Publications by authors named "Shantibhusan Senapati"

35 Publications

Molecular detection of infection in cattle by conventional PCR and quantitative real time PCR in India.

J Parasit Dis 2021 Mar 25;45(1):72-77. Epub 2020 Sep 25.

Institute of Life Sciences, Bhubaneswar, Odisha India.

() is a tick-borne apicomplexan parasite that affects bovine. It is endemic in many tropical and subtropics areas, including Odisha, India. The objective of this study is to identify infection in the peripheral blood of cattle as a biological sample by conventional PCR (cPCR) and quantitative PCR (qPCR). The phylogenetic analysis was done using the merozoite surface antigen () gene. Out of 552 samples of examined blood smears by microscopy, 454 (82.24%) animals were positive for species. Out of 454 samples, 96 samples were further examined by both cPCR and qPCR, 52 samples (54.16%) were found positive for in both PCR methodologies. Phylogenetic analysis revealed that Odisha isolate was closely related to Uttarakhand, India isolate (KM061799) and Hyderabad, India isolate (MK034702) with Nucleotide sequence identity 95.36%, 95.25%, respectively. This is the first study to detect by qPCR in Odisha and supported that both PCR techniques were equally effective for the detection of gene of in cattle's blood.
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http://dx.doi.org/10.1007/s12639-020-01278-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921255PMC
March 2021

The Hha-TomB toxin-antitoxin module in Salmonella enterica serovar Typhimurium limits its intracellular survival profile and regulates host immune response.

Cell Biol Toxicol 2021 Mar 2. Epub 2021 Mar 2.

School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, India.

The key to bacterial virulence relies on an exquisite balance of signals between microbe and hosts. Bacterial toxin-antitoxin (TA) system is known to play a vital role in response to stress adaptation, drug resistance, biofilm formation, intracellular survival, persistence as well as pathogenesis. In the present study, we investigated the role of Hha-TomB TA system in regulating virulence of Salmonella enterica serovar Typhimurium (S. Typhimurium) in a host model system, where we showed that deletion of hha and tomB genes displayed impaired cell adhesion, invasion, and uptake. The isogenic hha and tomB mutant strain was also found to be deficient in intracellular replication in vitro, with a highly repressed Salmonella Pathogenicity Island-2 (SPI-2) genes and downregulation of Salmonella Pathogenicity Island-1 (SPI-1) genes. In addition, the Δhha and ΔtomB did not show acute colitis in C57BL/6 mice and displayed less dissemination to systemic organs followed by their cecal pathology. The TA mutants also showed reduction in serum cytokine and nitric oxide levels both in vitro and in vivo. However, the inflammation phenotype was restored on complementing strain of TA gene to its mutant strain. In silico studies depicted firm interaction of Hha-TomB complex and the regulatory proteins, namely, SsrA, SsrB, PhoP, and PhoQ. Overall, we demonstrate that this study of Hha-TomB TA system is one of the prime regulating networks essential for S. Typhimurium pathogenesis. 1. Role of Hha-TomB toxin-antitoxin (TA) system in Salmonella pathogenesis was examined. 2. The TA mutants resulted in impaired invasion and intracellular replication in vitro. 3. The TA mutants displayed alteration in SPI-1 and SPI-2 regulatory genes inside host cells. 4. Mutation in TA genes also limited systemic colonization and inflammatory response in vivo.
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http://dx.doi.org/10.1007/s10565-021-09587-zDOI Listing
March 2021

Tissue Distribution of ACE2 Protein in Syrian Golden Hamster () and Its Possible Implications in SARS-CoV-2 Related Studies.

Front Pharmacol 2020 14;11:579330. Epub 2021 Jan 14.

Tumor Microenvironment and Animal Models Lab, Institute of Life Sciences, Bhubaneswar, India.

The Syrian golden hamster () has recently been demonstrated as a clinically relevant animal model for SARS-CoV-2 infection. However, lack of knowledge about the tissue-specific expression pattern of various proteins in these animals and the unavailability of reagents like antibodies against this species hampers these models' optimal use. The major objective of our current study was to analyze the tissue-specific expression pattern of angiotensin-converting enzyme 2, a proven functional receptor for SARS-CoV-2 in different organs of the hamster. Using two different antibodies (MA5-32307 and AF933), we have conducted immunoblotting, immunohistochemistry, and immunofluorescence analysis to evaluate the ACE2 expression in different tissues of the hamster. Further, at the mRNA level, the expression of in tissues was evaluated through RT-qPCR analysis. Both the antibodies detected expression of ACE2 in kidney, small intestine, tongue, and liver. Epithelium of proximal tubules of kidney and surface epithelium of ileum expresses a very high amount of this protein. Surprisingly, analysis of stained tissue sections showed no detectable expression of ACE2 in the lung or tracheal epithelial cells. Similarly, all parts of the large intestine were negative for ACE2 expression. Analysis of tissues from different age groups and sex didn't show any obvious difference in ACE2 expression pattern or level. Together, our findings corroborate some of the earlier reports related to ACE2 expression patterns in human tissues and contradict others. We believe that this study's findings have provided evidence that demands further investigation to understand the predominant respiratory pathology of SARS-CoV-2 infection and disease.
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http://dx.doi.org/10.3389/fphar.2020.579330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869018PMC
January 2021

Overlapping targets exist between the Par-4 and miR-200c axis which regulate EMT and proliferation of pancreatic cancer cells.

Transl Oncol 2021 Jan 10;14(1):100879. Epub 2020 Oct 10.

