Soluble CD147 (BSG) as a Prognostic Marker in Multiple Myeloma

CD147 (basigin, BSG) is a membrane-bound glycoprotein involved in energy metabolism that plays a role in cancer cell survival. Its soluble form is a promising marker of some diseases, but it is otherwise poorly studied. CD147 is overexpressed in multiple myeloma (MM) and is known to affect MM progression, while its genetic variants are associated with MM survival. In the present study, we aimed to assess serum soluble CD147 (sCD147) expression as a potential marker in MM. We found that sCD147 level was higher in MM patients compared to healthy individuals. It was also higher in patients with more advanced disease (ISS III) compared to both patients with less advanced MM and healthy individuals, while its level was observed to drop after positive response to treatment. Patients with high sCD147 were characterized by worse overall survival. sCD147 level did not directly correlate with bone marrow CD147 mRNA expression. In conclusion, this study suggests that serum sCD147 may be a prognostic marker in MM.

BSG (CD147) Serum Level and Genetic Variants Are Associated with Overall Survival in Acute Myeloid Leukaemia

Basigin (BSG, CD147) is a multifunctional protein involved in cancer cell survival, mostly by controlling lactate transport through its interaction with monocarboxylate transporters (MCTs) such as MCT1. Previous studies have found that single nucleotide polymorphisms (SNPs) in the gene coding for BSG and MCT1, as well as levels of the soluble form of BSG (sBSG), are potential biomarkers in various diseases. The goal of this study was to confirm BSG and MCT1 RNA overexpression in AML cell lines, as well as to analyse soluble BSG levels and selected BSG/MCT1 genetic variants as potential biomarkers in AML patients. We found that BSG and MCT1 were overexpressed in most AML cell lines. Soluble BSG was increased in AML patients compared to healthy controls, and correlated with various clinical parameters. High soluble BSG was associated with worse overall survival, higher bone marrow blast percentage, and higher white blood cell count. BSG SNPs rs4919859 and rs4682, as well as MCT1 SNP rs1049434, were also associated with overall survival of AML patients. In conclusion, this study confirms the importance of BSG/MCT1 in AML, and suggests that soluble BSG and BSG/MCT1 genetic variants may act as potential AML biomarkers.

RNA Exosome Component EXOSC4 Amplified in Multiple Cancer Types Is Required for the Cancer Cell Survival

The RNA exosome is a multi-subunit ribonuclease complex that is evolutionally conserved and the major cellular machinery for the surveillance, processing, degradation, and turnover of diverse RNAs essential for cell viability. Here we performed integrated genomic and clinicopathological analyses of 27 RNA exosome components across 32 tumor types using The Cancer Genome Atlas PanCancer Atlas Studies’ datasets. We discovered that the EXOSC4 gene, which encodes a barrel component of the RNA exosome, was amplified across multiple cancer types. We further found that EXOSC4 alteration is associated with a poor prognosis of pancreatic cancer patients. Moreover, we demonstrated that EXOSC4 is required for the survival of pancreatic cancer cells. EXOSC4 also repressed BIK expression and destabilized SESN2 mRNA by promoting its degradation. Furthermore, knockdown of BIK and SESN2 could partially rescue pancreatic cells from the reduction in cell viability caused by EXOSC4 knockdown. Our study provides evidence for EXOSC4-mediated regulation of BIK and SESN2 mRNA in the survival of pancreatic tumor cells.

Anesthesia and Cancer, Friend or Foe? A Narrative Review

Cancer remains the leading cause of death worldwide with close to 10 million deaths reported annually. Due to growth of the advanced age cohort in our population, it is predicted that the number of new cancer cases diagnosed between now until 2035 is to reach potentially 24 million individuals, a staggering increase in a relatively short time period. For many solid tumors, surgical resection along with chemotherapy is the best available approach to a potential cure which leads to almost 80% of cancer patients undergoing at least one surgical procedure during the course of their disease. During surgical intervention, the exposure to general anesthesia can be lengthy, complex and often involves various modalities resulting in an important question as to the role, if any, anesthesia may play in primary recurrence or metastatic conversion. Many components of the stress and inflammatory responses exhibited in the perioperative period can contribute to cancer growth and invasion. The agents used to induce and maintain general anesthesia have variable interactions with the immune and neuroendocrine systems and can influence the stress response during surgery. Thus, debating the best type of anesthesia that would help to attenuate sympathetic and/or pro-inflammatory responses while modulating cytokine release and transcription factors/oncogenes remains at the forefront. This may affect inducible cancer cell survival and migratory abilities not only intra-operatively, but also during the immediate post-operative phase of recovery. The ultimate question becomes how and whether the choice of anesthesia may influence the outcomes of cancer surgery with two major approaches being considered, i.e., regional and general anesthesia as well as the various hypnotics, analgesics and sympatholytics commonly used. In this review, we will address the latest information as to the role that anesthesia may play during cancer surgery with specific focus on primary recurrence and metastasis.

