Current Cancer Drug Targets - Volume 25, Issue 2, 2025

Hepatocellular carcinoma (HCC) is a global health problem with increasing morbidity and mortality, and exploring the diagnosis and treatment of HCC at the gene level has become a research hotspot in recent years. As the rate-limiting enzyme of carnosine hydrolysis, CNDP1 participates in the progress of many diseases, but its function in HCC has not been fully elucidated.

This study firstly screened differentially expressed genes from the biochip related to HCC by bioinformatic analysis, and CNDP1 was finally selected for in-depth study. Then the bioinformatics analysis results were validated by detecting the expression of CNDP1 in human HCC samples and hepatoma cell lines. Furthermore, the effect of CNDP1 on the malignant behavior of hepatoma cell lines were assessed using MTT colorimetric assay, EdU staining assay, colony formation, wound-healing assay and transwell, and the molecular mechanism was also preliminarily explored.

This study found that CNDP1 expression was decreased significantly in human HCC tissues and cell lines, and its overexpression could significantly suppress cell proliferation, migration and invasion of hepatoma cell lines. Mechanistically the GeneMANIA database predicted that CNDP1 could interact with various proteins involved in regulating PI3K-AKT-mTOR signaling pathway. Furthermore, this study showed that CNDP1 overexpression could effectively inhibit the activation of PI3K-AKT-mTOR signaling pathways, more significantly, inhibition of PI3K-AKT-mTOR signaling pathway could disrupt the anti-cancer effect of CNDP1 on HCC.

This study confirm that CNDP1 expression is decreased significantly in HCC, and has potential anti-cancer activity, this discovery provides a cytological basis for further understanding the biological function of CNDP1 and diagnosis and gene therapy of HCC in the future.

Lenvatinib resistance causes less than 40% of the objective response rate. Therefore, it is urgent to explore new therapeutic targets to reverse the lenvatinib resistance for HCC. HAND2-AS1 is a critical tumor suppressor gene in various cancers.

Here, we investigated the role of HAND2-AS1 in the molecular mechanism of lenvatinib resistance in HCC. It was found that HAND2-AS1 was lowly expressed in the HepG2 lenvatinib resistance (HepG2-LR) cells and HCC tissues and associated with progression-free intervals via TCGA. Overexpression of HAND2-AS1 (OE-HAND2-AS1) decreased the IC50 of lenvatinib in HepG2-LR cells to reverse lenvatinib resistance. Moreover, OE-HAND2-AS1 induced intracellular concentrations of malondialdehyde (MDA) and lipid ROS and decreased the ratio of glutathione to glutathione disulfide (GSH/GSSG) to promote ferroptosis.

A xenograft model in which nude mice were injected with OE-HAND2-AS1 HepG2-LR cells confirmed that OE-HAND2-AS1 could reverse lenvatinib resistance and decrease tumor formation in vivo. HAND2-AS1 promoted the expression of ferroptosis-related genes (TLR4, NOX2, and DUOX2) and promoted ferroptosis to reverse lenvatinib resistance by increasing TLR4/NOX2/DUOX2 via competing endogenous miR-219a-1-3p in HCC cells. Besides, patients with a low HAND2-AS1 level had early recurrence after resection.

HAND2-AS1 promotes ferroptosis in HCC cells and reverses lenvatinib resistance by regulating TLR4/NOX2/DUOX2 axis. It suggested that HAND2-AS1 may be a potential therapeutic target and an indicator of early recurrence for HCC.

Results from the TCGA database showed that phosphatidylinositol-specific phospholipase Cγ2 (PLCG2) expression level in Lung Adenocarcinoma (LUAD) was notably decreased compared to adjacent tissues, so we unveiled its role of LUAD.

This study aims to explore the expression and clinical significance of Phosphatidylinositol-specific phospholipase Cγ2 (PLCG2) in lung adenocarcinoma (LUAD) cells and its role in cell proliferation and metastasis.

Differential PLCG2 mRNA and protein levels between LUAD tissues and adjacent tissues were analyzed from the TCGA database, TIMER, and UALCAN database. Differentially expressed genes were screened for patients in the high and low PLCG2 mRNA expression groups by the R package as well as GSEA. The expression level of PLCG2 in LUAD cells was detected using qRT-PCR and CCK8, clone formation, Transwell, and Western blot assays.

PLCG2 was lowly expressed in LUAD and did not significantly correlate with the prognosis of LUAD. PLCG2 expression levels varied significantly in terms of patients' gender, age, T, N, and pathological stage. GO/KEGG enrichment analysis showed that co-expression of PLCG2 was mainly associated with the immune response- regulating cell-surface receptors, and so on. GSEA analysis showed enrichment pathways of PLCG2-related differential gees were primarily associated with the olfactory transduction pathway, ribosome, etc. R software analysis revealed a significant correlation between PLCG2 expression and six types of immune-infiltrating cells, positively correlated with immune checkpoint-related genes and negatively regulated by tumor mutational load. Overexpressing PLCG2 showed reduced LUAD cell proliferation, clone formation, cell migration and invasion, and epithelial-mesenchymal transition-associated proteins, compared with the control group.