Academy of Scientific & Innovative Research (AcSIR), New Delhi, India; Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, Jammu and Kashmir 180001, India. Electronic address:

The last decade has witnessed a substantial expansion in the field of microRNA (miRNA) biology, providing crucial insights into the role of miRNAs in disease pathology, predominantly in cancer progression and its metastatic spread. The discovery of tumor-suppressing miRNAs represents a potential approach for developing novel therapeutics. In this context, through miRNA microarray analysis, we examined the consequences of Prostate apoptosis response-4 (Par-4), a well-established tumor-suppressor, stimulation on expression of different miRNAs in Panc-1 cells. The results strikingly indicated elevated miR-200c levels in these cells upon Par-4 overexpression. Intriguingly, the Reverse Phase Protein Array (RPPA) analysis revealed differentially expressed proteins (DEPs), which overlap between miR200c- and Par-4-transfected cells, highlighting the cross-talks between these pathways. Notably, Phospho-p44/42 MAPK; Bim; Bcl-xL; Rb Phospho-Ser807, Ser811; Akt Phospho-Ser473; Smad1/5 Phospho-Ser463/Ser465 and Zyxin scored the most significant DEPs among the two data sets. Furthermore, the GFP-Par-4-transfected cells depicted an impeded expression of critical mesenchymal markers viz. TGF-β1, TGF-β2, ZEB-1, and Twist-1, concomitant with augmented miR-200c and E-cadherin levels. Strikingly, while Par-4 overexpression halted ZEB-1 at the transcriptional level; contrarily, silencing of endogenous Par-4 by siRNA robustly augmented the Epithelial-mesenchymal transition (EMT) markers, along with declining miR-200c levels. The pharmacological Par-4-inducer, NGD16, triggered Par-4 expression which corresponded with increased miR-200c resulting in the ZEB-1 downregulation. Noteworthily, tumor samples obtained from the syngenic mouse pancreatic cancer model revealed elevated miR-200c levels in the NGD16-treated mice that positively correlated with the Par-4 and E-cadherin levels in vivo; while a negative correlation was evident with ZEB-1 and Vimentin.
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http://dx.doi.org/10.1016/j.tranon.2020.100879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557890PMC
January 2021

Escherichia coli, a common constituent of benign prostate hyperplasia-associated microbiota induces inflammation and DNA damage in prostate epithelial cells.

Prostate 2020 11 24;80(15):1341-1352. Epub 2020 Aug 24.

Division of Cancer Biology, Tumor Microenvironment and Animal Models Lab, Institute of Life Sciences, Bhubaneswar, Odisha, India.

Background: The role of microbiota in the pathophysiology of benign prostate hyperplasia (BPH), especially in creating an inflammatory milieu may not be avoided. The major objectives of this study were to investigate the microbial composition of BPH tissues, its association with inflammation and check the effect of clinically isolated bacteria on prostate epithelial cells.

Methods: The study includes 36 patients with a pathological diagnosis of BPH. Following strict aseptic measures, tissues were collected after transurethral resection of prostate, multiple pieces of the resected tissues were subjected to histopathological analysis, bacterial culture and genomic DNA extraction. Microbial composition was analyzed by culture and/or next-generation sequencing methods. Annotation of operational taxonomy unit has been done with an in-house algorithm. The extent of inflammation was scored through histological evaluation of tissue sections. The effect of clinical isolates on nuclear factor-κB (NF-κB) activity and induction of DNA-damage in the prostate epithelial cells were evaluated.

Results: Histopathological analysis of the BPH tissues showed the presence of inflammation in almost all the tissues with a varied level at different regions of the same tissue section and the level of overall inflammation was different from patients to patients. Microbial culture of tissue samples showed the presence of live bacteria in 55.5% (20 out of 36) of the patient tissues. Majority of the isolates were coagulase-positive Staphylococcus, E. coli and Micrococcus spp. Further, V3 16S rRNA sequencing of the DNA isolated from BPH tissues showed the presence of multiple bacteria and the most common phylum in the BPH tissues were found to be Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes. The E. coli, isolated from one of the tissue was able to activate NF-κB and induce DNA damage in prostate epithelial cells. Phospho-histone γH2A.X staining confirmed the presence of cells with damaged DNA lesion in BPH tissues and also correlated with the severity of inflammation.

Conclusion: Our study has shown that the BPH tissues do have a divergent microbial composition including the commonly found E. coli (phylum Proteobacteria), and these bacteria might contribute to the BPH-associated inflammation and/or tissue damage. The BPH-associated E. coli induced NF-κB signaling and DNA damage in prostate epithelial cells in vitro.
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http://dx.doi.org/10.1002/pros.24063DOI Listing
November 2020

Macrophage migration inhibitory factor of Syrian golden hamster shares structural and functional similarity with human counterpart and promotes pancreatic cancer.

Sci Rep 2019 10 29;9(1):15507. Epub 2019 Oct 29.

Tumor Microenvironment and Animal Models Lab, Institute of Life Sciences, Bhubaneswar, Odisha, India.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that increasingly is being studied in cancers and inflammatory diseases. Though murine models have been instrumental in understanding the functional role of MIF in different pathological conditions, the information obtained from these models is biased towards a specific species. In experimental science, results obtained from multiple clinically relevant animal models always provide convincing data that might recapitulate in humans. Syrian golden hamster (Mesocricetus auratus), is a clinically relevant animal model for multiple human diseases. Hence, the major objectives of this study were to characterize the structure and function of Mesocricetus auratus MIF (MaMIF) and finally evaluate its effect on pancreatic tumor growth in vivo. Initially, the recombinant MaMIF was cloned, expressed and purified in a bacterial expression system. The MaMIF primary sequence, biochemical properties, and crystal structure analysis showed greater similarity with human MIF. The crystal structure of MaMIF illustrates that it forms a homotrimer as known in human and mouse. However, MaMIF exhibits some minor structural variations when compared to human and mouse MIF. The in vitro functional studies show that MaMIF has tautomerase activity and enhances activation and migration of hamster peripheral blood mononuclear cells (PBMCs). Interestingly, injection of MaMIF into HapT1 pancreatic tumor-bearing hamsters significantly enhanced the tumor growth and tumor-associated angiogenesis. Together, the current study shows a structural and functional similarity between the hamster and human MIF. Moreover, it has demonstrated that a high level of circulating MIF originating from non-tumor cells might also promote pancreatic tumor growth in vivo.
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http://dx.doi.org/10.1038/s41598-019-51947-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820718PMC
October 2019

Functional and mechanistic studies reveal MAGEA3 as a pro-survival factor in pancreatic cancer cells.

J Exp Clin Cancer Res 2019 Jul 8;38(1):294. Epub 2019 Jul 8.

Tumor Microenvironment and Animal Models Lab, Institute of Life Sciences, Bhubaneswar, Odisha, 751023, India.

