Photoresponse of Carbon Nanofiber-Based Photodetector and Its Enhancement on CuNi Nanoparticle Adsorption.

We explore the photodetection properties of a carbon nanofiber (CNF)-based p-CNF/n-Si heterojunction device in the 400-800 nm wavelength range and investigate the changes brought in by adsorption of CuNi (CN) nanoparticles on the CNFs. The nanoparticles and CN-CNF nanocomposites were synthesized by using chemical hydrothermal routes. The p-type semiconducting nature of the CNFs and nanocomposites was determined using X-ray photoelectron (XPS) and UV-vis spectroscopies. The p-CNF/n-Si device is found to be better than many carbon-nanotube-based devices in terms of its peak responsivity (0.6 A/W) and gain (1.6), with an acceptably moderate peak detectivity (1.3 × 109 Jones) at 450 nm and a -5 V bias. The p-CN-CNF/n-Si device displays an appreciable enhancement in the photoresponse with respect to the p-CNF/n-Si device, with a peak responsivity of 2.8 A/W, peak detectivity of 9.4 × 109 Jones, and gain of 8. With the aid of valence band XPS and Raman spectra, the enhancement is explainable in terms of a CN to CNF charge transfer and the resulting increase in the built-in potential at the heterojunction.

Terahertz tunable band-stop filter using topological valley photonic crystals.

In recent years, there has been a growing interest in the wideband propagation and control of terahertz (THz) radiation due to its potential for a variety of applications, such as 6G communication, sensing, and imaging. One promising approach in this area is the use of valley photonic crystals (VPCs), which exhibit properties like wider band gaps and robust propagation. In this paper, a two-dimensional dielectric silicon-air VPC is studied, which is constructed from a method of inversion symmetry breaking providing a band gap of 109.4 GHz at a mid-gap frequency of 0.376 THz. We employ an optimized bearded-stack interface to construct the VPC waveguide for wideband THz propagation along straight and Z-shaped paths. We demonstrate that a band-stop response can be achieved in a VPC by introducing periodic defects along the domain wall. Furthermore, the stop range can be tuned by varying the refractive index of the defects through incorporating liquid crystal along the domain wall of VPC. Our proposed structure and the techniques employed could be promising for the development of a band-stop filter (BSF) and other photonic components having potential applications in 6G communication and beyond.

ETV4 Facilitates Cell-Cycle Progression in Pancreatic Cells through Transcriptional Regulation of Cyclin D1.

The ETS family transcription factor ETV4 is aberrantly expressed in a variety of human tumors and plays an important role in carcinogenesis through upregulation of relevant target gene expression. Here, it is demonstrated that ETV4 is overexpressed in pancreatic cancer tissues as compared with the normal pancreas, and is associated with enhanced growth and rapid cell-cycle progression of pancreatic cancer cells. ETV4 expression was silenced through stable expression of a specific short hairpin RNA (shRNA) in two pancreatic cancer cell lines (ASPC1 and Colo357), while it was ectopically expressed in BXPC3 cells. Silencing of ETV4 in ASPC1 and Colo357 cells reduced the growth by 55.3% and 38.9%, respectively, while forced expression of ETV4 in BXPC3 cells increased the growth by 46.8% in comparison with respective control cells. Furthermore, ETV4-induced cell growth was facilitated by rapid transition of cells from G1- to S-phase of the cell cycle. Mechanistic studies revealed that ETV4 directly regulates the expression of Cyclin D1 CCND1, a protein crucial for cell-cycle progression from G1- to S-phase. These effects on the growth and cell cycle were reversed by the forced expression of Cyclin D1 in ETV4-silenced pancreatic cancer cells. Altogether, these data provide the first experimental evidence for a functional role of ETV4 in pancreatic cancer growth and cell-cycle progression.Implications: The functional and mechanistic data presented here regarding ETV4 in pancreatic cancer growth and cell-cycle progression suggest that ETV4 could serve as a potential biomarker and novel target for pancreatic cancer therapy. Mol Cancer Res; 16(2); 187-96. ©2017 AACR.

