Patricia Latham | The George Washington University (original) (raw)

Papers by Patricia Latham

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative for estrogen ... more Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative for estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2). It is typically associated with high rate of metastasis and limited targeted treatment options. Chemotherapy is the standard treatment for metastatic TNBC. However, the development of chemo-resistance limits its clinical application. Elevated expression of immune-related genes in TNBC suggests that immunotherapy strategies may provide new therapeutic options for TNBC. Programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors have been approved by the FDA for TNBC treatment. However, tumor immune evasion is considered an important obstacle. BRCA1 is a nuclear–cytoplasmic shuttling protein that plays a key role in preventing the development of a malignant phenotype. BRCA1 dysregulation and nuclear export are an important mechanism in cancer development and chemoresistance especially in TNBC. Blocking BRCA1 nuclear export could be used as a strategy to prevent resistance. BRCA1 nuclear export has been reported to be mediated by several proteins such as BRCA1-binding protein 2 (BRAP2) and chromosomal maintenance 1 (CRM1, also known as exportin 1, XPO1). CRM1-mediated events have been implicated in breast cancer and involved in chemoimmunotherapy. microRNA-200b (miR-200b) is a cell-autonomous suppressor of EMT (epithelial–mesenchymal transition) and involved in tumor metastasis. In our present work, we discovered that miR-200b overexpression resulted in significant BRCA1 nuclear retention accompanied by down-regulated expression of CRM1 and STAT1 (signal transducer and activator of transcription 1). Bioinformatics analysis indicated that miR-200b directly targets STAT1, which was confirmed by luciferase assay. We demonstrated that STAT1 is a transcription factor (TF) of CRM1, by both Transfac analysis and chromatin immunoprecipitation (ChIP)-qPCR assay. In patient tissue samples, we found that miR-200b expression was relatively lower in TNBC compared to non-TNBCs. Furthermore, we demonstrated that miR-200b-mediated BRCA1 nuclear retention is associated with significant PD-L1 downregulation, and sensitizes the TNBC cells to chemotherapeutic agents. In addition, high level PD-L1 expression is associated with not only chemoimmunoresistance but also tumor metastasis. These data provide strong evidence that miR-200b-mediated regulation of BRCA1 nucleus retention is through transcriptional regulation of CRM1 by STAT1, and miR-200b regulates PD-L1 expression in TNBC. In conclusion, this novel dual roles of miR-200b may serve as a strategy in metastatic TNBC therapy by repressing STAT1-mediated CRM1 transcription regulation, and reversing the chemoimmunoresistance via PD-L1 inhibition

American journal of cancer research, 2021

Esophageal cancer (EC) is extremely aggressive and has a very poor survival rate. Esophageal squa... more Esophageal cancer (EC) is extremely aggressive and has a very poor survival rate. Esophageal squamous cell carcinoma (ESCC) accounts for 80% of all ECs worldwide, with the majority of the remaining 20% being esophageal adenocarcinoma (EAC). Due to its occult and insidious presentation, ESCC is typically diagnosed and treated in its advanced stages, thereby limiting the success of present therapeutic modalities. microRNAs (miRNAs) can function as tumor suppressors or oncogenes, playing critical roles in cancer initiation and progression by regulating target genes in oncogenic pathways. In the current study, we demonstrated that microRNA-196b (miR-196b) is one of the most upregulated miRNAs in both ESCC and EAC. miR-196b was overexpressed in ESCC and EAC cell lines, cellular exosomal RNAs, and ESCC tissue samples. Functional studies revealed that miR-196b acted as an oncomiR by directly targeting a tumor suppressor, ephrin type-A receptor 7 (EPHA7). EPHA7 abrogates the activity of eph...