PLCG2 is lowly expressed in LUAD tissues and is involved in immune infiltration of LUAD, inhibiting LUAD cell proliferation and metastasis.

Hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4) is involved in the progression of hepatocellular carcinoma (HCC).

This study aimed to investigate the inhibitory effect of gamma-tocotrienol (γ-T3) on the proliferation and growth of HSD17B4-overexpressing HepG2 cells.

HepG2 cells were transfected with empty or HSD17B4-overexpressing plasmids, followed by vitamin E (VE) or γ-T3 treatment. MTS assay, Western blotting, qRT-PCR, and flow cytometry were employed to assess cell proliferation, protein expression, mRNA levels, and apoptosis. HSD17B4 interaction with γ-T3 was assessed by quantifying γ-T3 in the collected precipitate of HSD17B4 using anti-flag magnetic beads. Tumor xenografts were established in NSG mice, and tumor growth was monitored.

HSD17B4 overexpression significantly promoted HepG2 cell proliferation, which was effectively counteracted by VE or γ-T3 treatment in a dose-dependent manner. VE and γ-T3 did not exert their effects through direct regulation of HSD17B4 expression. Instead, γ-T3 was found to interact with HSD17B4, inhibiting its activity in catalyzing the conversion of estradiol (E2) into estrone. Moreover, γ-T3 treatment led to a reduction in cyclin D1 expression and suppressed key proliferation signaling pathways, such as ERK, MEK, AKT, and STAT3. Additionally, γ-T3 promoted apoptosis in HSD17B4-overexpressing HepG2 cells. In an in vivo model, γ-T3 effectively reduced the growth of HepG2 xenograft tumors.

In conclusion, our study demonstrates that γ-T3 exhibits potent anti-proliferative and anti-tumor effects against HepG2 cells overexpressing HSD17B4. These findings highlight the therapeutic potential of γ-T3 in HCC treatment and suggest its role in targeting HSD17B4-associated pathways to inhibit tumor growth and enhance apoptosis.

This study delved to understand the role of Kinase Insert Domain Receptor (KDR) and its associated miRNAs in renal cell carcinoma through an extensive computational analysis. The potential of our findings to guide future research in this area is significant.

Our methods, which included the use of UALCAN and GEPIA2 databases, as well as miRDB, MirDIP, miRNet v2.0, miRTargetLink, MiEAA v2.1, TarBase v8.0, INTERNET, and miRTarBase, were instrumental in identifying the regulation of miRNA associated with KDR expression. The predicted miRNA was validated with the TCGA-KIRC patients’ samples by implementing CancerMIRNome. The TargetScanHuman v8.0 was implemented to identify the associations between human miRNAs and KDR. A Patch Dock server analyzed the interactions between hsa-miR-200c-3p and KDR.

The KDR expression rate was investigated in the Kidney Renal Cell Carcinoma (KIRC) samples, and adjacent normal tissues revealed that the expression rate was significantly higher than the normal samples, which was evident from the strong statistical significance (P = 1.63e^-12). Likely, the KDR expression rate was estimated as high at tumor grade 1 and gradually decreased till the metastasis grade, reducing the survival rate of the KIRC patients. To identify these signals early, we predicted a miRNA that could alter the expression of KDR. Furthermore, we uncovered the potential associations between miR-200c-3p expressions by regulating KDR towards the progression of KIRC.

Upon examining the outcome, it became evident that miR-200c-3p was significantly downregulated in KIRC compared to the normal samples. Moreover, the negative correlation was obtained for hsa-miR-200c-3p (R = - 0.276) along with the KDR expression describing that the increased rate of hsa-miR-200c-3p might reduce the KDR expression rate, which may suppress the KIRC initiation or progression.

The in-silico analysis indicated that the significant increase in KDR expression during the initiation of KIRC could serve as an early diagnostic marker. Moreover, KDR could be utilized to identify advancements in KIRC stages. Additionally, hsa-miR-200c-3p was identified as a potential regulator capable of downregulating and upregulating KDR expression among the 24 miRNAs screened. This finding holds promise for future research endeavors. Concurrent administration of the FDA-approved 5-fluorouracil with KIRC drugs, such as sorafenib, zidovudine, and everolimus, may have the potential to enhance the therapeutic efficacy in downregulating hsa-miR-200c-3p. However, further in vitro studies are imperative to validate these findings and gain a comprehensive understanding of the intricate regulatory interplay involving hsa-miR-200c-3p, KDR, 5-fluorouracil, and other FDA-approved drugs for the treatment of KIRC. This will facilitate the identification of KIRC stage progression and its underlying preventative mechanisms.