Molecular Carcinogenesis最新文献

Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, often leads to a poor prognosis due to metastasis. The investigation of N6-methyladenosine (m⁶A) methylation, a crucial RNA modification, and its role in ccRCC, particularly through the m⁶A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), revealed significant insights. We found that IGF2BP2 was notably downregulated in ccRCC, which correlated with tumor aggressiveness and poor prognosis. Thus, IGFBP2 has emerged as an independent prognostic factor of ccRCC. Moreover, a strong positive correlation was observed between the expression of IGF2BP2 and Netrin-4. Netrin-4 was also downregulated in ccRCC, and its lower levels were associated with increased malignancy and poor prognosis. Overexpression of IGF2BP2 and Netrin-4 suppressed the invasion and migration of ccRCC cells, while Netrin-4 knockdown reversed these effects in ccRCC cell lines. RNA immunoprecipitation (RIP)-quantitative polymerase chain reaction validated the robust enrichment of Netrin-4 mRNA in anti-IGF2BP2 antibody immunoprecipitates. MeRlP showed significantly increased Netrin4 m⁶A levels after lGF2BP2 overexpression. Moreover, we found that IGF2BP2 recognized and bound to the m⁶A site within the coding sequence of Netrin-4, enhancing its mRNA stability. Collectively, these results showed that IGF2BP2 plays a suppressive role in the invasion and migration of ccRCC cells by targeting Netrin-4 in an m⁶A-dependent manner. These findings underscore the potential of IGF2BP2/Netrin-4 as a promising prognostic biomarker and therapeutic target in patients with ccRCC metastasis.

Lactate dehydrogenase A (LDHA) is known to promote the growth and invasion of various types of tumors, affects tumor resistance, and is associated with tumor immune escape. But how LDHA reshapes the tumor microenvironment and promotes the progression of renal cell carcinoma (RCC) remains unclear. In this study, we found that LDHA was highly expressed in clear cell RCC (ccRCC), and this high expression was associated with macrophage infiltration, while macrophages were highly infiltrated in ccRCC, affecting patient prognosis via M2-type polarization. Our in vivo and in vitro experiments demonstrated that LDHA and M2-type macrophages could enhance the proliferation, invasion, and migration abilities of ccRCC cells. Mechanistically, high expression of LDHA in ccRCC cells upregulated the expression of EPHA2 in exosomes derived from renal cancer. Exosomal EPHA2 promoted M2-type polarization of macrophages by promoting activation of the PI3K/AKT/mTOR pathway in macrophages, thereby promoting the progression of ccRCC. All these findings suggest that EPHA2 may prove to be a potential therapeutic target for advanced RCC.

Curcumin has been shown to have antitumor properties, but its low potency and bioavailability has limited its clinical application. We designed a novel curcuminoid, [1-propyl-3,5-bis(2-bromobenzylidene)-4-piperidinone] (PBPD), which has higher antitumor strength and improves bioavailability. Cell counting kit-8 was used to detect cell activity. Transwell assay was used to detect cell invasion and migration ability. Western blot and quantitative polymerase chain reaction were used to detect protein levels and their messenger RNA expression. Immunofluorescence was used to detect the protein location. PBPD significantly inhibited the proliferation of cervical cancer cells, with an IC₅₀ value of 4.16 μM for Hela cells and 3.78 μM for SiHa cells, leading to the induction of cuproptosis. Transcriptome sequencing analysis revealed that PBPD significantly inhibited the Notch1/Recombination Signal Binding Protein for Immunoglobulin kappa J Region (RBP-J) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways while upregulating ferredoxin 1 (FDX1) expression. Knockdown of Notch1 or RBP-J significantly inhibited NRF2 expression and upregulated FDX1 expression, leading to the inhibition of nicotinamide adenine dinucleotide phosphate activity and the induction of oxidative stress, which in turn activated endoplasmic reticulum stress and induced cell death. The overexpression of Notch1 or RBP-J resulted in the enrichment of RBP-J within the NRF2 promoter region, thereby stimulating NRF2 transcription. NRF2 knockdown resulted in increase in FDX1 expression, leading to cuproptosis. In addition, PBPD inhibited the acidification of tumor niche and reduced cell metabolism to inhibit cervical cancer cell invasion and migration. In conclusion, PBPD significantly inhibits the proliferation, invasion, and migration of cervical cancer cells and may be a novel potential drug candidate for treatment of cervical cancer.

Programmed cell death 1 (PD-1), a key immune checkpoint receptor, has been extensively studied for its role in regulating immune responses in cancer. However, recent research has unveiled a complex and dual role for PD-1 in tumorigenesis. While PD-1 is traditionally associated with immune cells, this article explores its expression in various cancer cells and its impact on cancer progression. PD-1's functions extend beyond immune regulation, as it has been found to both promote and suppress tumor growth, depending on the cancer type. These findings have significant implications for the future of cancer treatment and our understanding of the immune response in the context of cancer. This article calls for further research into the multifaceted roles of PD-1 to optimize its therapeutic potential and improve patient outcomes in the fight against cancer.

