Long non-coding intergenic RNA, LINC00273 induces cancer metastasis and stemness via miRNA sponging in triple negative breast cancer.

LncRNAs and miRNAs, being the master regulators of gene expression, are crucial functional mediators in cancer. Our study unveils the critical regulatory role of the metastatic long non-coding RNA LINC00273 as the master regulator of oncogenes involved in cancer metastasis, stemness, and chemoresistance via its miRNA sponging mechanism. M2 (a salt of bis-Schiff base) mediated G quadruplex (G4) stabilization at the LINC00273 gene promoter remarkably inhibits LINC00273 transcription. Therefore, low-level LINC00273 transcripts are unable to efficiently sponge the miRNAs, which subsequently become available to bind and downregulate their target oncogenes. We have observed significantly different global transcriptomic scenarios in LINC00273 upregulated and downregulated circumstances in MDA-MB-231 triple-negative breast cancer model. Additionally, we have found the G4 sequence in the LINC00273 RNA to play a critical role in miRNA sequestration. miRNAs (miR-6789-5p, miR200b, miR-125b-5p, miR-4268, miR3978) have base pairing complementarity within the G4 region of LINC00273 RNA and the 3'-UTR (untranslated region) of MAPK12, TGF-ß1, and SIX-1 transcripts. We have reported TGF-ß1, SIX-1, and MAPK12 to be the direct downstream targets of LINC00273. The correlation between abnormal expression of lncRNA LINC00273 and TNBC aggressiveness strongly evidenced in our study shall accelerate the development of lncRNA-based anti-metastatic therapeutics.

Unraveling the structural aspects of the G-quadruplex in SMO promoter and elucidating its contribution in transcriptional regulation.

We located a 25 nt G-rich sequence in the promoter region of SMO oncogene. We performed an array of biophysical and biochemical assays and confirmed the formation of a parallel G quadruplex (SMO1-GQ) by the identified sequence. SMO1-GQ is highly conserved in primates. For a comprehensive characterization of the SMO quadruplex structure, we have performed spectroscopic and in silico analysis with established GQ binder small molecules TMPyP4 and BRACO-19. We observed comparatively higher stable interaction of BRACO-19 with SMO1-GQ. Structure-based, rational drug design against SMO1-GQ to target SMO oncogene requires a detailed molecular anatomy of the G-quadruplex. We structurally characterised the SMO1-GQ using DMS footprinting assay and molecular modelling, docking, and MD simulation to identify the probable atomic regions that interact with either of the small molecules. We further investigated SMO1-GQ in vivo by performing chromatin immunoprecipitation (ChIP) assay. ChIP data revealed that this gene element functions as a scaffold for a number of transcription factors: specificity protein (Sp1), nucleolin (NCL), non-metastatic cell 2 (NM23-H2), cellular nucleic acid binding protein (CNBP), and heterogeneous nuclear ribonucleoprotein K (hnRNPK) which reflects the SMO1-P1 G-quadruplex to be the master regulator of SMO1 transcriptional activity. The strong binding interaction detected between SMO1-GQ and BRACO-19 contemplates the potential of the G quadruplex as a promising anti-cancer druggable target to downregulate SMO1 oncogene driven cancers.Communicated by Ramaswamy H. Sarma.

Noncoding RNA as an influential epigenetic modulator with promising roles in cancer therapeutics.

The epigenetic landscape has an important role in cellular homeostasis and its deregulation leads to cancer. Noncoding (nc)RNA networks function as major regulators of cellular epigenetic hallmarks via regulation of vital processes, such as histone modification and DNA methylation. They are integral intracellular components affecting multiple oncogenic pathways. Thus, it is important to elucidate the effects of ncRNA networks on epigenetic programming that lead to the initiation and progression of cancer. In this review, we summarize the effects of epigenetic modification influenced by ncRNA networks and crosstalk between diverse classes of ncRNA, which could aid the development of patient-specific cancer therapeutics targeting ncRNAs, thereby altering cellular epigenetics.