Cancer Research, 2018

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative for estrogen ... more Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative for estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2). It is typically associated with high rate of metastasis and limited targeted treatment options. Chemotherapy is the standard treatment for metastatic TNBC. However, the development of chemoresistance limits its clinical application. Elevated expression of immune-related genes in TNBC suggests that immunotherapy strategies may provide new therapeutic options for TNBC. Programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors have been approved by the FDA for TNBC treatment. However, tumor immune evasion is considered an important obstacle. BRCA1 is a nuclear-cytoplasmic shuttling protein that plays a key role in preventing the development of a malignant phenotype. BRCA1 dysregulation and nuclear export are an important mechanism in cancer development and chemoresistan...

Genes & cancer, Feb 1, 2024

Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer worldwide but is o... more Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer worldwide but is often diagnosed at an advanced incurable stage. Yet, despite the urgent need for blood-based biomarkers for early detection, few studies capture ongoing biology to identify risk-stratifying biomarkers. We address this gap using the TGF-β pathway because of its biological role in liver disease and cancer, established through rigorous animal models and human studies. Using machine learning methods with blood levels of 108 proteomic markers in the TGF-β family, we found a pattern that differentiates HCC from non-HCC in a cohort of 216 patients with cirrhosis, which we refer to as TGF-β based Protein Markers for Early Detection of HCC (TPEARLE) comprising 31 markers. Notably, 20 of the patients with cirrhosis alone presented Genes & Cancer www.genesandcancer.com an HCC-like pattern, suggesting that they may be a group with as yet undetected HCC or at high risk for developing HCC. In addition, we found two other biologically relevant markers, Myostatin and Pyruvate Kinase M2 (PKM2), which were significantly associated with HCC. We tested these for risk stratification of HCC in multivariable models adjusted for demographic and clinical variables, as well as batch and site. These markers reflect ongoing biology in the liver. They potentially indicate the presence of HCC early in its evolution and before it is manifest as a detectable lesion, thereby providing a set of markers that may be able to stratify risk for HCC.

Supplemental Table S1. Primer sequences used for 5' and 3' RACE of FGFR3 variant.

Supplemental Table S3. Relative phospho-protein expression with and without dovitinib treatment.

Upregulated or downregulated genes by PJA1 knockdown and TGF-β1 streatment in HepG2 cells

Upregulated or downregulated genes in samples expressing a high level of PJA1

Supplementary Materials and Methods

Gene numbers regulated by PJA1 knockdown and TGF-β1 treatment

bioRxiv (Cold Spring Harbor Laboratory), Feb 2, 2023

Chikungunya virus (CHIKV) is characterized by disabling joint pain that can cause persistent arth... more Chikungunya virus (CHIKV) is characterized by disabling joint pain that can cause persistent arthritis in approximately one-fourth of patients. Currently, no standard treatments are available for chronic CHIKV arthritis. Our preliminary data suggest that decreases in interleukin-2 (IL2) levels and regulatory T cell (Treg) function may play a role in CHIKV arthritis pathogenesis. Low-dose IL2-based therapies for autoimmune diseases have been shown to up-regulate Tregs, and complexing IL2 with anti-IL2 antibodies can prolong the half-life of IL2. A mouse model for post-CHIKV arthritis was used to test the effects of IL-2, an anti-IL2 monoclonal antibody (mAb), and the complex on tarsal joint inflammation, peripheral IL2 levels, Tregs, effector (Teff) T cells, and histological disease scoring. The complex treatment resulted in the highest levels of IL2 and Tregs, but also increased Teffs, and therefore did not significantly reduce inflammation or disease scores. However, the antibody group, which had moderately increased levels of IL2 and activated Tregs, resulted in a decreased average disease score. These results suggest the IL2/anti-IL2 complex stimulates both Tregs and Teffs in post-CHIKV arthritis, while the anti-IL2 mAb increases IL2 availability enough to shift the immune environment towards a tolerogenic one.