Evolution of nanostructured single-phase CoSb3 thin films by low-energy ion beam induced mixing and their thermoelectric performance.

Skutterudites are emerging as potential candidates that show high efficiency and thus provide an ideal platform for research. The properties of nanostructured films of skutterudites are different from those of the corresponding bulk. The present study reports the evolution of nanostructured single-phase CoSb3 fabricated by using low-energy ion irradiation of Co/Sb bilayer films and subsequent annealing at an optimized temperature and their Seebeck coefficients (S). The effects of ion beam parameters with annealing on the phase evolution and nanostructure modifications were studied. An increase in Xe+ ion fluence resulted in complete mixing of Co/Sb on postannealing forming flower-like nanostructures of single phase CoSb3. The temperature-dependent electrical resistivity (ρ) increases with the ion fluence because of defect creation which further increases on postannealing due to surface nanostructuring. The S of these films of CoSb3 is found to be higher and this is attributed to the formation of a uniform layer of nanostructured CoSb3 alloy thin film. The S and Hall coefficients of all these films are negative implying that they are n-type semiconductors.

Racial health disparities in ovarian cancer: not just black and white.

Ovarian cancer (OC) is the most lethal gynecological malignancy, which disproportionately affects African American (AA) women. Lack of awareness and socioeconomic factors are considered important players in OC racial health disparity, while at the same time, some recent studies have brought focus on the genetic basis of disparity as well. Differential polymorphisms, mutations and expressions of genes have been reported in OC patients of diverse racial and ethnic backgrounds. Combined, it appears that neither genetic nor the socioeconomic factors alone might explain the observed racially disparate health outcomes among OC patients. Rather, a more logical explanation would be the one that takes into consideration the combination and/or the interplay of these factors, perhaps even including some environmental ones. Hence, in this article, we attempt to review the available information on OC racial health disparity, and provide an overview of socioeconomic, environmental and genetic factors, as well as the epigenetic changes that can act as a liaison between the three. A better understanding of these underlying causes will help further research on effective cancer management among diverse patient population and ultimately narrow health disparity gaps.

MicroRNAs in gynecological cancers: Small molecules with big implications.

Gynecological cancers (GCs) are often diagnosed at advanced stages, limiting the efficacy of available therapeutic options. Thus, there remains an urgent and unmet need for innovative research for the efficient clinical management of GC patients. Research over past several years has revealed the enormous promise of miRNAs. These small non-coding RNAs can aid in the diagnosis, prognosis and therapy of all major GCs, viz., ovarian cancers, cervical cancers and endometrial cancers. Mechanistic details of the miRNAs-mediated regulation of multiple biological functions are under constant investigation, and a number of miRNAs are now believed to influence growth, proliferation, invasion, metastasis, chemoresistance and the relapse of different GCs. Modulation of tumor microenvironment by miRNAs can possibly explain some of their reported biological effects. miRNA signatures have been proposed as biomarkers for the early detection of GCs, even the various subtypes of individual GCs. miRNA signatures are also being pursued as predictors of response to therapies. This review catalogs the knowledge gained from collective studies, so as to assess the progress made so far. It is time to ponder over the knowledge gained, so that more meaningful pre-clinical and translational studies can be designed to better realize the potential that miRNAs have to offer.

Emerging evidence for the role of differential tumor microenvironment in breast cancer racial disparity: a closer look at the surroundings.

