The emerging role of miR-200 family in metastasis: focus on EMT,CSCs, angiogenesis,and anoikis

Introduction

Cancer is the second major threat to human society and one of the main challenges facing healthcare systems. One of the main problems of cancer care is the metastases of cancer cells that cause 90% of deaths due to cancer. Multiple molecular mechanisms are involved in cancer cell metastasis. Therefore, a better understanding of these molecular mechanisms is necessary for designing restrictive strategies against cancer cell metastasis. Accumulating data suggests that MicroRNAs (miRNAs) are involved in metastasis and invasion of human tumors through regulating multiple genes expression levels that are involved in molecular mechanisms of metastasis. The goal of this review is to present the molecular pathways by which the miR 200 family manifests its effects on EMT, cancer stem cells, angiogenesis, anoikis, and the effects of tumor cell metastases.

Methods

A detailed literature search was conducted to find information about the role of the miR-200 family in the processes involved in metastasis in various databases.

Results

Numerous lines of evidence revealed an association between the mir-200 family and metastasis of human tumors by impressing processes such as cancer stem cells, EMT, angiogenesis, and anoikis.

Conclusions

Understanding the molecular mechanisms associated with metastasis in which the miR-200 family is involved can be effective in treating metastatic cancers.

Graphic abstract

     

Synaptic mutation-driven male sterility in Panax sikkimensis Ban. (Araliaceae) from Eastern Himalaya, India

In higher plants, synaptic mutation-associated gametic abnormalities are reported mostly in crop plants, but studies have rarely focused on the natural plant populations. This is particularly so in threatened herbaceous perennials, some of which are known to suffer from loss of sexual reproduction driven by the genetic mutations. Cytological investigations of Panax species, viz. P. sikkimensis, P. sokpayensis and P. bipinnatifidus, revealed that all the species were diploid with 2n = 24 chromosomes. Natural occurrence of synaptic mutation was recorded in Panax sikkimensis in the Kalep population of North Sikkim, India. We recorded that 86.03% of pollen mother cells (PMCs) lacked bivalent formation and had 24 distinct univalents at prophase I in the mutant plants of P. sikkimensis. We found a significantly lower mean number of chiasmata per cell (0.31 ± 0.91; t test = 38.24, P < 0.001) in the mutant plants as compared to the normal plants (21.04 ± 4.56). The chromosomal associations in the PMCs of the synaptic mutants ranged from 25% bivalents and 75% univalents to 100% univalents at diplotene/diakinesis. The unequal distribution of chromosomes at anaphase I and II resulted in the formation of microspores and microcytes of differing sizes. The pollen stainability test in the mutant population of P. sikkimensis revealed very low (0.12%) pollen fertility reflecting the consequences of synaptic mutation. Synaptic mutation in the herbaceous perennial P. sikkimensis was considered to be responsible for the male sterility in the species.     

Insulin: Its binding to specific receptors and its stimulation of DNA synthesis and 2′,3′-cyclic nucleotide phosphohydrolase activity in cerebral cells cultured from embryonic mouse brain

The presence and specificity of insulin receptors was investigated in cultured cells obtained from 15–16 days old embryonic mouse cerebra. Developmental studies suggested that the maximum insulin binding occurred at about 11 days in vitro (DIV). Scatchard analysis of binding data revealed two types of binding sites. One type of receptor was the high affinity type (K _d=7.77×10^–9 M; number of receptor sites,B _max=350 fmol/mg protein) while the other type was of low affinity type (K _d=5.75×10^–8 M;B _max=1150 fmol/mg protein). The specificity of receptors for insulin was also confirmed by showing that [¹²⁵I]insulin was displaced by non-radioactive insulin but not by glucagon or growth hormone. Insulin displayed a clear dose-dependent stimulation of thymidine incorporation. It also stimulated the activity of the enzyme 2,3-cyclic nucleotide phosphohydrolase (CNPase), which is specifically associated with myelin produced from oligodendroglia. Thus insulin has a positive influence on the proliferation and differentiation of brain cells.     

Microbial transformation of heterocyclic molecules in deep subsurface sediments

Recently attempts have been made to establish the presence and to determine the metabolic versatility of microorganisms in the terrestrial deep subsurface at the Savannah River Plant, Aiken, SC, USA. Sediment samples obtained at 20 different depths of up to 526 m were examined to determine carbon mineralization under aerobic, sulfate-reducing, and methanogenic conditions. The evolution of¹⁴CO₂ from radiolabelled glucose was observed under aerobic conditions in all sediments, whereas pyridine was transformed in 50% of the 20 sediments and indole was metabolized in 85% of the sediments. Glucose mineralization in certain sediments was comparable to that in the surface environment. Sulfate was reduced in only five sediments, and two were carbon limited. Methane production was detected in ten sediments amended with formate only after long-term incubations. The transformation of indole and pyridine was only rarely observed under sulfate-reducing conditions and was never detected in methanogenic incubations. This study provides information concerning the metabolic capability of both aerobic and anaerobic microorganisms in the deep subsurface and may prove useful in determining the feasibility of microbial decontamination of such environments.     

