Current Molecular Medicine - Volume 23, Issue 4, 2023

Hypoxia-inducible factors (HIFs) are a collection of transcriptional factors that engage in the regulation of oxygen homeostasis. They are hypoxia-responsive stress factors whose expression is linked to tumor growth and angiogenesis. HIF is a crucial player in the progression of breast cancer. Patients with high levels of hypoxia-inducible HIFs in their primary tumor biopsies had a higher chance of metastasis, the leading cause of breast cancer-related death. HIF polymorphisms have been shown in several epidemiological studies to influence breast cancer susceptibility. In the oxygendependent degradation domain, several short nucleotide polymorphisms (SNPs) of the HIF gene have been connected with higher HIF activity. To find SNP that make up the genetic diversity that underpins the phenotypic difference found between individuals in their susceptibility to cancer and the course of their disease, researchers used a variety of potential pathway-based approaches.

Background: Accumulating research has demonstrated that aberrant levels of long noncoding RNAs (LncRNAs) are related to cancer progression. The effects of ORLNC1 in HER2+ breast cancer have yet to be explored. Methods: Real-time PCR was used to examine the expression of LncRNA ORLNC1 in HER+ breast cancer. CCK-8, wound healing and cell invasion assays were used to examine the effect of LncRNA ORLNC1 on HER+ breast cancer cells. Luciferase reporter assay was utilized to determine the regulatory relationship between LncRNA ORLNC1 and miR-296. Western blotting was used to measure the expression of PTEN. Xenograft mouse model was used to examine the effect of LncRNA ORLNC1 on tumor progression in vivo. Results: In this study, our findings revealed downregulation of ORLNC1 in HER2+ breast cancer specimens and cell lines. Low levels of ORLNC1 were related to poor prognosis and advanced cancer stage. Using gain- and loss-of-function assays, the ability of these tumor cells to proliferate was found to be inhibited by ORLNC1 in vitro and in vivo. Further analyses revealed that miR-296/PTEN axis is directly targeted by ORLNC1. Consequently, over-expression of miR-296 efficiently abrogated the upregulation of PTEN induced by ORLNC1, suggesting that ORLNC1 positively regulates PTEN expression by competitively binding to miR-296. Conclusion: Our results indicate that lncRNA ORLNC1 acts as a tumor suppressor by regulating the miR-296/PTEN axis in HER2+ breast cancer.

PIWI-interacting RNAs (piRNAs) constitute new small non-coding RNA molecules of around 24-31 nucleotides in length, mostly performing regulatory roles for the piwi protein family members. In recent times, developing evidence proposes that piRNAs are expressed in a tissue-specific way in various human tissues and act as moderate vital signalling pathways at the transcriptional or post-transcriptional level in addition to mammalian germline. Recent findings, however, show that the unusual expression of piRNAs is an exclusive and discrete feature in several diseases, including many human cancers. Recently, considerable evidence indicates that piRNAs could be dysregulated thus playing critical roles in tumorigenesis. The function and underlying mechanisms of piRNAs in cancer, particularly in colorectal carcinoma, are not fully understood to date. Abnormal expression of piRNAs is emerging as a critical player in cancer cell proliferation, apoptosis, invasion, and migration in vitro and in vivo. Functionally, piRNAs preserve genomic integrity and regulate the expression of downstream target genes through transcriptional or post-transcriptional mechanisms by repressing transposable elements' mobilization. However, little research has been done to check Piwi and piRNAs' potential role in cancer and preserve genome integrity by epigenetically silencing transposons via DNA methylation, especially in germline cancer stem cells. This review reveals emerging insights into piRNA functions in colorectal carcinoma, revealing novel findings behind various piRNA-mediated gene regulation mechanisms, biogenetic piRNA processes, and possible applications of piRNAs and piwi proteins in cancer diagnosis and their potential clinical significance in the treatment of colorectal carcinoma patients.

Esophageal cancer (EC) is one of the major causes of cancer-related death worldwide. EC is usually diagnosed at a late stage, and despite aggressive therapy, the five-year survival rate of patients remains poor. Exosomes play important roles in cancer biology. Indeed, exosomes are implicated in tumor proliferation, angiogenesis, and invasion. They contain bioactive molecules such as lipids, proteins, and non-coding RNAs. Exosome research has recently concentrated on microRNAs, which are tiny noncoding endogenous RNAs that can alter gene expression and are linked to nearly all physiological and pathological processes, including cancer. It is suggested that deregulation of miRNAs results in cancer progression and directly induces tumor initiation. In esophageal cancer, miRNA dysregulation plays an important role in cancer prognosis and patients’ responsiveness to therapy, indicating that miRNAs are important in tumorigenesis. In this review, we summarize the impact of exosomal miRNAs on esophageal cancer pathogenesis and their potential applications for EC diagnosis and therapy.

Bone morphogenetic protein 4 (BMP4) is a multifunctional secretory protein that belongs to the transforming growth factor β superfamily. BMPs transduce their signaling to the cytoplasm by binding to membrane receptors of the serine/threonine kinase family, including BMP type I and type II receptors. BMP4 participates in various biological processes, such as embryonic development, epithelial-mesenchymal transition, and maintenance of tissue homeostasis. The interaction between BMP4 and the corresponding endogenous antagonists plays a key role in the precise regulation of BMP4 signaling. In this paper, we review the pathogenesis of BMP4-related lung diseases and the foundation on which BMP4 endogenous antagonists have been developed as potential targets.