Peptide therapeutics in the management of metastatic cancers.

Cancer remains a leading health concern threatening lives of millions of patients worldwide. Peptide-based drugs provide a valuable alternative to chemotherapeutics as they are highly specific, cheap, less toxic and easier to synthesize compared to other drugs. In this review, we have discussed various modes in which peptides are being used to curb cancer. Our review highlights specially the various anti-metastatic peptide-based agents developed by targeting a plethora of cellular factors. Herein we have given a special focus on integrins as targets for peptide drugs, as these molecules play key roles in metastatic progression. The review also discusses use of peptides as anti-cancer vaccines and their efficiency as drug-delivery tools. We hope this work will give the reader a clear idea of the mechanisms of peptide-based anti-cancer therapeutics and encourage the development of superior drugs in the future.

Targeting Ca2+ signaling: A new arsenal against cancer.

The drug resistance of cancer cells is a major concern in medical oncology, resulting in the failure of chemotherapy. Ca2+ plays a pivotal role in inducing multidrug resistance in cancer cells. Calcium signaling is a critical regulator of many cancer hallmarks, such as angiogenesis, invasiveness, and migration. In this review, we describe the involvement of Ca2+ signaling and associated proteins in cancer progression and in the development of multidrug resistance in cancer cells. We also highlight the possibilities and challenges of targeting the Ca2+ channels, transporters, and pumps involved in Ca2+ signaling in cancer cells through structure-based drug design. This work will open a new therapeutic window to be used against cancer in upcoming years.

Social Injustice in the Neoliberal Pandemic Era for Homeless Persons With Mental Illness: A Qualitative Inquiry From India.

The Corona Virus Disease 2019 (COVID-19) pandemic has presented an unprecedented challenge globally. It is much bigger than a bio-medical concern now with the multitudes of socio-economic, socio-political, socio-cultural, and psycho-social impact, which are likely to outlast the pandemic itself by far and long. The pandemic and the resulting challenges across societies highlighted the existing social injustices in a neoliberal world for historically marginalized populations like homeless persons with mental illness (HPMI). The nationwide lockdown in India to resist the spread of the virus posed a unique challenge to this vulnerable population. The present study thus attempts to understand the experience of HPMI during the COVID-19 induced lockdown through the theoretical framework of social justice vis-à-vis injustice. Semi-structured interviews have been conducted on seven HPMI rehabilitated in the community through an NGO situated in Kolkata, India. Seven stakeholders have also been interviewed to understand their experience in providing services to the HPMI during the COVID-19 induced lockdown. Analyses of the narratives have been done using initial coding, focused coding and axial coding through the process of constant comparison of constructivist grounded theory (CGT) methodology. Critical insights from the study bring out experiences of HPMI during COVID-19 as a victim of structural violence, highlighting their exclusion and victimization due to the existing marginalized status, living closer to the edge as a consequence of the lockdown, lack of awareness of the gravity of the pandemic situation. The experiences of the stakeholders, on the other hand, pointed out the role of community members and social workers in partially mitigating the challenges. This study indicates that to mitigate the aftermaths, stakeholders, including community members, need to work together for rebuilding and enhancing the strength and resilience of the marginalized populations like HPMI, who are historically victims of social injustice in the neoliberal pandemic era.

Immune response and possible therapeutics in COVID-19.

COVID-19 has emerged as a pandemic affecting about 213 countries in all the continents of the globe, resulting in more than 37.8 million individuals getting infected and over 1.08 million deaths worldwide, jeopardizing global human health and the economy. This presents an urgent need to develop therapies that target the SARS-CoV2 virus specifically. This review aims at presenting the available information on the coronavirus disease 2019 along with various drugs that are having widespread use until a vaccine candidate is available to aid in the development of therapeutic strategies against COVID-19.