Phorbol ester receptors in cerebral cortex of cats with GM1 gangliosidosis

The pathogenesis of neuronal dysfunction in the gangliosidoses is poorly understood. Studies of the feline gangliosidoses and in vitro experiments implicate ganglioside inhibition of protein kinase C (PKC) in the pathogenesis of these neurological diseases. Therefore, in the present study, the binding of [³H]phorbol-12, 13 dibutyrate was measured to determine the levels of PKC in cerebral cortex of cats with GM₁ gangliosidosis (mutant) and age matched normal siblings. This binding of ([³H]PDB) to cerebral cortex homogenates in both normal and mutant cats was highly specific. The specificity of receptors was ascertained also from displacement studies using nonradioactive phorbol ester analogues to displace [³H]PDB bound to its receptors. In both mutant and normal cat brain, phorbol 12, 13-dibutyrate (PDB), 4--phorbol 12,13-didecanoate (-PDA) and 4--phorbol 12,13-dibenzoate (-PDBz) were highly potent (approximately to same degree) and effective in displacing [³H]PDB. On the other hand, 4- phorbol 12,13-diacetate (-PDA) was a weak displacer and 4--phorbol did not displace the bound [³H]PDB in either normal or mutant brain. Scatchard analysis of the binding data indicated a homogenous single class of binding sites in normal and mutant brain (Normal: K_d=1.42×10^–7 M, B_max=8.40 pmoles/mg protein. Mutant: K_d=1.60×10^–7 M, B_max=10.00 pmoles/mg protein). Sphingosine inhibited the binding to approximately the same extent in normal and mutant cortex. These studies demonstrate the presence of highly specific, homogenous, single type phorbol ester receptors in cerebral cortex of cats with GM₁ gangliosidosis which are qualitatively and quantitatively similar to normal cat brain.     

Kinetics of serotonin in platelets in essential hypertension.

In a study of the kinetics of 5-hydroxytryptamine (5-HT) in platelets in 26 hypertensive subjects with a mean systolic and diastolic blood pressure of 153.9 +/- 26.9 and 106.9 +/- 9.1 mm Hg respectively, it has been observed that in hypertensive platelets there was a marked decrease in 5-HT uptake and content, an increase in 5-HT efflux and an accompanying increase in Plasma 5-HT and 5-HIAA levels. Regression analysis of the data indicated a significant correlation between rise in diastolic blood pressure and these changes in 5-HT kinetics.     

Germinating pigeonpea (Cajanus cajan) seeds secrete factor(s) having antiethylene-like effects

Germinating pigeonpea seeds were found to release factor(s), which dramatically altered the growth pattern of rice seedlings. This included an increased sensitivity of roots to gravity, an increase in seminal root length, and increased density of branch roots on the seminal root and suppression of root hair formation. Furthermore, the known characteristic responses of rice to ethylene (namely, coleoptile growth promotion and induction of senescence) were inhibited by the presence of these factor(s). This altered growth pattern of rice seedlings was similar to that brought about by the ethylene-antagonist, silver nitrate. Further, the change in growth pattern in rice was specifically reversed by ethrel. In addition, in wild-type Arabidopsis thaliana these factors suppressed formation of root hair, the development of which is known to be promoted by ethylene. In contrast, in a mutant A. thaliana which shows constitutive ethylene response ( ctr1-1 ), the factors failed to inhibit root hair formation. These observations indicated that germinating pigeonpea seeds secrete factor(s), which have antiethylene-like effects.     

Modulatory effects of metanil yellow on immunity in rodents.

Pathomorphological and immunological studies were carried out on rodents following oral administration of 0, 0.1, 0.25 and 0.5% (w/w) metanil yellow, mixed in diet, for 30 days. No significant change in hematologic parameters and histologic architecture of liver, kidney, mesenteric lymph node, thymus and urinary bladder was observed except for mild desquamation of intestinal villi and moderate changes in Peyer's patches of small intestine with higher doses. Among immunological parameters, significant enhancement in the primary humoral immune response (anti-SRBC IgM plaque forming cells of spleen) was observed with the lowest dose of metanil yellow while higher doses produced opposing effects. An elevated cutaneous delayed type hypersensitivity (DTH) reaction to SRBC was seen in 0.1% metanil yellow treated animals but higher doses did not influence the reaction. The treatment also caused changes in functional capabilities of macrophages. Although these immune alterations could hardly influence the local immunity of gut, as measured by the capacity of animals to cause rejection of Nippostrongylus brasiliensis parasite, the potential to modulate the immunity in general by metanil yellow however assumes considerable biological significance.     

Chaos game representation of coding regions of human globin genes and alcohol dehydrogenase genes of phylogenetically divergent species

Summary Chaos game representation (CGR) is a novel holistic approach that provides a visual image of a DNA sequence quite different from the traditional linear arrangement of nucleotides. Although it is known that CGR patterns depict base composition and sequentiality, the biological significance of the specific features of each pattern is not understood. To systematically examine these features, we have examined the coding sequences of 7 human globin genes and 29 relatively conserved alcohol dehydrogenase (Adh) genes from phylogenetically divergent species. The CGRs of human globin cDNAs were similar to one another and to the entire human globin gene complex. Interestingly, human globin CGRs were also strikingly similar to human Adh CGRs. Adh CGRs were similar for genes of the same or closely related species but were different for relatively conserved Adh genes from distantly related species. Dinucleotide frequencies may account for the self-similar pattern that is characteristic of vertebrate CGRs and the genome-specific features of CGR patterns. Mutational frequencies of dinucleotides may vary among genome types. The special features of CG dinucleotides of vertebrates represent such an example. The CGR patterns examined thus far suggest that the evolution of a gene and its coding sequence should not be examined in isolation. Consideration should be given to genome-specific differential mutation rates for different dinucleotides or specific oligonucleotides. Offprint requests to: S. M. Singh