Decoding the Oncogenic Signals from the Long Non-Coding RNAs

Cancer is one of the leading causes of death worldwide. Multifactorial etiology of cancer and tumor heterogeneity are the two most acute challenges in existing diagnostic and therapeutic strategies for cancer. An effective precision cancer medicine strategy to overcome these challenges requires a clear understanding of the transcriptomic landscape of cancer cells. Recent innovative breakthroughs in high-throughput sequencing technologies have identified the oncogenic or tumor-suppressor role of several long non-coding RNAs (lncRNAs). LncRNAs have been characterized as regulating various signaling cascades which are involved in the pathobiology of cancer. They modulate cancer cell survival, proliferation, metabolism, invasive metastasis, stemness, and therapy-resistance through their interactions with specific sets of proteins, miRNAs and other non-coding RNAs, mRNAs, or DNAs in cells. By virtue of their ability to regulate multiple sets of genes and their cognate signaling pathways, lncRNAs are emerging as potential candidates for diagnostic, prognostic, and therapeutic targets. This review is focused on providing insight into the mechanisms by which different lncRNAs play a critical role in cancer growth, and their potential role in cancer diagnosis, prognosis, and therapy.

TXNRD1: A Key Regulator Involved in the Ferroptosis of CML Cells Induced by Cysteine Depletion In Vitro

Cysteine metabolism plays a critical role in cancer cell survival. Cysteine depletion was reported to inhibit tumor growth and induce pancreatic cancer cell ferroptosis. Nevertheless, the effect of cysteine depletion in chronic myeloid leukemia (CML) remains to be explored. In this work, we showed that cysteine depletion can induce K562/G01 but not K562 cell death in the form of ferroptosis. However, the glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathways of the two CML cell lines were both blocked after cysteine depletion. This unexpected outcome guided us to perform RNA-Seq to screen the key genes that affect the sensitivity of CML cells to cysteine depletion. Excitingly, thioredoxin reductase 1 (TXNRD1), which related to cell redox metabolism, was significantly upregulated in K562/G01 cells after cysteine depletion. We further inferred that the upregulation is negatively feedback by the enzyme activity decrease of TXNRD1. Then, we triggered the ferroptosis by applying TXNRD1 shRNA and TXNRD1 inhibitor auranofin in K562 cells after cysteine depletion. In summary, we have reason to believe that TXNRD1 is a key regulator involved in the ferroptosis of CML cells induced by cysteine depletion in vitro. These findings highlight that cysteine depletion serves as a potential therapeutic strategy for overcoming chemotherapy resistance CML.

Ceramide Transfer Protein (CERT): An Overlooked Molecular Player in Cancer

Sphingolipids are a class of essential lipids implicated in constructing cellular membranes and regulating nearly all cellular functions. Sphingolipid metabolic network is centered with the ceramide–sphingomyelin axis. Ceramide is well-recognized as a pro-apoptotic signal; while sphingomyelin, as the most abundant type of sphingolipids, is required for cell growth. Therefore, the balance between these two sphingolipids can be critical for cancer cell survival and functioning. Ceramide transfer protein (CERT) dictates the ratio of ceramide to sphingomyelin within the cell. It is the only lipid transfer protein that specifically delivers ceramide from the endoplasmic reticulum to the Golgi apparatus, where ceramide serves as the substrate for sphingomyelin synthesis. In the past two decades, an increasing body of evidence has suggested a critical role of CERT in cancer, but much more intensive efforts are required to draw a definite conclusion. Herein, we review all research findings of CERT, focusing on its molecular structure, cellular functions and implications in cancer. This comprehensive review of CERT will help to better understand the molecular mechanism of cancer and inspire to identify novel druggable targets.

A Comprehensive Review on PCSK9 as Mechanistic Target Approach in Cancer Therapy

: PCSK9 is a strongly expressed protein in the liver and brain that binds to the LDLR and regulates cholesterol in the liver effectively. Other receptors with which it interacts include VLDLR, LRP1, ApoER2, and OLR1. PCSK9 gain-of-function results in lysosomal degradation of these receptors, which may result in hyperlipidemia. PCSK9 deficiency results in a lower amount of cholesterol, which reduces cholesterol's accessibility to cancer cells. PCSK9 regulates several proteins and signaling pathways in cancer, including JNK, NF-κВ, and the mitochondrial-mediated apoptotic pathway. In the liver, breast, lungs, and colon tissue, PCSK9 initiates and facilitates cancer development, while in prostate cancer cells, it induces apoptosis. PCSK9 has a significant impact on brain cancer, promoting cancer cell survival by manipulating the mitochondrial apoptotic pathway and exhibiting apoptotic activity in neurons by influencing the NF-κВ, JNK, and caspase-dependent pathways. The PCSK9 impact in cancer at different organs is explored in this study, as well as the targeted signaling mechanisms involved in cancer growth. As a result, these signaling mechanisms may be aimed for the development and exploration of anti-cancer drugs in the immediate future.

Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis

Amino acid availability is sensed by various signaling molecules, including general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). However, it is unclear how these sensors are associated with cancer cell survival under low amino acid availability. In the present study, we investigated AKT activation in non-small cell lung cancer (NSCLC) cells deprived of each one of 20 amino acids. Among the 20 amino acids, deprivation of glutamine, arginine, methionine, and lysine induced AKT activation. AKT activation was induced by GCN2/ATF4/REDD1 axis-mediated mTORC2 activation under amino acid deprivation. In CRISPR-Cas9-mediated REDD1-knockout cells, AKT activation was not induced by amino acid deprivation, indicating that REDD1 plays a major role in AKT activation under amino acid deprivation. Knockout of REDD1 sensitized cells cultured under glutamine deprivation conditions to radiotherapy. Taken together, GCN2/ATF4/REDD1 axis induced by amino acid deprivation promotes cell survival signal, which might be a potential target for cancer therapy.