Background: In the era of personalized therapy, functional annotation of less frequent genetic aberrations will be instrumental in adapting effective therapeutic in clinic. Overexpression of Melanoma associated antigen A3 (MAGEA3) is reported in certain pancreatic cancer (PCA) patients. The major objective of the current study was to investigate the functional role of MAGEA3 in pancreatic cancer cells (PCCs) growth and survival.

Methods: Using overexpression (tet-on regulated system and constitutive expression system) and knockdown (by siRNA and shRNA) approach, we dissected the mechanistic role of MAGEA3 in pancreatic cancer pathogenesis. We generated MAGEA3 expressing stable PCA cell lines and mouse primary pancreatic epithelial cells. MAGEA3 was also depleted in certain MAGEA3 positive PCCs by siRNA or shRNA. The stable cells were subjected to in vitro assays like proliferation and survival assays under growth factor deprivation or in the presence of cytotoxic drugs. The MAGEA3 overexpressing or depleted stable PCCs were evaluated in vivo using xenograft model to check the role of MAGEA3 in tumor progression. We also dissected the mechanism behind the MAGEA3 role in tumor progression using western blot analysis and CCL2 neutralization.

Results: MAGEA3 overexpression in PCA cells did not alter the cell proliferation but protected the cells during growth factor deprivation and also in the presence of cytotoxic drugs. However, depletion of MAGEA3 in MAGEA3 positive cells resulted in reduced cell proliferation and increased apoptosis upon growth factor deprivation and also in response to cytotoxic drugs. The in vivo xenograft study revealed that overexpression of MAGEA3 promoted tumor growth however depleting the same hindered the tumor progression. Mechanistically, our in vitro and in vivo study revealed that MAGEA3 has tumor-promoting role by reducing macro-autophagy and overexpressing pro-survival molecules like CCL2 and survivin.

Conclusion: Our data proves tumor-promoting role of MAGEA3 and provides the rationale to target MAGEA3 and/or its functional mediators like CCL2 for PCA, which may have a better impact in PCA therapy.
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http://dx.doi.org/10.1186/s13046-019-1272-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615156PMC
July 2019

CID-6033590 inhibits p38MAPK pathway and induces S-phase cell cycle arrest and apoptosis in DU145 and PC-3 cells.

Toxicol In Vitro 2019 Oct 5;60:420-436. Epub 2019 Jun 5.

School of Life Sciences, Jawaharlal Nehru University, New Delhi, India. Electronic address:

Metastatic prostate cancer, with no effective treatment, is among the leading causes of cancer-associated deaths in men. Overexpression of p38αMAPK has been observed in neuroendocrine prostate cancer patients and in both DU145 and PC-3 cell lines and represents a good drug target. Sulfonamide derivatives have shown biological activities against many human diseases, including cancer. CID-6033590, a sulfonylhydrazide compound, screened from PubChem database by molecular docking with p38αMAPK, was evaluated for anti-cancerous activities. CID-6033590 induced toxicity in both DU145 and PC-3 cells in a concentration and time-dependent manner with an IC value of 60 μM and 66 μM, respectively. Sub-cytotoxic concentrations of the compound significantly induced S-phase cell cycle arrest, inhibited cyclinA/CDK2 complex and blocked cell proliferation. Further, CID-6033590 downregulated phosphorylation of p38MAPK (P-p38) as well as its downstream targets, Activating transcription factor 2 (ATF-2) and Heat shock protein 27 (Hsp27). The compound increased ROS and decreased mitochondrial membrane potential (Δψm), downregulated Bcl-2 and survivin and cleaved poly ADP ribose polymerase (PARP) and caspase-3, indicating the induction of apoptosis. The evaluaion of the compound on noncancerous, human prostatic epithelial cell line RWPE-1, and healthy murine tissues yielded no significant toxicity. Taken together, we suggest CID-6033590 as a potential candidate for prostate cancer therapy.
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http://dx.doi.org/10.1016/j.tiv.2019.06.003DOI Listing
October 2019

Lipopolysaccharide (LPS) enhances prostate cancer metastasis potentially through NF-κB activation and recurrent dexamethasone administration fails to suppress it in vivo.

Prostate 2019 02 27;79(2):168-182. Epub 2018 Sep 27.

Tumor Microenvironment and Animal Models Lab, Institute of Life Sciences, Bhubaneswar, Odisha, India.

Background: Previous studies have shown the effect of bacterial lipopolysaccharide (LPS) on enhanced cancer cells' growth and metastasis. However, the effect of LPS on prostate cancer (PCa) cells metastasis has not been investigated in details. This study aimed to investigate the functional role of LPS on PCa cells metastasis and determine the effect of dexamethasone (DEX) on this event.

Methods: Two different PCa reporter cells lines (DU145-NF-κB-Luc and MAT-LyLu- NF-κB-Luc) were used to assess the direct effect of LPS on NF-κB activation in PCa cells. Plasma collected from LPS-stimulated human and rodent blood were used to check the indirect effect of LPS on NF-κB activation in PCa cells. Trans-well migration assay and two different orthotopic PCa animal models were used to investigate the effect of LPS on DU145 and MAT-LyLu cells migration or metastasis in vitro and in vivo, respectively. In all the studies DEX was used with or without LPS stimulation.

Results: LPS and secretory factors present in plasma collected from LPS-stimulated blood, significantly activated NF-κB in DU145, and MAT-LyLu cells and enhanced their migration in vitro. DEX significantly suppressed LPS-mediated activation of cancer and blood cells and abrogated the direct and indirect pro-migratory effect of LPS on PCa cells. Systemic administration of LPS activated NF-κB in DU145 cells in vivo; however, failed to alter the metastatic properties of these cells. On the other hand, systemic administration of LPS to MAT-LyLu tumor bearing animals significantly enhanced the incidence of metastasis without altering the overall growth of primary tumors. Unexpectedly, though DEX significantly suppressed MAT-LyLu primary tumor weights, it aggravated metastasis of cancer cells in presence and absence of LPS. Moreover, consecutive DEX pre-treatment enhanced experimental peritoneal metastasis of MAT-LyLu cells. At the molecular level, LPS, and/or DEX induced overexpression of immunosuppressive molecules in MAT-LyLu tumors.