Cancer Research, 2021

Background/Aims: The global epidemic of obesity has led to an alarming rise in nonalcoholic steat... more Background/Aims: The global epidemic of obesity has led to an alarming rise in nonalcoholic steatohepatitis (NASH) and hepatocellular cancer (HCC). In addition to abnormal fat accumulation and liver injury, fibrosis is a key predictive factor for progression and transformation. Yet, our understanding of how a major fibrosis pathway, transforming growth factor β (TGF-β), and how members, SMAD3 with its adaptor SPTBN 1 -contribute to the progression of NASH-driven HCC remains unclear. Here, we sought to better understand the role of TGF-β1/SMAD3/SPTBN1 in regulating the switch between NASH and HCC. Methods: We generated liver-specific SPTBN1 knockout mice (Albumin Cre+Sptbn1loxp/loxp, LKO). LKO and controls were given a high-fat diet (HFD) or DEN; Phenotypic analyses and mechanistic insight were obtained through RNA-seq, mass spectrometry, structure modeling, cell fractionation, and imaging-immunofluorescence, immunohistochemistry, and interactions studies were performed in human HCC ...

Cancer Research, 2021

Background: Hepatocellular carcinoma (HCC) is the fastest rising cancer in the USA and is the fou... more Background: Hepatocellular carcinoma (HCC) is the fastest rising cancer in the USA and is the fourth leading cause of cancer deaths globally. A critical unmet need to reduce high mortality associated with advanced HCC is the ability to identify high-risk individuals for cost-effective, targeted screening, early detection, and prevention strategies. Human genomics and animal models have revealed etiological patterns and multiple genes and signaling pathways such as TGF-β, WNT, VEGF to be associated with the initiation and progression of HCC. We used integrated functional approaches (combining bioinformatics analysis, in vivo mouse models, and in vitro biological and biochemical methods) and identified potential biomarkers for HCC. We examined and validated 10 functional biomarkers for HCC risk prediction. We further harnessed machine learning tools and Artificial Intelligence (AI)-based technology to validate manual analyses of Immunohistochemical (IHC) labeled slides across differen...

The FASEB Journal, 2015

13 consenting first-year medical students at a large, urban medical school completed a 7-question... more 13 consenting first-year medical students at a large, urban medical school completed a 7-question, modified Likert scale evaluation prepared by the anatomy and pathology departments to assess the impact of this new teaching tool in the curriculum. • Students were asked for feedback about the MAA as a whole and, in particular, the cardiovascular histology and pathology images. Methods

Esophageal cancer is the sixth most common cause of cancer related death. Although multiple genet... more Esophageal cancer is the sixth most common cause of cancer related death. Although multiple genetic and epigenetic alterations have been detected in esophageal cancer, molecular markers for early diagnosis and prediction of prognosis or treatment responses are quite limited. microRNA (miRNA) is a class of small-regulatory non-coding RNA, acting as either a tumor suppressor or oncogene by regulating gene expression through pairing with complementary seed of the targeted messenger RNAs (mRNA). A number of miRNA expression profiling studies have been conducted in esophageal cancer. By cross-referencing esophageal cancer data with miRNA expression profiling, we identify a group of dysregulated miRNAs in esophageal cancer, including upregulated miR-196b and miR-135a, and downregulated miR-141, miR-200a-5p, miR-200b-3p, miR-27b, miR-210. We first assessed the expression of miRNAs in esophageal cancer cell lines and primary esophageal cancer tissues by real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). Significantly overexpression of miR-196b was observed in human esophageal cell lines KYSE-70 and KYSE-180 compared with normal esophageal squamous cell line HET-1A. Furthermore, the overexpressed miR-196b was detected in 12 out of 14 (86%) cancer tissues compared with matched normal tissues. TargetScan and miRanda bioinformatics tools were used to identify target genes of miR-196b. A list of targets was obtained, including ephrin type-A receptor 7 (EPHA7), one of members of the ephrin receptor (EPH) subfamily of the protein-tyrosine kinase family. We found a significant inverse correlation between miR-196b and EPHA7 expression in both cell lines and tissues. Luciferase assays revealed that miR-196b directly targets the 3\u27-UTR of EPHA7 gene. Forced expression of miR-196b resulted in significant downregulation of EPHA7 and promoted the proliferation and invasion in KYSE-70 and KYSE-180 cells. It has been reported that low EphA7 expression correlated with lymph node metastasis and poor prognosis for esophageal cancer. These indicate that EPHA7 may function as a tumor suppressor with immediate therapeutic potential. Our data suggest that miR-196b acts as an oncomiR by downregulating EPHA7 in esophageal cancer. Inhibition of miR-196b may improve anti-tumor efficiency by restoring the expression of EPHA7. Therefore, miR-196b might serves as a therapeutic target for esophageal cancer

