MicroRNA deregulation is frequent in human colorectal cancers (CRCs), but little is known as to whether it represents a bystander event or actually drives tumor progression in vivo. We show that ...miR-135b overexpression is triggered in mice and humans by APC loss, PTEN/PI3K pathway deregulation, and SRC overexpression and promotes tumor transformation and progression. We show that miR-135b upregulation is common in sporadic and inflammatory bowel disease-associated human CRCs and correlates with tumor stage and poor clinical outcome. Inhibition of miR-135b in CRC mouse models reduces tumor growth by controlling genes involved in proliferation, invasion, and apoptosis. We identify miR-135b as a key downsteam effector of oncogenic pathways and a potential target for CRC treatment.
•miR-135b is overexpressed in mouse and human colorectal cancer•miR-135b overexpression is associated with poor clinical outcome•miR-135b activation is triggered by oncogenic pathways in colorectal cancer•miR-135b represents a therapeutic target for colorectal cancer
Valeri et al. identify miR-135b as a key oncogenic pathway effector involved in transformation and colorectal cancer (CRC) progression. Upregulation of miR-135b in human CRCs correlates with poor clinical outcome. miR-135b targets several tumor suppressor genes and is a potential target for CRC therapy.
Several evidence suggests that, in addition to the respiratory tract, also the gastrointestinal tract is a main site of severe acute respiratory syndrome CoronaVirus 2 (SARS‐CoV‐2) infection, as an ...example of a multi‐organ vascular damage, likely associated with poor prognosis. To assess mechanisms SARS‐CoV‐2 responsible of tissue infection and vascular injury, correlating with thrombotic damage, specimens of the digestive tract positive for SARS‐CoV‐2 nucleocapsid protein were analyzed deriving from three patients, negative to naso‐oro‐pharyngeal swab for SARS‐CoV‐2. These COVID‐19–negative patients came to clinical observation due to urgent abdominal surgery that removed different sections of the digestive tract after thrombotic events. Immunohistochemical for the expression of SARS‐CoV‐2 combined with a panel of SARS‐CoV‐2 related proteins angiotensin‐converting enzyme 2 receptor, cluster of differentiation 147 (CD147), human leukocyte antigen‐G (HLA‐G), vascular endothelial growth factor (VEGF) and matrix metalloproteinase‐9 was performed. Tissue samples were also evaluated by electron microscopy for ultrastructural virus localization and cell characterization. The damage of the tissue was assessed by ultrastructural analysis. It has been observed that CD147 expression levels correlate with SARS‐CoV‐2 infection extent, vascular damage and an increased expression of VEGF and thrombosis. The confirmation of CD147 co‐localization with SARS‐CoV‐2 Spike protein binding on gastrointestinal tissues and the reduction of the infection level in intestinal epithelial cells after CD147 neutralization, suggest CD147 as a possible key factor for viral susceptibility of gastrointestinal tissue. The presence of SARS‐CoV‐2 infection of gastrointestinal tissue might be consequently implicated in abdominal thrombosis, where VEGF might mediate the vascular damage.
Brief Reports
Severe Acute Respiratory Syndrome CoronaVirus 2 could infect digestive tissues regardless of respiratory tract. Cluster of differentiation 147 might increase viral susceptibility of virus entry into these tissues and vascular endothelial growth factor performs a pivotal thrombotic function.
Inactivation of mismatch repair (MMR) is the cause of the common cancer predisposition disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), as well as 10–40% ...of sporadic colorectal, endometrial, ovarian, gastric, and urothelial cancers. Elevated mutation rates (mutator phenotype), including simple repeat instability microsatellite instability (MSI) are a signature of MMR defects. MicroRNAs (miRs) have been implicated in the control of critical cellular pathways involved in development and cancer. Here we show that overexpression of miR-155 significantly down-regulates the core MMR proteins, hMSH2, hMSH6, and hMLH1, inducing a mutator phenotype and MSI. An inverse correlation between the expression of miR-155 and the expression of MLH1 or MSH2 proteins was found in human colorectal cancer. Finally, a number of MSI tumors with unknown cause of MMR inactivation displayed miR-155 overexpression. These data provide support for miR-155 modulation of MMR as a mechanism of cancer pathogenesis.