Although increased awareness leading to early detection and prevention, as well as advancements in treatment strategies, have resulted in superior clinical outcomes, African American women with breast cancer continue to have greater mortality rates, compared to Caucasian American counterparts. Moreover, African American women are more likely to have breast cancer at a younger age and be diagnosed with aggressive tumor sub-types. Such racial disparities can be attributed to socioeconomic differences, but it is increasingly being recognized that these disparities may indeed be due to certain genetic and other non-genetic biological differences. Tumor microenvironment, which provides a favorable niche for the growth of tumor cells, is comprised of several types of stromal cells and the various proteins secreted as a consequence of bi-directional tumor-stromal cross-talk. Emerging evidence suggests inherent biological differences in the tumor microenvironment of breast cancer patients from different racial backgrounds. Tumor microenvironment components, affected by the genetic make-up of the tumor cells as well as other non-tumor-associated factors, may also render patients more susceptible to the development of aggressive tumors and faster progression of disease resulting in early onset, thus adversely affecting patients' survival. This review provides an overview of breast cancer racial disparity and discusses the existence of race-associated differential tumor microenvironment and its underlying genetic and non-genetic causal factors. A better understanding of these aspects would help further research on effective cancer management and improved approaches for reducing the racial disparities gaps in breast cancer patients.

Exploring quantum Griffiths phase in Ni1-x V x nanoalloys.

Metallic Ni1-x V x alloys exhibit a ferromagnetic to paramagnetic disordered quantum phase transition in bulk. Such a phase transition is accompanied by a quantum Griffiths phase (QGP), featuring fractional power-law temperature dependences of physical variables, like magnetic susceptibility and specific heat, at low temperatures. As nanoparticles (NP's) usually exhibit properties significantly different from their bulk counterparts, it is intriguing to explore the occurrence of quantum Griffiths phase in Ni1-x V x nanoalloys. NP's of Ni1-x V x (0 ≤ x ≤ 0.17) alloys are prepared by a chemical reflux method. The structure and composition of the nanoalloys are determined by X-ray diffraction, X-ray photoelectron spectroscopy and electron microscopy techniques. Metallicity of the samples has been ensured by electrical resistivity measurements. DC magnetization results suggest that ferromagnetism persists in the NP's until x = 0.17. Low-temperature upturns in magnetic susceptibility and heat capacity hint at critical fluctuations evolving with V-doping. The fluctuations might stem from isolated Ni-clusters within the ferromagnetic NP, indicating a QGP region ranging from x = 0.085 to x ≫ 0.17.

Resistin potentiates chemoresistance and stemness of breast cancer cells: Implications for racially disparate therapeutic outcomes.

Breast cancer (BC) continues to be the most frequently diagnosed cancer in American women, which disproportionately affects women of African-American (AA) descent. Previously, we reported greater serum levels of resistin in AA BC patients relative to Caucasian-American (CA) patients, and established its role in growth and aggressiveness of breast tumor cells. Here we have investigated the role of resistin in BC-chemoresistance. MDA-MB-231 and MDA-MB-468 BC cells of CA and AA origin, respectively, were incubated with resistin prior to doxorubicin treatment. Our data suggest that resistin conferred chemoresistance to both BC cell lines; however, the effect on AA cells was more profound. Furthermore, the resistin-induced doxorubicin-resistance was shown to occur due to suppression of apoptosis. Resistin treatment also affected the stemness of BC cells, as suggested by reduced cell surface expression of CD24, induced expression of CD44 and ALDH1, and increased capability of cells to form mammospheres. Mechanistic studies revealed that resistin-induced chemoresistance, apoptosis and stemness of BC cells were mediated through STAT3 activation. Taken together, our findings provide novel insight into the role of resistin in BC biology, and strengthen its role in racially disparate clinical outcomes.

Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK.