Conclusions: Overall, our study has shown that LPS and/or LPS induced inflammation can increase PCa metastasis and immunosuppressive dose of DEX might further enhance cancer metastasis.
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http://dx.doi.org/10.1002/pros.23722DOI Listing
February 2019

TRIM16 controls assembly and degradation of protein aggregates by modulating the p62-NRF2 axis and autophagy.

EMBO J 2018 09 24;37(18). Epub 2018 Aug 24.

Cell Biology and Infectious Diseases Unit, Institute of Life Sciences, Bhubaneswar, India

Sequestration of protein aggregates in inclusion bodies and their subsequent degradation prevents proteostasis imbalance, cytotoxicity, and proteinopathies. The underlying molecular mechanisms controlling the turnover of protein aggregates are mostly uncharacterized. Herein, we show that a TRIM family protein, TRIM16, governs the process of stress-induced biogenesis and degradation of protein aggregates. TRIM16 facilitates protein aggregate formation by positively regulating the p62-NRF2 axis. We show that TRIM16 is an integral part of the p62-KEAP1-NRF2 complex and utilizes multiple mechanisms for stabilizing NRF2. Under oxidative and proteotoxic stress conditions, TRIM16 activates ubiquitin pathway genes and p62 via NRF2, leading to ubiquitination of misfolded proteins and formation of protein aggregates. We further show that TRIM16 acts as a scaffold protein and, by interacting with p62, ULK1, ATG16L1, and LC3B, facilitates autophagic degradation of protein aggregates. Thus, TRIM16 streamlines the process of stress-induced aggregate clearance and protects cells against oxidative/proteotoxic stress-induced toxicity and Taken together, this work identifies a new mechanism of protein aggregate turnover, which could be relevant in protein aggregation-associated diseases such as neurodegeneration.
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http://dx.doi.org/10.15252/embj.201798358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138442PMC
September 2018

Possible Autocrine Function of Galectin-3 in Pancreatic Stellate Cells.

Gastroenterology 2018 09 6;155(3):933-934. Epub 2018 Aug 6.

Tumor Microenvironment and Animal Models Lab, Institute of Life Sciences, Bhubaneswar, Odisha, India.

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http://dx.doi.org/10.1053/j.gastro.2018.01.076DOI Listing
September 2018

Probiotics L. acidophilus and B. clausii Modulate Gut Microbiota in Th1- and Th2-Biased Mice to Ameliorate Salmonella Typhimurium-Induced Diarrhea.

Probiotics Antimicrob Proteins 2019 09;11(3):887-904

School of Biological Sciences, National Institute of Science Education and Research (NISER), HBNI, P.O. Bhimpur-Padanpur, Jatni, Khurdha, Odisha, 752050, India.

Gut microbiota play important role in maintaining health. Probiotics are believed to augment it further. We aimed at comparing effects of probiotics, Lactobacillus acidophilus (LA) and Bacillus clausii (BC) (a) on the gut microbiota abundance and diversity and (b) their contributions to control intestinal dysbiosis and inflammation in Th1- and Th2-biased mice following Salmonella infection. We report how could gut microbiota and the differential immune bias (Th1 or Th2) of the host regulate host responses when challenged with Salmonella typhimurium in the presence and absence of either of the probiotics. LA was found to be effective in ameliorating the microbial dysbiosis and inflammation caused by Salmonella infection, in Th1 (C57BL/6) and Th2 (BALB/c)-biased mouse. BC was able to ameliorate Salmonella-induced dysbiosis and inflammation in Th2 but not in Th1-biased mouse. These results may support probiotics LA as a treatment option in the case of Salmonella infection.
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http://dx.doi.org/10.1007/s12602-018-9436-5DOI Listing
September 2019

Iron(III) Coordinated Polymeric Nanomaterial: A Next-Generation Theranostic Agent for High-Resolution T-Weighted Magnetic Resonance Imaging and Anticancer Drug Delivery.

ACS Biomater Sci Eng 2018 May 25;4(5):1738-1749. Epub 2018 Apr 25.

Tumor Microenvironment and Animal Models Laboratory, Institute of Life Sciences, Bhubaneswar, Odisha 751023, India.

Theranostic-based nanomedicine plays a crucial role in the field of cancer therapy. This is due to having the capability to combine both therapy and diagnosis together in a single system. Herein a new class of metal-ligand-based nanocarrier in a norbornene backbone has been designed as a theranostic system. Fe-terpyridine complex has been used here as T contrast agent for high-resolution MR imaging, and hydrazone-linked doxorubicin is used for effective pH-responsive delivery. Polyethylene glycol functionalized with a folic acid (peg folate) motif is used to make the entire polymeric system dispersible in water for longer retention and site-specific therapy. All these specialty functional groups are anchored in a single system by using the ring-opening metathesis polymerization (ROMP) technique under the norbornene backbone. Relaxivity study and 1D image experiments have shown the utility of complex as an effective T contrast agent. studies are performed to confirm the promising potentiality of the nanocarrier as the efficient nanotheranostic system in prostate cancer.
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http://dx.doi.org/10.1021/acsbiomaterials.8b00294DOI Listing
May 2018

Dual role of Par-4 in abrogation of EMT and switching on Mesenchymal to Epithelial Transition (MET) in metastatic pancreatic cancer cells.

Mol Carcinog 2018 09 15;57(9):1102-1115. Epub 2018 May 15.

Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.