Hypertension, 2019

Dopamine receptor D2 (D2R) plays a significant role in kidney function by maintaining normal bloo... more Dopamine receptor D2 (D2R) plays a significant role in kidney function by maintaining normal blood pressure (BP) and preventing renal inflammation and injury. D2R silencing in the mouse kidney increases BP and increases renal injury. To study the effects of D2R in the renal proximal tubule we generated Drd2 fl/fl , P SGLT2 ::Cre+ mice (D2R PT-/- ) that lack D2R only in the renal proximal tubule and Drd2 fl/fl , P SGLT2 ::Cre- mice (D2R PT+/+ ) that do not have the deletion. We studied male and female mice on normal salt (NS; 0.4% NaCl) and high salt (HS; 4% NaCl) diets. Mice were genotyped for Drd2 fl/fl and a smaller amplicon representing the Cre deletion mutant. On NS diet, male D2R PT-/- had higher systolic BP (SBP) measured under anesthesia than male D2R PT+/+ (113±1 vs 102±3 mmHg, n=5/group; P<0.05) and female D2R PT-/- (104±5 mmHg) or female D2R PT+/+ (106±3 mmHg). SBPs on HS diet were similar in D2R PT-/- females and males. On NS diet renal mRNA expressions of TNF-α, TGFβ1...

