Can CD147 work as a therapeutic target for tumors through COVID-19 infection?

In this review, we discussed an interesting case infected with "COVID-19" (Corona Virus Disease 2019). The patients with Hodgkin's lymphoma recovered after infection with COVID-19. It may be that COVID-19 activates the patient's immune system, or it may be a coincidence. COVID-19 spike protein can interact with CD147 and use it as an entry to invade host cells. CD147 is a partner of SLC3A2, which is the chaperone subunit of cystine/glutamate reverse transporter (system XC). The catalytic subunit of system XC is SLC7A11. SLC7A11 mediated cysteine uptake plays a key role in ferroptosis. Through literature review and data analysis, we suggest that CD147, as a new potential COVID-19 infection entry, may also lead to ferroptosis of host cells. Our hypothesis is that spike protein of COVID-19 induced ferroptosis in host cells via CD147/SLC3A2/SLC7A11 complex. This is another explanation for the cancer patient recovered after COVID-19 infection.

Different races have different immune microenvironments: comparison of White and Asian patients with liver cancer.

Different ethnic groups have different incidence rate of hepatocellular carcinoma (HCC). In addition to lifestyle and environmental factors, genetic susceptibility is also an important reason. In this study, we screened the immune related genes and stromal related genes in White and Asian liver cancer patients cohort of The Cancer Genome Atlas (TCGA) the using ESTIMATE algorithm. Hub genes that significantly associated with overall survival (OS) were selected from White and Asian liver cancer patients, respectively. In addition, we validated the functions of two hub genes, IL-18RAP and GPM6A, in vivo and in vitro. We confirmed different races have different tumor immune microenvironments. Immune microenvironment can influence and change the efficacy of immunotherapy for liver cancer patients.

Effect of secretory DKK3 on circulating CD56bright natural killer cells in patients with liver cancer.

BACKGROUND: Liver cancer seriously threatens human health. Natural killer (NK) cells are an important part of the innate immune system and have strong anti-tumor ability. Immunotherapy based on NK cells has become a hot topic in the treatment of liver cancer. METHODS: In this study, we checked the serum DKK3 (sDKK3) and circulating CD56bright NK cells using ELISA and flow cytometry, respectively, in the blood of liver cancer patients. The effect on recombinant human DKK3 (rhDKK3) on CD56bright NK cells was analyzed in vitro. RESULTS: We found low levels of sDKK3 in liver cancer patients and a negative correlation between sDKK3 and circulating CD56bright NK cells. In addition, we found that DKK3 induced the differentiation and improved the cytotoxicity of CD56bright NK cells for the first time. It could be used as an agonist for NK cell-based immunotherapy. CONCLUSIONS: Improving the clinical efficacy of NK cells through DKK3 will become a new strategy for cancer immunotherapy.

Differences of ferroptosis-related genes between White and Asian patients with liver cancer.

Ferroptosis results from metabolic dysregulation and is closely linked to liver cancer. Although a ferroptosis-related gene signature in liver cancer has been established, the precise regulatory mechanism is still unclear. To identify shared pathogenic genes linked to ferroptosis across liver cancer patients from diverse racial backgrounds, we evaluated various ferroptosis-related genes, constructing a signature for both Asian and White patients using The Cancer Genome Atlas (TCGA) database. Based on the differential expression and functionality of ferroptosis-associated genes, we selected Farnesyl diphosphate farnesyl transferase 1 (FDFT1), Acyl-CoA synthetase long-chain 4 (ACSL4) and Endoplasmic reticulum membrane protein complex 2 (EMC2) for further study in liver cancer cells. FDFT1, ACSL4 and EMC2 induced ferroptosis of liver cancer cells though upregulation of reactive oxygen species (ROS) levels and downregulation of glutathione peroxidase (GPX4). Current data indicate no notable influence of racial differences on the functionality of ferroptosis-related genes. Our data suggests potential novel therapeutic avenues for liver cancer treatment.