BACKGROUND: Chemoresistance is a significant clinical problem in pancreatic cancer (PC) and underlying molecular mechanisms still remain to be completely understood. Here we report a novel exosome-mediated mechanism of drug-induced acquired chemoresistance in PC cells. METHODS: Differential ultracentrifugation was performed to isolate extracellular vesicles (EVs) based on their size from vehicle- or gemcitabine-treated PC cells. Extracellular vesicles size and subtypes were determined by dynamic light scattering and marker profiling, respectively. Gene expression was examined by qRT-PCR and/or immunoblot analyses, and direct targeting of DCK by miR-155 was confirmed by dual-luciferase 3'-UTR reporter assay. Flow cytometry was performed to examine the apoptosis indices and reactive oxygen species (ROS) levels in PC cells using specific dyes. Cell viability was determined using the WST-1 assay. RESULTS: Conditioned media (CM) from gemcitabine-treated PC cells (Gem-CM) provided significant chemoprotection to subsequent gemcitabine toxicity and most of the chemoresistance conferred by Gem-CM resulted from its EVs fraction. Sub-fractionation grouped EVs into distinct subtypes based on size distribution and marker profiles, and exosome (Gem-Exo) was the only sub-fraction that imparted chemoresistance. Gene expression analyses demonstrated upregulation of SOD2 and CAT (ROS-detoxifying genes), and downregulation of DCK (gemcitabine-metabolising gene) in Gem-Exo-treated cells. SOD/CAT upregulation resulted, at least in part, from exosome-mediated transfer of their transcripts and they suppressed basal and gemcitabine-induced ROS production, and partly promoted chemoresistance. DCK downregulation occurred through exosome-delivered miR-155 and either the functional suppression of miR-155 or restoration of DCK led to marked abrogation of Gem-Exo-mediated chemoresistance. CONCLUSIONS: Together, these findings establish a novel role of exosomes in mediating the acquired chemoresistance of PC.

Biological basis of cancer health disparities: resources and challenges for research.

Last few decades have witnessed remarkable progress in our understanding of cancer initiation and progression leading to refinement of prevention and treatment approaches. Although these advances have improved the survival of cancer patients in general, certain racial/ethnic groups have benefited only partially. Footprints of cancer-associated racial disparities are very much evident in cancers of the prostate, breast, cervical, colorectal, endometrium, liver and lung. These health inequalities are mostly attributed to socioeconomic differences among races, but there is a growing realization that these may actually be due to inherent biological differences as well. Indeed, significant data now exist to support the biological basis of racial disparities in cancer, warranting basic research investigations, using appropriate tools and model systems. In this article, we have aimed to succinctly review the literature supporting the biological bases of racial disparities in cancer, along with available resources, databases and model systems that will be of interest to researchers. Moreover, we have highlighted the specific areas that need attention in terms of development of resources and/or tools, and discuss the opportunities and challenges in basic biological research in cancer health disparities.

Racial disparities in prostate cancer: a molecular perspective.

Prostate cancer incidence and mortality rates are remarkably higher in African-American men as compared to their European-Americans counterparts. Despite these recognitions, precise causes underlying such prevalent racial disparities remain poorly understood. Although socioeconomic factors could account for such differences up to a certain extent, it is now being increasingly realized that such disparity has a molecular basis. Indeed, several differences, including genetic polymorphism, gene mutations, epigenetic modifications, miRNAs alterations, etc., have been reported in malignant prostate tissues from patients of diverse racial backgrounds. Here, we attempt to provide a molecular perspective on prostate cancer racial disparities by gathering available information on these associated factors and discussing their potential significance in disproportionate incidence and clinical outcomes.

Comparative analysis of the relative potential of silver, Zinc-oxide and titanium-dioxide nanoparticles against UVB-induced DNA damage for the prevention of skin carcinogenesis.

Sunscreen formulations containing UVB filters, such as Zinc-oxide (ZnO) and titanium-dioxide (TiO2) nanoparticles (NPs) have been developed to limit the exposure of human skin to UV-radiations. Unfortunately, these UVB protective agents have failed in controlling the skin cancer incidence. We recently demonstrated that silver nanoparticles (Ag-NPs) could serve as novel protective agents against UVB-radiations. Here our goal was to perform comparative analysis of direct and indirect UVB-protection efficacy of ZnO-, TiO2- and Ag-NPs. Sun-protection-factor calculated based on their UVB-reflective/absorption abilities was the highest for TiO2-NPs followed by Ag- and ZnO-NPs. This was further confirmed by studying indirect protection of UVB radiation-induced death of HaCaT cells. However, only Ag-NPs were active in protecting HaCaT cells against direct UVB-induced DNA-damage by repairing bulky-DNA lesions through nucleotide-excision-repair mechanism. Moreover, Ag-NPs were also effective in protecting HaCaT cells from UVB-induced oxidative DNA damage by enhancing SOD/CAT/GPx activity. In contrast, ZnO- and TiO2-NPs not only failed in providing any direct protection from DNA-damage, but rather enhanced oxidative DNA-damage by increasing ROS production. Together, these findings raise concerns about safety of ZnO- and TiO2-NPs and establish superior protective efficacy of Ag-NPs.

Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor-stromal cross-talk.

The poor clinical outcome of pancreatic cancer (PC) is largely attributed to its aggressive nature and refractoriness to currently available therapeutic modalities. We previously reported antitumor efficacy of honokiol (HNK), a phytochemical isolated from various parts of Magnolia plant, against PC cells in short-term in vitro growth assays. Here, we report that HNK reduces plating efficiency and anchorage-independent growth of PC cells and suppresses their migration and invasiveness. Furthermore, significant inhibition of pancreatic tumor growth by HNK is observed in orthotopic mouse model along with complete-blockage of distant metastases. Histological examination suggests reduced desmoplasia in tumors from HNK-treated mice, later confirmed by immunohistochemical analyses of myofibroblast and extracellular matrix marker proteins (α-SMA and collagen I, respectively). At the molecular level, HNK treatment leads to decreased expression of sonic hedgehog (SHH) and CXCR4, two established mediators of bidirectional tumor-stromal cross-talk, both in vitro and in vivo . We also show that the conditioned media (CM) from HNK-treated PC cells have little growth-inducing effect on pancreatic stellate cells (PSCs) that could be regained by the addition of exogenous recombinant SHH. Moreover, pretreatment of CM of vehicle-treated PC cells with SHH-neutralizing antibody abolishes their growth-inducing potential on PSCs. Likewise, HNK-treated PC cells respond poorly to CM from PSCs due to decreased CXCR4 expression. Lastly, we show that the transfection of PC cells with constitutively active IKKß mutant reverses the suppressive effect of HNK on nuclear factor-kappaB activation and partially restores CXCR4 and SHH expression. Taken together, these findings suggest that HNK interferes with tumor-stromal cross-talk via downregulation of CXCR4 and SHH and decreases pancreatic tumor growth and metastasis.

Deep sequencing and in silico analyses identify MYB-regulated gene networks and signaling pathways in pancreatic cancer.

We have recently demonstrated that the transcription factor MYB can modulate several cancer-associated phenotypes in pancreatic cancer. In order to understand the molecular basis of these MYB-associated changes, we conducted deep-sequencing of transcriptome of MYB-overexpressing and -silenced pancreatic cancer cells, followed by in silico pathway analysis. We identified significant modulation of 774 genes upon MYB-silencing (p < 0.05) that were assigned to 25 gene networks by in silico analysis. Further analyses placed genes in our RNA sequencing-generated dataset to several canonical signalling pathways, such as cell-cycle control, DNA-damage and -repair responses, p53 and HIF1α. Importantly, we observed downregulation of the pancreatic adenocarcinoma signaling pathway in MYB-silenced pancreatic cancer cells exhibiting suppression of EGFR and NF-κB. Decreased expression of EGFR and RELA was validated by both qPCR and immunoblotting and they were both shown to be under direct transcriptional control of MYB. These observations were further confirmed in a converse approach wherein MYB was overexpressed ectopically in a MYB-null pancreatic cancer cell line. Our findings thus suggest that MYB potentially regulates growth and genomic stability of pancreatic cancer cells via targeting complex gene networks and signaling pathways. Further in-depth functional studies are warranted to fully understand MYB signaling in pancreatic cancer.

MYB Promotes Desmoplasia in Pancreatic Cancer through Direct Transcriptional Up-regulation and Cooperative Action of Sonic Hedgehog and Adrenomedullin.