Late‐onset Intrauterine growth restriction (IUGR) refers to impaired growth and development of the fetus, characterized by placental morphological abnormalities that affect the fetus's supply of ...nutrients. Human leukocyte antigen‐G (HLA‐G) is physiologically expressed during pregnancy, but decreased in normal placenta during the last weeks of gestation possibly inducing childbirth. Several viruses involved in congenital infection, such as herpesviruses, exploit HLA‐G expression as an immune‐escape mechanism. To date, despite different congenital herpetic infections having been associated with late IUGR, no direct implication of Human herpesvirus 6 (HHV‐6) infection has been reported. We evaluated HLA‐G expression and HHV‐6 infection in 11 placentas from late‐onset IUGR newborns and 11 placentas from uncomplicated pregnancies by histopathological and immunohistochemistry analysis. We found higher levels of HLA‐G expression and HHV‐6 presence in IUGR placenta samples compared with control placenta samples. We report HHV‐6 staining in IUGR placenta samples, characterized by high HLA‐G expression. These preliminary data suggest a possible involvement of HHV‐6 infection in HLA‐G deregulation that might affect vessel remodeling and prevent the correct pregnancy outcome in the IUGR condition.
Highlights
This is a retrospective analysis describing the role of HLA‐G expression and HHV‐6 infection in late‐onset intrauterine growth restriction (IUGR) placenta samples.
For the first time it has been suggested a possible involvement of HHV‐6 infection in HLA?G deregulation that might affect vessel remodeling and prevent the correct pregnancy outcome in the IUGR condition.
Uncontrolled inflammatory response arising from the tumor microenvironment (TME) significantly contributes to cancer progression, prompting an investigation and careful evaluation of ...counter-regulatory mechanisms. We identified a trimeric complex at the mitochondria-associated membranes (MAMs), in which the purinergic P2X7 receptor - NLRP3 inflammasome liaison is fine-tuned by the tumor suppressor PML. PML downregulation drives an exacerbated immune response due to a loss of P2X7R-NLRP3 restraint that boosts tumor growth. PML mislocalization from MAMs elicits an uncontrolled NLRP3 activation, and consequent cytokines blast fueling cancer and worsening the tumor prognosis in different human cancers. New mechanistic insights are provided for the PML-P2X7R-NLRP3 axis to govern the TME in human carcinogenesis, fostering new targeted therapeutic approaches.
Adenosine is a ubiquitous nucleoside that accumulates at high levels in hypoxic regions of solid tumors, and A(3) adenosine receptors have been recently demonstrated to play a pivotal role in the ...adenosine-mediated inhibition of tumor cell proliferation. In the present work, we addressed the question of the putative relevance of A(3) subtypes in colorectal adenocarcinomas.
Seventy-three paired samples of tumor and surrounding peritumoral normal mucosa at a distance of 2 and 10 cm from the tumor and blood samples obtained from a cohort of 30 patients with colorectal cancer were investigated to determine the presence of A(3) receptors by means of binding, immunocytochemistry, and real-time reverse transcription-polymerase chain reaction studies.
As measured by receptor binding assays, the density of A(3) receptor was higher in colon carcinomas as compared with normal mucosa originating from the same individuals (P < 0.05). Overexpression of A(3) receptors at the protein level was confirmed by immunohistochemical studies, whereas no changes in A(3) mRNA accumulation in tumors as compared with the corresponding normal tissue were revealed. The overexpression of A(3) receptors in tumors was reflected in peripheral blood cells, where the density was approximately 3-fold higher compared with healthy subjects (P < 0.01). In a cohort of 10 patients studied longitudinally, expression of A(3) receptors in circulating blood cells returned to normal after surgical resection for colorectal cancer.
This study provides the first evidence that A(3) receptor plays a role in colon tumorigenesis and, more importantly, can potentially be used as a diagnostic marker or a therapeutic target for colon cancer.
Recent studies reported a differential expression of both ACE2 and CD147 in pregnant women associated to SARS-CoV-2 placental infection. The aim of this study is to further investigate the placental ...SARS-CoV-2 infection and the potential effect on protein expression (ACE2, CD147, HLA-G and CD56).