Molecular and Cellular Biology / Genetics, 2019

Esophageal cancer (EC), including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (E... more Esophageal cancer (EC), including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), is one of the deadliest cancers with extremely aggressive nature and poor survival rate. Diagnostic methods for EC mainly include endoscopy, barium swallow and ultrasound, which are either invasive or lack of sensitivity and specificity at early stages. Therefore, the development of a non-invasive and reliable diagnostic method with high sensitivity and specificity is crucial in improving early detection, diagnosis and treatment. microRNAs (miRNAs) are small RNA molecules that regulate the expression of protein-coding genes by directly binding to target mRNAs in a sequence-specific manner. The aim of this study is to identify novel miRNA biomarkers for EC diagnosis. By cross-referencing our data with others’ from NCBI, we identified a list of dysregulated miRNAs in EC, including miR-375. We assessed the expression of miR-375 in EC cell lines and tissues using real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). We found that miR-375 expression is significantly decreased in human EC cell lines (KEYS-70, KEYS-180, FLO-1 and JHU-ad1) compared to the normal esophageal squamous cell line, Het-1A. Using microdissection technique, we isolated normal epithelium, dysplasia, and invasive EC components from formalin-fixed, paraffin-embedded (FFPE) tissue followed by qRT-PCR analysis. Decreased expression of miR-375 was detected in 12 of 14 EC tissue samples (86%) compared to the matched normal tissues. MTT and Matrigel invasion assay demonstrated that forced expression of miR-375 suppressed the proliferation and invasion in EC cell lines. TargetScanS and miRanda were used to identify potential target genes of miR-375, which includes epidermal growth factor receptor 2 (HER2) and YES-associated protein (YAP1), both of them act as oncogenes in EC development. Interestingly, forced expression of miR-375 resulted in significantly reduced expression of human vascular endothelial growth factor-A (VEGF-A) gene, which is a downstream target gene of YAP1/ERBB2 pathway involving in tumor angiogenesis in EC cell lines. More functional analysis is under way. These findings suggest that miR-375 may act as a tumor suppressor, and could serve as a marker for EC diagnosis and management. Citation Format: Shuchang Ren, Xiaohui Tan, Xiaoling Wu, Tao Chen, Patricia Latham, Sidney W. Fu. miR-375 downregulates VEGFA via YAP1-EBRR2 pathway in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 783.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative for estrogen ... more Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative for estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2). It is typically associated with high rate of metastasis and limited targeted treatment options. Chemotherapy is the standard treatment for metastatic TNBC. However, the development of chemo-resistance limits its clinical application. Elevated expression of immune-related genes in TNBC suggests that immunotherapy strategies may provide new therapeutic options for TNBC. Programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors have been approved by the FDA for TNBC treatment. However, tumor immune evasion is considered an important obstacle. BRCA1 is a nuclear–cytoplasmic shuttling protein that plays a key role in preventing the development of a malignant phenotype. BRCA1 dysregulation and nuclear export are an important mechanism in cancer development and chemoresistance especially in TNBC. Blocking BRCA1 nuclear export could be used as a strategy to prevent resistance. BRCA1 nuclear export has been reported to be mediated by several proteins such as BRCA1-binding protein 2 (BRAP2) and chromosomal maintenance 1 (CRM1, also known as exportin 1, XPO1). CRM1-mediated events have been implicated in breast cancer and involved in chemoimmunotherapy. microRNA-200b (miR-200b) is a cell-autonomous suppressor of EMT (epithelial–mesenchymal transition) and involved in tumor metastasis. In our present work, we discovered that miR-200b overexpression resulted in significant BRCA1 nuclear retention accompanied by down-regulated expression of CRM1 and STAT1 (signal transducer and activator of transcription 1). Bioinformatics analysis indicated that miR-200b directly targets STAT1, which was confirmed by luciferase assay. We demonstrated that STAT1 is a transcription factor (TF) of CRM1, by both Transfac analysis and chromatin immunoprecipitation (ChIP)-qPCR assay. In patient tissue samples, we found that miR-200b expression was relatively lower in TNBC compared to non-TNBCs. Furthermore, we demonstrated that miR-200b-mediated BRCA1 nuclear retention is associated with significant PD-L1 downregulation, and sensitizes the TNBC cells to chemotherapeutic agents. In addition, high level PD-L1 expression is associated with not only chemoimmunoresistance but also tumor metastasis. These data provide strong evidence that miR-200b-mediated regulation of BRCA1 nucleus retention is through transcriptional regulation of CRM1 by STAT1, and miR-200b regulates PD-L1 expression in TNBC. In conclusion, this novel dual roles of miR-200b may serve as a strategy in metastatic TNBC therapy by repressing STAT1-mediated CRM1 transcription regulation, and reversing the chemoimmunoresistance via PD-L1 inhibition

American journal of cancer research, 2021

Esophageal cancer (EC) is extremely aggressive and has a very poor survival rate. Esophageal squa... more Esophageal cancer (EC) is extremely aggressive and has a very poor survival rate. Esophageal squamous cell carcinoma (ESCC) accounts for 80% of all ECs worldwide, with the majority of the remaining 20% being esophageal adenocarcinoma (EAC). Due to its occult and insidious presentation, ESCC is typically diagnosed and treated in its advanced stages, thereby limiting the success of present therapeutic modalities. microRNAs (miRNAs) can function as tumor suppressors or oncogenes, playing critical roles in cancer initiation and progression by regulating target genes in oncogenic pathways. In the current study, we demonstrated that microRNA-196b (miR-196b) is one of the most upregulated miRNAs in both ESCC and EAC. miR-196b was overexpressed in ESCC and EAC cell lines, cellular exosomal RNAs, and ESCC tissue samples. Functional studies revealed that miR-196b acted as an oncomiR by directly targeting a tumor suppressor, ephrin type-A receptor 7 (EPHA7). EPHA7 abrogates the activity of eph...

Cancer Research, 2018

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative for estrogen ... more Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative for estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2). It is typically associated with high rate of metastasis and limited targeted treatment options. Chemotherapy is the standard treatment for metastatic TNBC. However, the development of chemoresistance limits its clinical application. Elevated expression of immune-related genes in TNBC suggests that immunotherapy strategies may provide new therapeutic options for TNBC. Programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors have been approved by the FDA for TNBC treatment. However, tumor immune evasion is considered an important obstacle. BRCA1 is a nuclear-cytoplasmic shuttling protein that plays a key role in preventing the development of a malignant phenotype. BRCA1 dysregulation and nuclear export are an important mechanism in cancer development and chemoresistan...