SLC3A2, as an indirect target gene of ALDH2, exacerbates alcohol-associated liver cancer via the sphingolipid biosynthesis pathway.

Excessive drinking is one of the main causes of liver cancer. In the process of alcohol metabolism, aldehyde dehydrogenase 2 (ALDH2) is the key enzyme of acetaldehyde metabolism. ALDH2 gene deficiency is positively associated with the risk of hepatocellular carcinoma (HCC). However, no studies have shown a connection between ALDH2 and another metabolic regulatory gene, SLC3A2. In this study, we analyzed the expression levels of ALDH2 and SLC3A2 in liver cancer tissues based on the TCGA database. Subsequently, we constructed ALDH2 knockout and SLC3A2 knock-in transgenic mice to check the roles of ALDH2 and SLC3A2 in tumorigenesis in vivo. In addition, we examined the mechanisms of ALDH2 and SLC3A2 in HCC cells using small RNA interference technology. Consistent with previous studies, we also confirmed the functions of ALDH2 in inhibiting hepatocarcinogenesis, while SLC3A2 had the opposite effect. The main finding of this study is that ALDH2 inhibited BSG expression through the TGF-ß1 pathway, which indirectly inhibited SLC3A2 expression; subsequently, the sphingolipid metabolism pathway was also inhibited in HCC cells. Therefore, SLC3A2 is a novel target for HCC treatment.

The role of the stemness index-associated signature in the analysis of the tumorigenesis of liver cancer patients of different races.

Cancer stem cells (CSCs) are a subset of cancer cells with stem cell characteristics. The discovery of CSCs has opened a new era for cancer research. CSCs not only play a critical role in tumorigenesis, but also are responsible for the failure of cancer treatments. Here, we performed weighted gene co-expression network analysis (WGCNA) to identify key stemness genes and prognostic signatures using the data of an Asian liver cancer patient cohort and a White liver cancer patient cohort in The Cancer Genome Atlas (TCGA) database. To compare the difference in tumorigenesis between the Asian patients and the White patients, the prognostic value of the key genes from the Asian patients was evaluated in the White patient cohort and vice versa. We found that some key genes could predict the survival of the patients regardless of race. In addition, the key genes, NUCB2 and KLF4A, were selected from Asian patients and White patients, respectively, for further experimental validation. Knocking down NUCB2 could inhibit the activity of the AKT/mTOR signaling pathway and reverse the epithelial-mesenchymal transition (EMT) in liver cancer cells. We also confirmed that the knockdown of KLF4A suppressed ABCG2 activity and reduced the side population (SP) in liver cancer cells for the first time. Our results suggest that the stemness index is a useful method to identify key genes in tumorigenesis. Compared to the analysis for all patients, applying this index to the analysis of the patients of different races will provide more potential therapeutic targets for cancer treatment.

Metabolism in Cancer Stem Cells: Targets for Clinical Treatment.

Cancer stem cells (CSCs) have high tumorigenicity, high metastasis and high resistance to treatment. They are the key factors for the growth, metastasis and drug resistance of malignant tumors, and are also the important reason for the occurrence and recurrence of tumors. Metabolic reprogramming refers to the metabolic changes that occur when tumor cells provide sufficient energy and nutrients for themselves. Metabolic reprogramming plays an important role in regulating the growth and activity of cancer cells and cancer stem cells. In addition, the immune cells or stromal cells in the tumor microenvironment (TME) will change due to the metabolic reprogramming of cancer cells. Summarizing the characteristics and molecular mechanisms of metabolic reprogramming of cancer stem cells will provide new ideas for the comprehensive treatment of malignant tumors. In this review, we summarized the changes of the main metabolic pathways in cancer cells and cancer stem cells.

Both In Situ and Circulating SLC3A2 Could Be Used as Prognostic Markers for Human Lung Squamous Cell Carcinoma and Lung Adenocarcinoma.