Extensive desmoplasia is a prominent pathological characteristic of pancreatic cancer (PC) that not only impacts tumor development, but therapeutic outcome as well. Recently, we demonstrated a novel role of MYB, an oncogenic transcription factor, in PC growth and metastasis. Here we studied its effect on pancreatic tumor histopathology and associated molecular and biological mechanisms. Tumor-xenografts derived from orthotopic-inoculation of MYB-overexpressing PC cells exhibited far-greater desmoplasia in histological analyses compared with those derived from MYB-silenced PC cells. These findings were further confirmed by immunostaining of tumor-xenograft sections with collagen-I, fibronectin (major extracellular-matrix proteins), and α-SMA (well-characterized marker of myofibroblasts or activated pancreatic stellate cells (PSCs)). Likewise, MYB-overexpressing PC cells provided significantly greater growth benefit to PSCs in a co-culture system as compared with the MYB-silenced cells. Interrogation of deep-sequencing data from MYB-overexpressing versus -silenced PC cells identified Sonic-hedgehog (SHH) and Adrenomedullin (ADM) as two differentially-expressed genes among others, which encode for secretory ligands involved in tumor-stromal cross-talk. In-silico analyses predicted putative MYB-binding sites in SHH and ADM promoters, which was later confirmed by chromatin-immunoprecipitation. A cooperative role of SHH and ADM in growth promotion of PSCs was confirmed in co-culture by using their specific-inhibitors and exogenous recombinant-proteins. Importantly, while SHH acted exclusively in a paracrine fashion on PSCs and influenced the growth of PC cells only indirectly, ADM could directly impact the growth of both PC cells and PSCs. In summary, we identified MYB as novel regulator of pancreatic tumor desmoplasia, which is suggestive of its diverse roles in PC pathobiology.

p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling.

Pancreatic cancer (PC) remains a highly lethal malignancy due to its unusual chemoresistance and high aggressiveness. A subpopulation of pancreatic tumor cells, known as cancer stem cells (CSCs), is considered responsible not only for tumor-maintenance, but also for its widespread metastasis and therapeutic failure. Here we investigated the role of p-21 activated kinase 4 (PAK4) in driving PC stemness properties. Our data demonstrate that triple-positive (CD24(+)/CD44(+)/EpCAM(+)) subpopulation of pancreatic CSCs exhibits greater level of PAK4 as compared to triple-negative (CD24(-)/CD44(-)/EpCAM(-)) cells. Moreover, PAK4 silencing in PC cells leads to diminished fraction of CD24, CD44, and EpCAM positive cells. Furthermore, we show that PAK4-silenced PC cells exhibit decreased sphere-forming ability and increased chemosensitivity to gemcitabine toxicity. PAK4 expression is also associated with enhanced levels of stemness-associated transcription factors (Oct4/Nanog/Sox2 and KLF4). Furthermore, our data show decreased nuclear accumulation and transcriptional activity of STAT3 in PAK4-silenced PC cells and restitution of its activity leads to restoration of stem cell phenotypes. Together, our findings deliver first experimental evidence for the involvement of PAK4 in PC stemness and support its clinical utility as a novel therapeutic target in PC.

MYB is a novel regulator of pancreatic tumour growth and metastasis.