Epithelial-mesenchymal transition (EMT) is a critical event that occurs during the invasion and metastatic spread of cancer cells. Here, we conceive a dual mechanism of Par-4-mediated inhibition of EMT and induction of MET in metastatic pancreatic cancer cells. First, we demonstrate that 1,1'-β-D-glucopyranosyl-3,3'-bis(5-bromoindolyl)-octyl methane (NGD16), an N-glycosylated derivative of medicinally important phytochemical 3,3'-diindolylmethane (DIM) abrogates EMT by inducing pro-apoptotic protein Par-4. Induction of Par-4 (by NGD16 or ectopic overexpression) strongly impedes invasion with inhibition of major mesenchymal markers viz. Vimentin and Twist-1 epithelial marker- E-cadherin. Further, NGD16 triggers MET phenotypes in pancreatic cancer cells by augmenting ALK2/Smad4 signaling in a Par-4-dependent manner. Conversely, siRNA-mediated silencing of endogenous Par-4 unveil reversal of MET with diminished E-cadherin expression and invasive phenotypes. Additionally, we demonstrate that intact Smad4 is essential for Par-4-mediated maintenance of E-cadherin level in MET induced cells. Notably, we imply that Par-4 induction regulates E-cadherin levels in the pancreatic cancer cells via modulating Twist-1 promoter activity. Finally, in vivo studies with syngenic mouse metastatic pancreatic cancer model reveal that NGD16 strongly suppresses metastatic burden, ascites formation, and prolongs the overall survival of animals effectively.
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http://dx.doi.org/10.1002/mc.22828DOI Listing
September 2018

Nicotine associated breast cancer in smokers is mediated through high level of EZH2 expression which can be reversed by methyltransferase inhibitor DZNepA.

Cell Death Dis 2018 02 2;9(2):152. Epub 2018 Feb 2.

Cancer Biology Laboratory, Department of Gene Function and Regulation, Institute of Life Sciences, Bhubaneswar, Odisha, India.

Recent studies show substantial growth-promoting properties of nicotine (NIC) in cancer, which is a combined outcome of genetic and epigenetic alterations. However, the role of epigenetic modifiers in response to NIC in breast cancer is less studied. In the present study, for the first time we have shown NIC-induced enhanced EZH2 expression. Six pairs of smoking-associated breast cancer patient tissues were analyzed. Samples from smoking breast cancer patients showed distinguished enhanced EZH2 expression in comparison to non-smoking ones. The upregulation in EZH2, which is due to NIC, was further confirmed in breast carcinoma cell lines using 10 µM NIC, 1 µM DZNepA, and EZH2si. The upregulation of EZH2 was concomitant with upregulation in Myc and α9-nAChR. The xenograft of breast cancer cells in BALB/c nude mice in the presence or absence of NIC showed significantly higher tumor uptake in the NIC injected group, which clearly demonstrates the effect of NIC in breast cancer progression. Interestingly, DZNepA considerably suppressed the NIC-mediated tumor growth. CHIP-qPCR assay confirmed the increased Myc enrichment on EZH2 promoter upon NIC treatment, thereby strengthening our findings that there exists an association between NIC, Myc, and EZH2. Overall, the present study identifies a strong association between NIC and EZH2 particularly in the progression of breast cancer in smokers through a novel axis involving nAChR and Myc. Moreover, the findings provide preliminary evidence suggesting potential of high level of EZH2 expression as a prognostic marker in smoking-associated breast cancer.
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http://dx.doi.org/10.1038/s41419-017-0224-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833686PMC
February 2018

Experimental models of pancreatic cancer desmoplasia.

Lab Invest 2018 01 20;98(1):27-40. Epub 2017 Nov 20.

Tumor Microenvironment and Animal Models Lab, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India.

Desmoplasia is a fibro-inflammatory process and a well-established feature of pancreatic cancer. A key contributor to pancreatic cancer desmoplasia is the pancreatic stellate cell. Various in vitro and in vivo methods have emerged for the isolation, characterization, and use of pancreatic stellate cells in models of cancer-associated fibrosis. In addition to cell culture models, genetically engineered animal models have been established that spontaneously develop pancreatic cancer with desmoplasia. These animal models are currently being used for the study of pancreatic cancer pathogenesis and for evaluating therapeutics against pancreatic cancer. Here, we review various in vitro and in vivo models that are being used or have the potential to be used to study desmoplasia in pancreatic cancer.
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http://dx.doi.org/10.1038/labinvest.2017.127DOI Listing
January 2018

Ambient endotoxin in PM and association with inflammatory activity, air pollutants, and meteorology, in Chitwan, Nepal.

Sci Total Environ 2018 Mar 13;618:1331-1342. Epub 2017 Oct 13.

International Centre for Integrated Mountain Development (ICIMOD), G.P.O. Box 3226, Kathmandu, Nepal. Electronic address:

Background: Endotoxin associated with ambient PM (particulate matter) has been linked to adverse respiratory symptoms, but there have been few studies of ambient endotoxin and its association with co-pollutants and inflammation.

Objectives: Our aim was to measure endotoxin associated with ambient PM (particulate matter with aerodynamic diameter<10μm) in summer 2016 at four locations in Chitwan, Nepal, and investigate its association with meteorology, co-pollutants, and inflammatory activity.

Methods: PM concentrations were recorded and filter paper samples were collected using E-samplers; PM PM, black carbon (BC), methane (CH), and carbon monoxide (CO) were also measured. The Limulus amebocyte lysate (LAL) assay was used for endotoxin quantification and the nuclear factor kappa B (NFκB) activation assay to assess inflammatory activity.

Results: The mean concentration of PM at the different locations ranged from 136 to 189μg/m, and of endotoxin from 0.29 to 0.53EU/m. Pollutant presence was positively correlated with endotoxin. Apart from relative humidity, meteorological variations had no significant impact on endotoxin concentration. NF-κB activity was negatively correlated with endotoxin concentration.

Conclusions: To the best of our knowledge, this study provides the first measurements of ambient endotoxin associated with PM in Nepal. Endotoxin and co-pollutants were positively associated indicating a similar source. Endotoxin was negatively correlated with inflammatory activity as a result of a time-limited forest fire event during the sampling period. Studies of co-pollutants suggested that the higher levels of endotoxin related to biomass burning were accompanied by increased levels of anti-inflammatory agents, which suppressed the endotoxin inflammatory effect.
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http://dx.doi.org/10.1016/j.scitotenv.2017.09.249DOI Listing
March 2018

E2f8 mediates tumor suppression in postnatal liver development.

J Clin Invest 2016 08 25;126(8):2955-69. Epub 2016 Jul 25.

E2F-mediated transcriptional repression of cell cycle-dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8's tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8's DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development.
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http://dx.doi.org/10.1172/JCI85506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966321PMC
August 2016

Urinary bladder stone associated with seminal vesicle and prostate infection in a Copenhagen rat.

J Nat Sci Biol Med 2016 Jul-Dec;7(2):193-7

Department of Pathology, Apollo Hospital, Bhubaneswar, Odisha, India.