Genes & cancer, Feb 1, 2024

Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer worldwide but is o... more Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer worldwide but is often diagnosed at an advanced incurable stage. Yet, despite the urgent need for blood-based biomarkers for early detection, few studies capture ongoing biology to identify risk-stratifying biomarkers. We address this gap using the TGF-β pathway because of its biological role in liver disease and cancer, established through rigorous animal models and human studies. Using machine learning methods with blood levels of 108 proteomic markers in the TGF-β family, we found a pattern that differentiates HCC from non-HCC in a cohort of 216 patients with cirrhosis, which we refer to as TGF-β based Protein Markers for Early Detection of HCC (TPEARLE) comprising 31 markers. Notably, 20 of the patients with cirrhosis alone presented Genes & Cancer www.genesandcancer.com an HCC-like pattern, suggesting that they may be a group with as yet undetected HCC or at high risk for developing HCC. In addition, we found two other biologically relevant markers, Myostatin and Pyruvate Kinase M2 (PKM2), which were significantly associated with HCC. We tested these for risk stratification of HCC in multivariable models adjusted for demographic and clinical variables, as well as batch and site. These markers reflect ongoing biology in the liver. They potentially indicate the presence of HCC early in its evolution and before it is manifest as a detectable lesion, thereby providing a set of markers that may be able to stratify risk for HCC.

Supplemental Table S1. Primer sequences used for 5' and 3' RACE of FGFR3 variant.

Supplemental Table S3. Relative phospho-protein expression with and without dovitinib treatment.

Upregulated or downregulated genes by PJA1 knockdown and TGF-β1 streatment in HepG2 cells

Upregulated or downregulated genes in samples expressing a high level of PJA1

Supplementary Materials and Methods

Gene numbers regulated by PJA1 knockdown and TGF-β1 treatment

bioRxiv (Cold Spring Harbor Laboratory), Feb 2, 2023

Chikungunya virus (CHIKV) is characterized by disabling joint pain that can cause persistent arth... more Chikungunya virus (CHIKV) is characterized by disabling joint pain that can cause persistent arthritis in approximately one-fourth of patients. Currently, no standard treatments are available for chronic CHIKV arthritis. Our preliminary data suggest that decreases in interleukin-2 (IL2) levels and regulatory T cell (Treg) function may play a role in CHIKV arthritis pathogenesis. Low-dose IL2-based therapies for autoimmune diseases have been shown to up-regulate Tregs, and complexing IL2 with anti-IL2 antibodies can prolong the half-life of IL2. A mouse model for post-CHIKV arthritis was used to test the effects of IL-2, an anti-IL2 monoclonal antibody (mAb), and the complex on tarsal joint inflammation, peripheral IL2 levels, Tregs, effector (Teff) T cells, and histological disease scoring. The complex treatment resulted in the highest levels of IL2 and Tregs, but also increased Teffs, and therefore did not significantly reduce inflammation or disease scores. However, the antibody group, which had moderately increased levels of IL2 and activated Tregs, resulted in a decreased average disease score. These results suggest the IL2/anti-IL2 complex stimulates both Tregs and Teffs in post-CHIKV arthritis, while the anti-IL2 mAb increases IL2 availability enough to shift the immune environment towards a tolerogenic one.