Male infertility is a major issue, and numerous factors contribute to it. One of the important organelles involved in the functioning of human spermatozoa is mitochondria. There are 50-75 mitochondria helically arranged in mid-piece bearing one mitochondrial DNA each. Sperm mitochondria play a crucial role in sperm functions, including the energy production required for sperm motility and the production of reactive oxygen species, which in the physiological range helps in sperm maturation, capacitation, and acrosome reaction. It also plays a role in calcium signaling cascades, intrinsic apoptosis, and sperm hyperactivation. Any structural or functional dysfunction of sperm mitochondria results in increased production of reactive oxygen species and, a state of oxidative stress, decreased energy production, all leading to sperm DNA damage, impaired sperm motility and semen parameters, and reduced male fertility. Furthermore, human sperm mitochondrial DNA mutations can result in impaired sperm motility and parameters leading to male infertility. Numerous types of point mutations, deletions, and missense mutations have been identified in mtDNA that are linked with male infertility. Methods: Recent literature was searched from English language peer-reviewed journals from databases including PubMed, Scopus, EMBASE, Scholar, and Web of Science till September 2021. Search terms used were “Sperm mitochondria and male fertility”, “Bioenergetics of sperm”, “Sperm mitochondria and reactive oxygen species”, “Sperm mitochondrial mutations and infertility”. Conclusion: Sperm mitochondria is an important organelle involved in various functions of human spermatozoa and sperm mitochondrial DNA has emerged as one of the potent biomarkers of sperm quality and male fertility.

5-HT3 receptor antagonists corresponding to ondansetron, granisetron, tropisetron, and palonosetron are clinically accustomed to treating nausea and emesis in chemotherapy patients. However, current and previous studies reveal novel potentials of those ligands in other diseases involving the nervous system, such as addiction, pruritus, and neurological disorders, such as anxiety, psychosis, nociception, and cognitive function. This review gathers existing studies to support the role of 5-HT3 receptors in CIPN modulation. It has been reported that chemotherapy drugs increase the 5-HT content that binds with the 5-HT3 receptor, which later induces pain. As also shown in pre-clinical and clinical studies that various neuropathic pains could be blocked by the 5-HT3 receptor antagonists, we proposed that 5-HT3 receptor antagonists via 5- HT3 receptors may also inhibit neuropathic pain induced by chemotherapy. Our review suggests that future studies focus more on the 5-HT3 receptor antagonists and their modulation in CIPN to reduce the gap in the current pharmacotherapy for cancer-related pain.

The process of tissue damage, repair, and regeneration in the skeletal muscle system involves complex inflammatory processes. Factors released in the inflammatory microenvironment can affect the phenotypic changes of macrophages, thereby changing the inflammatory process, making macrophages an important target for tissue repair treatment. Mesenchymal stem cells exert anti-inflammatory effects by regulating immune cells. In particular, exosomes secreted by mesenchymal stem cells have become a new cell-free treatment strategy due to their low tumorigenicity and immunogenicity. This article focuses on the mechanism of the effect of exosomes derived from mesenchymal stem cells on the phenotype of macrophages after skeletal muscle system injury and explores the possible mechanism of macrophages as potential therapeutic targets after tissue injury.

Introduction: Cellular damage by oxidation occurs in numerous chronic diseases, such as obesity, type II diabetes, cardiovascular disease, nonalcoholic fatty liver, etc. The oxidized compound 3-nitrotyrosine is a marker of oxidative stress and protein oxidation damage. Objective: The article aims to assess whether 3-nitrotyrosine levels are higher in young people with obesity than in the same population without obesity. Methods: Anthropometry and blood chemistry analyses were performed on 24 young Mexican participants (18-30 years old), categorized into two groups based on their waist circumference: Withobesity (≥ 80 cm women; ≥ 90 cm men) and without-obesity (<80 cm women; <90 cm men). Additionally, 3-nitrotyrosine blood values were quantified by ELISA. Results: Except for HDL-cholesterol, the mean values of lipids increased in women and men with obesity (p<0.05), and 3-nitrotyrosine concentration (nM/μg total protein) was higher by 60% in the group with-obesity compared to the group without-obesity, both for women (66.21 ± 23.85 vs. 40.69 ± 16.25, p<0.05) and men (51.72 ± 20.56 vs. 30.52 ± 5.21, p<0.05). Conclusion: Oxidative damage measured by compound 3-nitrotyrosine was higher in the group with obesity than in the group without obesity, which, if not controlled, could lead to a chronic oxidative condition and thereby to a degree of cellular aging with adverse health effects.

Aims: This study aimed to investigate the role of E2F1 in breast cancer biology. Background: Expression of E2F1, a transcription factor of many oncogenes and tumor suppressor genes, is lowered in several malignancies, including breast carcinoma. Objectives: In the present study, we analyzed the status of E2F1 expression in association with diverse attributes of breast malignancy and its impact on cancer progression. Methods: For this purpose, we used various freely available online applications for gene enrichment, expression, and methylation analysis to extract mutation-based E2F1 map, to measure E2F1 drug sensitivity, and to determine E2F1 association with DNA damage response proteins. Results: Results revealed tissue-specific regulatory behavior of E2F1. Moreover, the key role of E2F1 in the promotion of metastasis, stem cell-mediated carcinogenesis, estrogen-mediated cell proliferation, and cellular defense system, has therefore highlighted it as a metaplastic marker and hot member of key resistome pathways. Conclusion: The information thus generated can be employed for future implications in devising rational therapeutic strategies. Moreover, this study has provided a more detailed insight into the diagnostic and prognostic potential of E2F1.