We report a very rare case of urinary bladder stone in a laboratory rat, which was associated with severe prostatitis and seminal vesiculitis. Importantly, the histopathological analysis revealed the rare variety of keratinizing desquamative squamous metaplasia of bladder, prostate, and seminal vesicle epithelium. Immunohistochemistry for alpha smooth muscle actin protein and aniline blue staining for collagen clearly showed interstitial prostate fibrosis. The detail information about these findings and subsequent discussion are provided here.
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http://dx.doi.org/10.4103/0976-9668.184711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4934114PMC
July 2016

Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia.

Oncotarget 2016 Jul;7(27):41825-41842

Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India.

Desmoplasia in human pancreatic cancer (PC) promotes cancer progression and hinders effective drug delivery. The objectives of this study were to characterize a homologous orthotopic model of PC in Syrian golden hamster and investigate the effect of anti-fibrotic (pirfenidone), antioxidant (N-acetyl cysteine, NAC) and anti-addiction (disulfiram, DSF) drugs on desmoplasia and tumor growth in this model. The HapT1 PC cells when implanted orthotopically into hamsters formed tumors with morphological, cellular and molecular similarities to human PC. Protein profiling of activated hamster pancreatic stellate cells (ha-PSCs) revealed expression of proteins involved in fibrosis, cancer cells growth and metastasis. Pirfenidone, suppressed growth of HapT1 cells and the desmoplastic response in vivo; these effects were enhanced by co-administration of NAC. Disulfiram alone or in combination with copper (Cu) was toxic to HapT1 cells and PSCs in vitro; but co-administration of DSF and Cu accelerated growth of HapT1 cells in vivo. Moreover, DSF had no effect on tumor-associated desmoplasia. Overall, this study identifies HapT1-derived orthotopic tumors as a useful model to study desmoplasia and tumor-directed therapeutics in PC. Pirfenidone in combination with NAC could be a novel combination therapy for PC and warrants investigation in human subjects.
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http://dx.doi.org/10.18632/oncotarget.9729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173099PMC
July 2016

Plant-derived SAC domain of PAR-4 (Prostate Apoptosis Response 4) exhibits growth inhibitory effects in prostate cancer cells.

Front Plant Sci 2015 7;6:822. Epub 2015 Oct 7.

Department of Gene Function and Regulation, Institute of Life Sciences, Department of Biotechnology, Government of India Bhubaneswar, India.

The gene Par-4 (Prostate Apoptosis Response 4) was originally identified in prostate cancer cells undergoing apoptosis and its product Par-4 showed cancer specific pro-apoptotic activity. Particularly, the SAC domain of Par-4 (SAC-Par-4) selectively kills cancer cells leaving normal cells unaffected. The therapeutic significance of bioactive SAC-Par-4 is enormous in cancer biology; however, its large scale production is still a matter of concern. Here we report the production of SAC-Par-4-GFP fusion protein coupled to translational enhancer sequence (5' AMV) and apoplast signal peptide (aTP) in transgenic Nicotiana tabacum cv. Samsun NN plants under the control of a unique recombinant promoter M24. Transgene integration was confirmed by genomic DNA PCR, Southern and Northern blotting, Real-time PCR, and Nuclear run-on assays. Results of Western blot analysis and ELISA confirmed expression of recombinant SAC-Par-4-GFP protein and it was as high as 0.15% of total soluble protein. In addition, we found that targeting of plant recombinant SAC-Par-4-GFP to the apoplast and endoplasmic reticulum (ER) was essential for the stability of plant recombinant protein in comparison to the bacterial derived SAC-Par-4. Deglycosylation analysis demonstrated that ER-targeted SAC-Par-4-GFP-SEKDEL undergoes O-linked glycosylation unlike apoplast-targeted SAC-Par-4-GFP. Furthermore, various in vitro studies like mammalian cells proliferation assay (MTT), apoptosis induction assays, and NF-κB suppression suggested the cytotoxic and apoptotic properties of plant-derived SAC-Par-4-GFP against multiple prostate cancer cell lines. Additionally, pre-treatment of MAT-LyLu prostate cancer cells with purified SAC-Par-4-GFP significantly delayed the onset of tumor in a syngeneic rat prostate cancer model. Taken altogether, we proclaim that plant made SAC-Par-4 may become a useful alternate therapy for effectively alleviating cancer in the new era.
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http://dx.doi.org/10.3389/fpls.2015.00822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595782PMC
October 2015

Magnetic Nanoparticles Labeled Mesenchymal Stem Cells: A Pragmatic Solution toward Targeted Cancer Theranostics.

Adv Healthc Mater 2015 Oct 1;4(14):2078-2089. Epub 2015 Sep 1.

Institute of Life Sciences, Nalco Square, Chandrasekharpur, Bhubaneswar, 751023, India.

Mesenchymal stem cells (MSCs) have gained much interest to be used as targeting vehicle in cancer therapy due to the intrinsic tumor-homing behavior associated with them. In this scenario, superparamagnetic nanoparticles are emerging as an ideal probe for noninvasive cell tracking for different stem cell applications. In the study, it is demonstrated that the formulated aqueous dispersible glyceryl monooleate coated magnetic nanoparticles (MNPs) can act as a better labeling and efficient tracking agent without affecting the inherent properties of MSCs. The MNPs-MSCs facilitate the stem cell tracking by magnetic resonance imaging at a very low cell number having high T relaxivity and potentiates the use of MNPs-MSCs as a prospective diagnostic tool. Most importantly, the homing of MNPs-MSCs toward inflammation site, subcutaneous prostate tumor (small as well as large tumor), and in orthotopic prostate tumor suggests the clinical relevance of the system. In addition, intraperitoneal delivery of MNPs-MSCs shows enhanced tumor accumulation and less sequestration in liver as revealed by in vivo imaging and histological studies. The results here demonstrate that MNPs-MSCs may prove as a better targeted delivery agent for early diagnosis of tumors even of smaller size.
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http://dx.doi.org/10.1002/adhm.201500343DOI Listing
October 2015

TLR4 activation by lipopolysaccharide confers survival advantage to growth factor deprived prostate cancer cells.

