoma cells via the complement pathway.

AIMS: Ficolin 3 (FCN3) has the highest complement-activating capacity through the lectin pathway and is synthesized mainly in the liver and lung. Yet, its potential molecular mechanism in hepatocarcinogenesis is not fully understood. MATERIALS AND METHODS: The expression of FCN3 in hepatocellular carcinoma (HCC) tumor and non-tumor tissues was analyzed by RT-qPCR, Western blotting and immunofluorescence staining assays. Lentivector-mediated ectopic overexpression was performed to explore the role of FCN3 in vitro and in vivo. Whether FCN3 inhibited HCC cell growth and survival via complement pathway was determined with immunocytochemical staining for C3b, membrane attack complex (MAC) formation and complement killing assay using recombinant FCN3 (rFCN3) in combination with human serum with or without heat inactivation, and with C6 blocking antibody. KEY FINDINGS: The transcript and protein of FCN3 were found to be remarkably down-regulated in HCC tumor tissues. FCN3 expression was found to be associated with better survival of HCC patients. Restoration of FCN3 expression significantly inhibited proliferation, migration and anchorage independent growth of HCC cell lines, and xenograft tumor growth. FCN3 expression induced apoptosis of HCC cells. C3 and MAC formation was stimulated by FCN3 overexpression or rFCN3 treatment. rFCN3 enhanced human serum-induced complement activation and cell death. C6 blocking antibody significantly attenuated complement-mediated cell death and restored the growth of FCN3-overexpressing HCC cells. SIGNIFICANCE: FCN3 has a malignant suppressor role in HCC cells. Our study provides new insights into the molecular mechanisms that drive HCC progression and potential therapeutic targets for treating HCC.

Integrative multi-omics characterization of hepatocellular carcinoma in hispanic patients.

BACKGROUND: The incidence and mortality rates of hepatocellular carcinoma (HCC) among Hispanic individuals in the United States are much higher than in non-Hispanic white people. We conducted multi-omics analyses to elucidate molecular alterations in HCC among Hispanic patients. METHODS: Paired tumor and adjacent non-tumor samples were collected from 31 Hispanic HCCs in South Texas (STX-Hispanic) for genomic, transcriptomic, proteomic, and metabolomic profiling. Serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed HCC. RESULTS: Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in STX Hispanic HCCs, suggesting a predominant activation of the Wnt/ß-catenin pathway. TERT promoter mutations were also significantly more frequent in the Hispanic cohort (Fisher's exact test, p < .05). Cell cycles and liver function were positively and negatively enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in serum samples of HCC patients (paired t-test, p < .0001). Two HCC subtypes from our Hispanic cohort were identified and validated with the TCGA liver cancer cohort. Patients with better overall survival showed higher activity of immune and angiogenesis signatures, and lower activity of liver function-related gene signatures. They also had higher levels of immune checkpoint and immune exhaustion markers. CONCLUSIONS: Our study revealed specific molecular features of Hispanic HCC and potential biomarkers for therapeutic management. It provides a unique resource for studying Hispanic HCC.

Integrative multi-omics characterization of hepatocellular carcinoma in Hispanic patients.

Background: The incidence and mortality rates of hepatocellular carcinoma (HCC) among Hispanics in the United States are much higher than those of non-Hispanic whites. We conducted comprehensive multi-omics analyses to understand molecular alterations in HCC among Hispanic patients. Methods: Paired tumor and adjacent non-tumor samples were collected from 31 Hispanic HCC in South Texas (STX-Hispanic) for genomic, transcriptomic, proteomic, and metabolomic profiling. Additionally, serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed HCC. Results: Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in STX Hispanic HCCs, suggesting a predominant activation of the Wnt/ß-catenin pathway. The TERT promoter mutation frequency was also remarkably high in the Hispanic cohort. Cell cycles and liver functions were identified as positively- and negatively-enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in the serum samples of HCC patients. Two HCC subtypes from our Hispanic cohort were identified and validated with the TCGA liver cancer cohort. The subtype with better overall survival showed higher activity of immune and angiogenesis signatures, and lower activity of liver function-related gene signatures. It also had higher levels of immune checkpoint and immune exhaustion markers. Conclusions: Our study revealed some specific molecular features of Hispanic HCC and potential biomarkers for therapeutic management of HCC and provides a unique resource for studying Hispanic HCC.

Identifying and Addressing Barriers to Screening Mammography in a Medically Underserved Community.

RATIONALE AND OBJECTIVES: Breast cancer mortality is 40% higher for Black women compared to White women. This study seeks to assess knowledge of breast cancer screening recommendations and identify barriers to risk assessment and mammographic screening among a medically underserved, low-income, predominantly Black community in West Philadelphia. MATERIALS AND METHODS: During a free mobile mammography screening event, women were offered surveys to assess perceptions of and barriers to breast cancer risk assessment and screening. Among those who subsequently underwent mobile screening, health insurance and time to additional diagnostic imaging and biopsy, when relevant, were retrospectively collected. RESULTS: 233 women completed surveys (mean age 54 ± 13 years). Ninety-three percent of respondents identified as Black. The most frequently cited barrier to screening mammography was cost and/or lack of insurance coverage (30%). Women under 50 reported more barriers to screening compared to older women. Among those recalled from screening and recommended to undergo biopsy, there was a trend toward longer delays between screening and biopsy among those without a PCP (median 45 days, IQR 25-53) compared to those with a PCP (median 24 days, IQR 16-29) (p = 0.072). CONCLUSION: In a study of a medically underserved community of primarily Black patients, barriers to breast cancer risk assessment, screening, and diagnosis were identified by self-report and by documented care delays. While free mobile mammography initiatives that bring medical professionals into communities can help mitigate barriers to screening, strategies for navigation and coordination of follow-up are critical to promote timely diagnostic resolution for all patients.

Together We Go Farther: Improving Access to Cancer Screening Through a Multidisciplinary, One-Stop-Shop Approach.

RATIONALE AND OBJECTIVES: Despite significant scientific advances in cancer treatment in recent decades, Black Americans still face marked inequities in cancer screening, diagnosis, and treatment. Redressing these persistent inequities will require innovative strategies for community engagement. Radiologists, as experts in cancer screening and diagnosis for multiple malignancies, including breast, lung, and colon, are ideally suited to lead and implement community-based strategies to address local cancer disparities. MATERIALS AND METHODS: Through an established academic-community partnership in West Philadelphia built over the course of multiple prior community healthcare events, the authors piloted a novel radiology-led multidisciplinary approach to improve access to cancer screening for the predominantly Black, medically-underserved residents. Using a "one-stop-shop" framework to provide a comprehensive suite of screening and ancillary services in the heart of the community, the authors sought to remove as many impediments to screening as possible. RESULTS: Approximately 350 participants attended the health fair, and a total of 232 screening tests or assessments were completed. Data from this event suggest that this inclusive approach, as well as the use of a health fair "passport" to incentivize engagement, can successfully improve access to screening and follow-up in an underserved community. CONCLUSION: This "one-stop-shop" community approach can be replicated by radiology-led teams in other settings as a high-value, scalable opportunity to reduce disparities in access to cancer screening.