The study was on three subgroups: i) 18 subjects positive for SARS-CoV-2 swab at delivery; ii) 9 subjects that had a positive SARS-CoV-2 swab during pregnancy but resulted negative at delivery; iii) 11 control subjects with physiological pregnancy and with no previous or concomitant SARS-CoV-2 swab positivity. None of the subjects were vaccinated for SARS-CoV-2 infection. The placenta samples were analyzed for SARS-CoV-2 NP (Nucleocapsid protein) positivity and the expression of ACE2, CD147, HLA-G and CD56.
We observed a higher percentage of SARS-CoV-2 NP positive placenta samples in the group of SARS-CoV-2 PCR positive at delivery in comparison with SARS-CoV-2 PCR negative at delivery. The localization of SARS-CoV-2 NP positivity in placenta samples was mainly in syncytiotrophoblast (ST) of SARS-CoV-2 PCR positive at delivery group and in extra-villous trophoblast (EVT) of SARS-CoV-2 PCR negative at delivery group. CD147, HLA-G positivity was higher in ST of SARS-CoV-2 PCR positive at delivery group, while CD56-expressing immune cells were decreased in comparison with control subjects.
We confirmed the ability of SARS-CoV-2 to infect placenta tissues. The simultaneous SARS-CoV-2 swab positivity at delivery and the positivity of the placenta tissue for SARS-CoV-2 NP seems to create an environment that modifies the expression of specific molecules, as CD147 and HLA-G. These data suggest a possible impact of SARS-CoV-2 infection during pregnancy, that might be worthy to be monitored also in vaccinated subjects.
•SARS-CoV-2 infects placenta tissues.•CD147 and HLA-G positivity was higher in SARS-CoV-2 positive women at delivery.•CD56-expressing immune cells decreased in SARS-CoV-2 positive women at delivery.•SARS-CoV-2 positive pregnant women must be monitored for pregnancy follow-up.•SARS-CoV-2 positive pregnant women must be monitored for clinical manifestations.
To evaluate the in vitro effect of tofacitinib on autophagy activity of psoriatic arthritis (PsA) fibroblast-like synoviocytes (FLS), and to confirm its activity on inflammatory and invasive ...properties of FLS and synovial cells, deepening the impact on mitochondrial function.
FLS, peripheral blood mononuclear cells (PBMCs), and synovial cells from active PsA patients were cultured with tofacitinib 1 μM or vehicle control for 24 h. Autophagy was measured by Western blot and by fluorescence microscopy. Chemokines/cytokines released into culture supernatants were quantified by ELISA, while invasive properties of FLS by migration assays. Specific mitochondrial probes were adopted to measure intracellular reactive oxygen species (ROS), mitochondrial potential, morphology, turnover and mitophagy. Oxygen consumption rate (OCR), reflecting oxidative phosphorylation, was quantified using the Seahorse technology. Differences were determined by adopting the non-parametric Wilcoxon signed rank test.
18 patients with moderately-to-severely active PsA were enrolled. Tofacitinib significantly increased the levels of the autophagy markers LC3-II and ATG7 in PsA FLS compared to vehicle control, suggesting an increase in spontaneous autophagy activity; no effect was highlighted in PBMCs and synovial cells cultures. Tofacitinib reduced migration properties of PsA FLS, and reduced MCP-1 and IL-6 release into FLS and synovial cells cultures supernatants. Furthermore, tofacitinib decreased intracellular ROS production, increased basal OCR, ATP production and maximal respiratory capacity, and enhanced mitophagy and mitochondrial turnover.
The JAK inhibitor tofacitinib reduces the pro-invasive and pro-inflammatory properties of PsA FLS. Autophagy induction and mitochondrial quality control modulation by tofacitinib might contribute to FLS function restoration.
•Tofacitinib enhances autophagy and improves mitochondrial function in PsA FLS.•Autophagy induction by tofacitinib permits the removal of damaged mitochondria.•Healthier mitochondria contribute to a metabolic shift in FLS, reducing mitochondrial stress.•This study connects the anti-inflammatory and pro-metabolic activity of tofacitinib in PsA.
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