Prostate 2015 Jul 2;75(10):1020-33. Epub 2015 Apr 2.

Institute of Life Sciences, Bhubaneswar, Odisha, India.

Background: Prostate cancer (PCa) cells express Toll-like receptor-4 (TLR4), a known pro-tumorigenic molecule for different cancer cells. The cancer cells residing in the avascular region of the tumor confront various metabolic stresses and continuously adapt mechanisms to overcome them. We hypothesized that TLR4 activation might provide direct survival advantage to metabolically stressed PCa cells.

Methods: We first investigated the effect of LPS on survival of serum deprived PCa cells. To understand the molecular mechanisms involved in TLR4 mediated PCa survival, we next investigated change in expression of markers for apoptosis, senescence and autophagy. Ultimately, the effect of LPS on established prostate tumors was confirmed in vivo using a syngeneic rat model for PCa.

Results: Lipopolysaccharide (LPS)-mediated TLR4 activation significantly enhanced survival of serum deprived (SD) PC3, DU145 and MAT-LyLu PCa cells. TLR4 inhibition by a specific inhibitor resulted in rapid death of SD-PC3 cells, which was significantly suppressed by LPS. Interestingly, LPS treatment suppressed macroautophagy in SD-PC3 cells and increased expression of CCL2 (C-C motif ligand-2), a known autophagy inhibitor and pro-survival factor. Intra-tumor LPS injection resulted in increased tumor mass, induced TLR4 activation, suppressed autophagy, and increased the macrophage population in MAT-LyLu-tumors.

Conclusions: Our study reveals that bacterial LPS enhance survival of PCa cells under conditions of nutrient stress through TLR4 activation. Moreover, LPS induces overexpression of CCL2 involved in the suppression of starvation-induced macroautophagy in PCa cells, and enhanced macrophage population in prostate tumors in vivo. Taken together, the current study suggests the importance of bacterial infection or TLR4-activation in prostate cancer pathogenesis.
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http://dx.doi.org/10.1002/pros.22983DOI Listing
July 2015

Effective control of Salmonella infections by employing combinations of recombinant antimicrobial human β-defensins hBD-1 and hBD-2.

Antimicrob Agents Chemother 2014 Nov 8;58(11):6896-903. Epub 2014 Sep 8.

Division of Gene Function and Regulation, Institute of Life Sciences, Department of Biotechnology, Government of India, Bhubaneswar, Odisha, India

We successfully produced two human β-defensins (hBD-1 and hBD-2) in bacteria as functional peptides and tested their antibacterial activities against Salmonella enterica serovar Typhi, Escherichia coli, and Staphylococcus aureus employing both spectroscopic and viable CFU count methods. Purified peptides showed approximately 50% inhibition of the bacterial population when used individually and up to 90% when used in combination. The 50% lethal doses (LD50) of hBD-1 against S. Typhi, E. coli, and S. aureus were 0.36, 0.40, and 0.69 μg/μl, respectively, while those for hBD-2 against the same bacteria were 0.38, 0.36, and 0.66 μg/μl, respectively. Moreover, we observed that bacterium-derived antimicrobial peptides were also effective in increasing survival time and decreasing bacterial loads in the peritoneal fluid, liver, and spleen of a mouse intraperitoneally infected with S. Typhi. The 1:1 hBD-1/hBD-2 combination showed maximum effectiveness in challenging the Salmonella infection in vitro and in vivo. We also observed less tissue damage and sepsis formation in the livers of infected mice after treatment with hBD-1 and hBD-2 peptides individually or in combination. Based on these findings, we conclude that bacterium-derived recombinant β-defensins (hBD-1 and hBD-2) are promising antimicrobial peptide (AMP)-based substances for the development of new therapeutics against typhoid fever.
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http://dx.doi.org/10.1128/AAC.03628-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249419PMC
November 2014

X-gal staining of canine skin tissues: A technique with multiple possible applications.

J Nat Sci Biol Med 2014 Jul;5(2):245-9

Institute of Life Sciences, Department of Translational Research and Technology Development, Nalco Square, Bhubaneswar, Orissa, India.

Background: Estimation of β-galactosidase (βgal) activity in human cells and tissues indicate its possible use as a marker of senescence.

Objectives: This study was done to detect senescence-associated βgal (SA-βgal) activity in canine skin tissue by using its substrate 5-bromo-4-chloro-3-indolyl β-D-galactosidase (X-gal).

Materials And Methods: Skin samples were collected through rapid necropsy process. The X-gal staining was done by altering different factors of the staining procedure like pH of the reagents and incubation time. Further, effect of tissue preservation procedure was also evaluated.

Results: Typical X-gal staining was detected in old dogs' skin samples and it was detectable both at pH 6 and pH 7.3. The cells present in the inner lining of the hair follicles and sebaceous glands are the major cells that have high SA-βgal activity. The X-gal staining intensity was more prominent in tissues preserved in liquid nitrogen at -196°C than in -80°C freezer. Prolonged incubation period increased the intensity of staining.

Conclusions: This study indicates possibility of X-gal staining in canine tissues and opens an avenue for further in-depth studies that might be useful for different research and clinical studies like determination of dog's approximate age.
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http://dx.doi.org/10.4103/0976-9668.136147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121891PMC
July 2014

Canonical and atypical E2Fs regulate the mammalian endocycle.

Nat Cell Biol 2012 Nov 14;14(11):1192-202. Epub 2012 Oct 14.

Solid Tumor Biology Program, Department of Molecular Virology, Immunology and Medical Genetics, Department of Molecular Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.

The endocycle is a variant cell cycle consisting of successive DNA synthesis and gap phases that yield highly polyploid cells. Although essential for metazoan development, relatively little is known about its control or physiologic role in mammals. Using lineage-specific cre mice we identified two opposing arms of the E2F program, one driven by canonical transcription activation (E2F1, E2F2 and E2F3) and the other by atypical repression (E2F7 and E2F8), that converge on the regulation of endocycles in vivo. Ablation of canonical activators in the two endocycling tissues of mammals, trophoblast giant cells in the placenta and hepatocytes in the liver, augmented genome ploidy, whereas ablation of atypical repressors diminished ploidy. These two antagonistic arms coordinate the expression of a unique G2/M transcriptional program that is critical for mitosis, karyokinesis and cytokinesis. These results provide in vivo evidence for a direct role of E2F family members in regulating non-traditional cell cycles in mammals.
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http://dx.doi.org/10.1038/ncb2595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616487PMC
November 2012

Recent trends in antibody-based oncologic imaging.