SLC3A2, the heavy chain of the CD98 protein, is highly expressed in many cancers, including lung cancer. It can regulate the proliferation and the metastasis of cancer cells via the integrin signaling pathway. Liquid biopsy is a novel method for tumor diagnosis. The diagnostic or prognostic roles of serum SLC3A2 in lung cancer are still not clear. In this study, we analyzed SLC3A2 mRNA levels in human lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) using the TCGA database and serum SLC3A2 protein levels using ELISA. We confirmed high SLC3A2 levels in both the serum and tissue of LUAD and LUSC patients. Both serum and tissue SLC3A2 could be used as prognostic markers for overall LUAD and subgroups of LUSC patients. SLC3A2 induced tumorigenesis via the MEK/ERK signaling pathway in LUAD and LUSC cells.

Amino acid profiles in the tissue and serum of patients with liver cancer.

Most patients with liver cancer were found late and lost the chance of surgery. Liquid biopsy can monitor the risk of tumor recurrence and metastasis, quickly evaluate the curative effect of tumor treatment, and is conducive to early screening and auxiliary diagnosis of high-risk groups. Amino acid (AA) profiling has been used to the diagnosis and the prognosis for cancers. However, little was known about the profiles of AA of liver cancer. In this study, we used tRNA in Cancer database to analyze the AA levels in liver cancer tissues. Blood samples of patients with liver cancer were collected and analyzed using the automatic AA analyzer. We found that valine, isoleucine, and leucine were decreased significantly both in the plasma and the tumor tissues of patients with liver cancer. However, upregulation of methionine was observed in tissues and plasma of patients with liver cancer. Interestingly, tyrosine, and phenylalanine were decreased in tumor tissue but increased in the plasma of patients with liver cancer. This is the first report provided an overview of AA profile in both plasma and tissue for patients with liver cancer. AA levels can be used as diagnostic and prognostic markers of patients with liver cancer.

Integrative Analysis of CD133 mRNA in Human Cancers Based on Data Mining.

CD133 is a wildly used cancer stem cell marker. The purpose of this study was to explore the significance of CD133 mRNA in human cancers mainly based on The Cancer Genome Atlas (TCGA) database. Bioinformatic analyses were done by using public repositories, including BioGPS, SAGE Genie tools, Oncomine analysis, Regulome Explorer, COSMIC analysis, and Kaplan-Meier Plotter. The main findings in this study were: 1) High CD133 mRNA was correlated with a benign survival rate of gastric cancer and lung cancer; 2) Transmembrane protein 125 (TMEM125) in bladder urothelial carcinoma and intercellular adhesion molecule 2 (ICAM2) in ovarian serous cystadenocarcinoma were closely related to CD133 expression; 3) The location and the topological structure of CD133 protein were not determined by its transcript variant in cancer cells; 4) CD38 and CD200 may be used as novel surface markers for solid cancers. However, the mechanism of these findings is not completely clear, further studies have to be performed in the future.

The roles of CD133 expression in the patients with non-small cell lung cancer.

BACKGROUND: This study was carried out to investigate the correlation between CD133 and non-small cell lung cancer (NSCLC) clinicopathological features and its impact on survival of the patients with NSCLC. METHODS: In the first, we detected the level and localization of CD133 protein in NSCLC specimens and confirmed that CD133 expression was closely linked to poor prognosis of NSCLC. Secondly, TCGA genomic data for LUNG (Provisional) was retrieved and analyzed for genetic alterations of CD133 in different lung cancer subtypes. In the last, a comprehensive literature search for relevant studies published up to December 2015 was performed using Medline, EMBASE Classic + EMBASE, and The Cochrane Central Register of Controlled Trials. RESULTS AND CONCLUSION: Both our experimental results and pooled results of previous studies indicated that CD133 may be used as a prognostic marker for the patients with NSCLC. However, more studies are required to evaluate CD133 potential use in predicting patients' outcome.