BACKGROUND: MYB encodes for a transcription factor regulating the expression of a wide array of genes involved in cellular functions. It is reported to be amplified in a sub-set of pancreatic cancer (PC) cases; however, its pathobiological association has remained unclear thus far. METHODS: Expression of MYB and other cellular proteins was analysed by immunoblot or qRT-PCR analyses. MYB was stably overexpressed in non-expressing (BxPC3) and silenced in highly expressing (MiaPaCa and Panc1) PC cells. Effect on growth was analysed by automated cell counting at 24-h interval. Cell-cycle progression and apoptotic indices of PC cells with altered MYB expression were measured through flow cytometry upon staining with respective biomarkers. Cell motility/invasion was examined in a Boyden's chamber assay using non-coated or Matrigel-coated membranes. Effect on tumorigenicity and metastatic potential was examined by non-invasive imaging and through end-point measurements of luciferase-tagged MYB-altered PC implanted in the pancreas of nude mice. RESULTS: MYB was aberrantly expressed in all malignant cases of pancreas, whereas remained undetectable in normal pancreas. All the tested established PC cell lines except BxPC3 also exhibited MYB expression. Forced expression of MYB in BxPC3 cells promoted their growth, cell-cycle progression, survival and malignant behaviour, whereas its silencing in MiaPaCa and Panc1 cells produced converse effects. More importantly, ectopic MYB expression was sufficient to confer tumorigenic and metastatic capabilities to non-tumorigenic BxPC3 cells, while its silencing resulted in significant loss of the same in MYB-overexpressing cells as demonstrated in orthotopic mouse model. We also identified several MYB-regulated genes in PC cells that might potentially mediate its effect on tumour growth and metastasis. CONCLUSIONS: MYB is aberrantly overexpressed in PC cells and acts as a key determinant of pancreatic tumour growth and metastasis.

Development and Characterization of a Novel in vitro Progression Model for UVB-Induced Skin Carcinogenesis.

Epidemiological studies suggest ultraviolet B (UVB) component (290-320 nm) of sun light is the most prevalent etiologic factor for skin carcinogenesis--a disease accounting for more than two million new cases each year in the USA alone. Development of UVB-induced skin carcinoma is a multistep and complex process. The molecular events that occur during UVB-induced skin carcinogenesis are poorly understood largely due to the lack of an appropriate cellular model system. Therefore, to make a progress in this area, we have developed an in vitro model for UVB-induced skin cancer using immortalized human epidermal keratinocyte (HaCaT) cells through repetitive exposure to UVB radiation. We demonstrate that UVB-transformed HaCaT cells gain enhanced proliferation rate, apoptosis-resistance, and colony- and sphere-forming abilities in a progressive manner. Moreover, these cells exhibit increased aggressiveness with enhanced migration and invasive potential and mesenchymal phenotypes. Furthermore, these derived cells are able to form aggressive squamous cell carcinoma upon inoculation into the nude mice, while parental HaCaT cells remain non-tumorigenic. Together, these novel, UVB-transformed progression model cell lines can be very helpful in gaining valuable mechanistic insight into UVB-induced skin carcinogenesis, identification of novel molecular targets of diagnostic and therapeutic significance, and in vitro screening for novel preventive and therapeutic agents.

MicroRNA-345 induces apoptosis in pancreatic cancer cells through potentiation of caspase-dependent and -independent pathways.

BACKGROUND: Previously, miR-345 was identified as one of the most significantly downregulated microRNAs in pancreatic cancer (PC); however, its functional significance remained unexplored. METHODS: miR-345 was overexpressed in PC cells by stable transfection, and its effect on growth, apoptosis and mitochondrial-membrane potential was examined by WST-1, Hoechst-33342/Annexin-V, and JC-1 staining, respectively. Gene expression was examined by quantitative reverse-transcription-PCR and/or immunoblotting, and subcellular fractions prepared and caspase-3/7 activity determined by commercially available kits. miR-345 target validation was performed by mutational analysis and luciferase-reporter assay. RESULTS: miR-345 is significantly downregulated in PC tissues and cell lines relative to normal pancreatic cells, and its expression decreases gradually in PC progression model cell lines. Forced expression of miR-345 results in reduced growth of PC cells because of the induction of apoptosis, accompanied by a loss in mitochondrial membrane potential, cytochrome-c release, caspases-3/7 activation, and PARP-1 cleavage, as well as mitochondrial-to-nuclear translocation of apoptosis-inducing factor. These effects could be reversed by the treatment of miR-345-overexpressing PC cells with anti-miR-345 oligonucleotides. BCL2 was characterised as a novel target of miR-345 and its forced-expression abrogated the effects of miR-345 in PC cells. CONCLUSIONS: miR-345 downregulation confers apoptosis resistance to PC cells, and its restoration could be exploited for therapeutic benefit.