Cancer Lett 2012 Feb 20;315(2):97-111. Epub 2011 Oct 20.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Antibodies, with their unmatched ability for selective binding to any target, are considered as potentially the most specific probes for imaging. Their clinical utility, however, has been limited chiefly due to their slow clearance from the circulation, longer retention in non-targeted tissues and the extensive optimization required for each antibody-tracer. The development of newer contrast agents, combined with improved conjugation strategies and novel engineered forms of antibodies (diabodies, minibodies, single chain variable fragments, and nanobodies), have triggered a new wave of antibody-based imaging approaches. Apart from their conventional use with nuclear imaging probes, antibodies and their modified forms are increasingly being employed with non-radioisotopic contrast agents (MRI and ultrasound) as well as newer imaging modalities, such as quantum dots, near infra red (NIR) probes, nanoshells and surface enhanced Raman spectroscopy (SERS). The review article discusses new developments in the usage of antibodies and their modified forms in conjunction with probes of various imaging modalities such as nuclear imaging, optical imaging, ultrasound, MRI, SERS and nanoshells in preclinical and clinical studies on the diagnosis, prognosis and therapeutic responses of cancer.
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http://dx.doi.org/10.1016/j.canlet.2011.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249014PMC
February 2012

Novel INTeraction of MUC4 and galectin: potential pathobiological implications for metastasis in lethal pancreatic cancer.

Clin Cancer Res 2011 Jan 8;17(2):267-74. Epub 2010 Nov 8.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5870, USA.

Purpose: Several studies have reported aberrant expression of MUC4 in pancreatic cancer (PC), which is associated with tumorigenicity and metastasis. Mechanisms through which MUC4 promote metastasis of PC cells to distant organs are poorly defined.

Experimental Design: Identification of MUC4-galectin-3 interaction and its effect on the adhesion of cancer cells to endothelial cells were done by immunoprecipitation and cell-cell adhesion assays, respectively. Serum galectin-3 level for normal and PC patients were evaluated through ELISA.

Results: In the present study, we have provided clinical evidence that the level of galectin-3 is significantly elevated in the sera of PC patients with metastatic disease compared with patients without metastasis (P = 0.04) and healthy controls (P = 0.00001). Importantly, for the first time, we demonstrate that MUC4 present on the surface of circulating PC cells plays a significant role in the transient and reversible attachment (docking) of circulating tumor cells to the surface of endothelial cells. Further, exogenous galectin-3 at concentrations similar to that found in the sera of PC patients interacts with MUC4 via surface glycans such as T antigens, which results in the clustering of MUC4 on the cell surface and a stronger attachment (locking) of circulating tumor cells to the endothelium.

Conclusions: Altogether, these findings suggest that PC cell-associated MUC4 helps in the docking of tumor cells on the endothelial surface. During cancer progression, MUC4-galectin-3 interaction-mediated clustering of MUC4 may expose the surface adhesion molecules, which in turn promotes a stronger attachment (locking) of tumor cells to the endothelial surface.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-1937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023008PMC
January 2011

Expression of intestinal MUC17 membrane-bound mucin in inflammatory and neoplastic diseases of the colon.

J Clin Pathol 2010 Aug;63(8):702-7

Department of Biochemistry and Molecular Biology, University of Nebraska, Omaha, Nebraska, USA.

Aim: To determine the cellular location and expression of MUC17 mucin in specimens of normal, inflamed and neoplastic colon.

Methods: Immunohistochemical analysis of human surgical resection specimens (n=106) was performed with a specific antibody to the MUC17 apomucin protein. A semi-quantitative scoring system was used to measure MUC17 expression. In various colon cancer cell lines, the MUC17 expression was examined by immunoblot analysis and normal RT-PCR.

Results: MUC17 was highly expressed on the surface epithelium and crypts of colonic mucosa. In contrast, the expression of MUC17 was significantly decreased in colonic mucosa of chronic ulcerative colitis (p<0.0001) and ischaemic colitis (p=0.003). Similarly, MUC17 expression was decreased in hyperplastic polyps (p=0.0003), tubular and tubulovillous adenomas (p<0.0001) and colon cancers (p<0.0001). Furthermore, of eight different colon cancer cell lines, MUC17 expression was only detected in LS174T and LS180 cells.

Conclusion: Results indicate that the potential protective effects of this membrane-bound mucin are primarily or secondarily diminished in inflammatory and neoplastic conditions. Further research is needed to determine the specific role of MUC17 in the pathogenesis of these conditions.
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http://dx.doi.org/10.1136/jcp.2010.078717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997570PMC
August 2010

MUC4 down-regulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progenies.

Cancer Lett 2010 Sep 19;295(1):69-84. Epub 2010 Mar 19.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.

The present study was undertaken to estimate the therapeutic benefit to down-regulate the MUC4 mucin for reversing chemoresistance of pancreatic cancer (PC) stem/progenitor cells and their progenies. The results have revealed that MUC4 mucin is overexpressed in CD133(+) and CD133(-) pancreatic cells (PCs) detected in patient's adenocarcinoma tissues while no significant expression was seen in normal pancreatic tissues. The gain- and loss-of-function analyses have indicated that the overexpression of MUC4 in PC lines is associated with a higher resistance to the anti-proliferative, anti-invasive and apoptotic effects induced by gemcitabine. Importantly, the treatment of the MUC4-overexpressing CD18/HPAF-Src cells with gemcitabine resulted in an enrichment of the side population (SP) cells expressing CD133 while the total PC cells including non-SP cells detected in MUC4 knockdown CD18/HPAF-shMUC4 cells were responsive to the cytotoxic effects induced by gemcitabine. These data suggest that the MUC4 down-regulation may constitute a potential therapeutic strategy for improving the efficacy of gemcitabine to eradicate the total PC cell mass, and thereby preventing disease relapse.
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http://dx.doi.org/10.1016/j.canlet.2010.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891434PMC
September 2010