Cancer Research, 2021

Background/Aims: The global epidemic of obesity has led to an alarming rise in nonalcoholic steat... more Background/Aims: The global epidemic of obesity has led to an alarming rise in nonalcoholic steatohepatitis (NASH) and hepatocellular cancer (HCC). In addition to abnormal fat accumulation and liver injury, fibrosis is a key predictive factor for progression and transformation. Yet, our understanding of how a major fibrosis pathway, transforming growth factor β (TGF-β), and how members, SMAD3 with its adaptor SPTBN 1 -contribute to the progression of NASH-driven HCC remains unclear. Here, we sought to better understand the role of TGF-β1/SMAD3/SPTBN1 in regulating the switch between NASH and HCC. Methods: We generated liver-specific SPTBN1 knockout mice (Albumin Cre+Sptbn1loxp/loxp, LKO). LKO and controls were given a high-fat diet (HFD) or DEN; Phenotypic analyses and mechanistic insight were obtained through RNA-seq, mass spectrometry, structure modeling, cell fractionation, and imaging-immunofluorescence, immunohistochemistry, and interactions studies were performed in human HCC ...

Cancer Research, 2021

Background: Hepatocellular carcinoma (HCC) is the fastest rising cancer in the USA and is the fou... more Background: Hepatocellular carcinoma (HCC) is the fastest rising cancer in the USA and is the fourth leading cause of cancer deaths globally. A critical unmet need to reduce high mortality associated with advanced HCC is the ability to identify high-risk individuals for cost-effective, targeted screening, early detection, and prevention strategies. Human genomics and animal models have revealed etiological patterns and multiple genes and signaling pathways such as TGF-β, WNT, VEGF to be associated with the initiation and progression of HCC. We used integrated functional approaches (combining bioinformatics analysis, in vivo mouse models, and in vitro biological and biochemical methods) and identified potential biomarkers for HCC. We examined and validated 10 functional biomarkers for HCC risk prediction. We further harnessed machine learning tools and Artificial Intelligence (AI)-based technology to validate manual analyses of Immunohistochemical (IHC) labeled slides across differen...

The FASEB Journal, 2015

13 consenting first-year medical students at a large, urban medical school completed a 7-question... more 13 consenting first-year medical students at a large, urban medical school completed a 7-question, modified Likert scale evaluation prepared by the anatomy and pathology departments to assess the impact of this new teaching tool in the curriculum. • Students were asked for feedback about the MAA as a whole and, in particular, the cardiovascular histology and pathology images. Methods

Esophageal cancer is the sixth most common cause of cancer related death. Although multiple genet... more Esophageal cancer is the sixth most common cause of cancer related death. Although multiple genetic and epigenetic alterations have been detected in esophageal cancer, molecular markers for early diagnosis and prediction of prognosis or treatment responses are quite limited. microRNA (miRNA) is a class of small-regulatory non-coding RNA, acting as either a tumor suppressor or oncogene by regulating gene expression through pairing with complementary seed of the targeted messenger RNAs (mRNA). A number of miRNA expression profiling studies have been conducted in esophageal cancer. By cross-referencing esophageal cancer data with miRNA expression profiling, we identify a group of dysregulated miRNAs in esophageal cancer, including upregulated miR-196b and miR-135a, and downregulated miR-141, miR-200a-5p, miR-200b-3p, miR-27b, miR-210. We first assessed the expression of miRNAs in esophageal cancer cell lines and primary esophageal cancer tissues by real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). Significantly overexpression of miR-196b was observed in human esophageal cell lines KYSE-70 and KYSE-180 compared with normal esophageal squamous cell line HET-1A. Furthermore, the overexpressed miR-196b was detected in 12 out of 14 (86%) cancer tissues compared with matched normal tissues. TargetScan and miRanda bioinformatics tools were used to identify target genes of miR-196b. A list of targets was obtained, including ephrin type-A receptor 7 (EPHA7), one of members of the ephrin receptor (EPH) subfamily of the protein-tyrosine kinase family. We found a significant inverse correlation between miR-196b and EPHA7 expression in both cell lines and tissues. Luciferase assays revealed that miR-196b directly targets the 3\u27-UTR of EPHA7 gene. Forced expression of miR-196b resulted in significant downregulation of EPHA7 and promoted the proliferation and invasion in KYSE-70 and KYSE-180 cells. It has been reported that low EphA7 expression correlated with lymph node metastasis and poor prognosis for esophageal cancer. These indicate that EPHA7 may function as a tumor suppressor with immediate therapeutic potential. Our data suggest that miR-196b acts as an oncomiR by downregulating EPHA7 in esophageal cancer. Inhibition of miR-196b may improve anti-tumor efficiency by restoring the expression of EPHA7. Therefore, miR-196b might serves as a therapeutic target for esophageal cancer

Hypertension, 2019

Dopamine receptor D2 (D2R) plays a significant role in kidney function by maintaining normal bloo... more Dopamine receptor D2 (D2R) plays a significant role in kidney function by maintaining normal blood pressure (BP) and preventing renal inflammation and injury. D2R silencing in the mouse kidney increases BP and increases renal injury. To study the effects of D2R in the renal proximal tubule we generated Drd2 fl/fl , P SGLT2 ::Cre+ mice (D2R PT-/- ) that lack D2R only in the renal proximal tubule and Drd2 fl/fl , P SGLT2 ::Cre- mice (D2R PT+/+ ) that do not have the deletion. We studied male and female mice on normal salt (NS; 0.4% NaCl) and high salt (HS; 4% NaCl) diets. Mice were genotyped for Drd2 fl/fl and a smaller amplicon representing the Cre deletion mutant. On NS diet, male D2R PT-/- had higher systolic BP (SBP) measured under anesthesia than male D2R PT+/+ (113±1 vs 102±3 mmHg, n=5/group; P<0.05) and female D2R PT-/- (104±5 mmHg) or female D2R PT+/+ (106±3 mmHg). SBPs on HS diet were similar in D2R PT-/- females and males. On NS diet renal mRNA expressions of TNF-α, TGFβ1...

Molecular and Cellular Biology / Genetics, 2019

Esophageal cancer (EC), including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (E... more Esophageal cancer (EC), including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), is one of the deadliest cancers with extremely aggressive nature and poor survival rate. Diagnostic methods for EC mainly include endoscopy, barium swallow and ultrasound, which are either invasive or lack of sensitivity and specificity at early stages. Therefore, the development of a non-invasive and reliable diagnostic method with high sensitivity and specificity is crucial in improving early detection, diagnosis and treatment. microRNAs (miRNAs) are small RNA molecules that regulate the expression of protein-coding genes by directly binding to target mRNAs in a sequence-specific manner. The aim of this study is to identify novel miRNA biomarkers for EC diagnosis. By cross-referencing our data with others’ from NCBI, we identified a list of dysregulated miRNAs in EC, including miR-375. We assessed the expression of miR-375 in EC cell lines and tissues using real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). We found that miR-375 expression is significantly decreased in human EC cell lines (KEYS-70, KEYS-180, FLO-1 and JHU-ad1) compared to the normal esophageal squamous cell line, Het-1A. Using microdissection technique, we isolated normal epithelium, dysplasia, and invasive EC components from formalin-fixed, paraffin-embedded (FFPE) tissue followed by qRT-PCR analysis. Decreased expression of miR-375 was detected in 12 of 14 EC tissue samples (86%) compared to the matched normal tissues. MTT and Matrigel invasion assay demonstrated that forced expression of miR-375 suppressed the proliferation and invasion in EC cell lines. TargetScanS and miRanda were used to identify potential target genes of miR-375, which includes epidermal growth factor receptor 2 (HER2) and YES-associated protein (YAP1), both of them act as oncogenes in EC development. Interestingly, forced expression of miR-375 resulted in significantly reduced expression of human vascular endothelial growth factor-A (VEGF-A) gene, which is a downstream target gene of YAP1/ERBB2 pathway involving in tumor angiogenesis in EC cell lines. More functional analysis is under way. These findings suggest that miR-375 may act as a tumor suppressor, and could serve as a marker for EC diagnosis and management. Citation Format: Shuchang Ren, Xiaohui Tan, Xiaoling Wu, Tao Chen, Patricia Latham, Sidney W. Fu. miR-375 downregulates VEGFA via YAP1-EBRR2 pathway in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 783.