Osteosarcoma (OS) is a common primary malignant bone tumor, and it is necessary to further investigate the molecular mechanism of OS progression. The expression of kinetochore associated protein 1 (KNTC1) and minichromosome maintenance 2 (MCM2) was detected by immunohistochemistry, quantitative PCR (qPCR) and Western blot. Gene knockdown or overexpression cell models were constructed and the proliferation, apoptosis, cell cycle and migration were detected in vitro, besides, xenograft models were established to explore the effects of KNTC1 downregulation in vivo. Public databased and bioinformatics analysis were performed to screen the downstream molecules and determine the expression of MCM2 in cancers. KNTC1 was overexpressed in OS tissues and positively correlated with overall survival of OS patients. KNTC1 knockdown inhibited the proliferation and migration, and arrested G2 phase, and induced apoptosis. Besides, KNTC1 downregulation restricted the xenograft tumor formation. MCM2, one of the coexpressed genes, was highly expressed in sarcoma and downregulated after KNTC1 knockdown. MCM2 overexpression heightened the proliferation and migration ability of OS cells, which was reversed the inhibiting effects of KNTC1 knockdown. KNTC1 was overexpressed in OS and promoted the progression of OS by upregulating MCM2.

Retraction: X. Fu, J. Lin, F. Qin, Z. Yang, Y. Ding, Y. Zhang, L. Han, X. Zhu and Q. Zhang, "LncAPC Drives Wnt/Β-Catenin Activation and Liver TIC Self-Renewal Through EZH2 Mediated APC Transcriptional Inhibition," Molecular Carcinogenesis 57, no. 3 (2018): 408-418, https://doi.org/10.1002/mc.22764. The above article, published online on 16 November 2017 in Wiley Online Library (wileyonlinelibrary.com), and its correction, https://doi.org/10.1002/mc.23443, have been retracted by Wiley Periodicals, LLC. The retractions have been agreed following an investigation into concerns raised by a third party, which revealed inappropriate duplications of images with overlapping field of view between this and another article that was previously published in a different scientific context. Thus, the conclusions of this manuscript are substantially compromised. The authors and their institute were informed of the decision to retract but remained unresponsive.

The serine protease CORIN catalyzes pro-atrial natriuretic peptide (pro-ANP) into an active ANP and maintains homeostasis of the internal environment. However, it is unclear whether CORIN participates in the regulation of tumor progression. We analyzed the expression profile of CORIN in gastric cancer tissues (GCs) and adjacent nontumoral tissues (NTs). We investigated the prognostic value of CORIN in GC patients. We characterized the in vitro and in vivo activity of CORIN in cultured GC cells with gain-of-function and loss-of-function experiments. The underlying mechanism was explored by using bioinformatics, a signaling antibody array, and confirmative western blot analyses, as well as rescue experiments with highly selective small-molecule inhibitors targeting the ERK1/2 MAPK signaling pathway. CORIN was upregulated in GCs than in NTs. Overexpression of CORIN was correlated with unfavorable prognoses in patients with GC. Ectopic expression of CORIN was promoted, whereas silencing of CORIN suppressed proliferation, colony formation, migration and invasion of GC cells, and tumor growth in vivo. Overexpression of CORIN-induced epithelial-mesenchymal transition (EMT) and activation of the ERK1/2 MAPK signaling pathway, while silencing of CORIN yielded opposite results. The in vitro tumor-promoting potency of CORIN could be antagonized by selective inhibitors targeting the ERK1/2 MAPK pathway. In conclusion, CORIN is a potential prognostic marker and therapeutic target for GC patients, which may promote tumor progression by mediating the ERK1/2 MAPK signaling pathway and EMT in GC cells.

Paclitaxel serves as the cornerstone chemotherapy for ovarian cancer, yet its prolonged administration frequently culminates in drug resistance, presenting a substantial challenge. Here we reported that inducing alkaliptosis, rather than apoptosis or ferroptosis, effectively overcomes paclitaxel resistance. Mechanistically, ATPase H⁺ transporting V0 subunit D1 (ATP6V0D1), a key regulator of alkaliptosis, plays a pivotal role by mediating the downregulation of ATP-binding cassette subfamily B member 1 (ABCB1), a multidrug resistance protein. Both ATP6V0D1 overexpression through gene transfection and pharmacological enhancement of ATP6V0D1 protein stability using JTC801 effectively inhibit ABCB1 upregulation, resulting in growth inhibition in drug-resistant cells. Additionally, increasing intracellular pH to alkaline (pH 8.5) via sodium hydroxide application suppresses ABCB1 expression, whereas reducing the pH to acidic conditions (pH 6.5) with hydrochloric acid amplifies ABCB1 expression in drug-resistant cells. Collectively, these results indicate a potentially effective therapeutic strategy for targeting paclitaxel-resistant ovarian cancer by inducing ATP6V0D1-dependent alkaliptosis.

Triple-negative breast cancer (TNBC) is a malignant tumor with high degree of malignancy and lack of effective target treatment. The research aims to explore the role and mechanism of X collagen alpha-1 chain protein (COL10A1 gene) in TNBC. UALCAN and Kaplan-Meier were used to detect the expression of COL10A1 and its role in the prognosis of breast cancer patients. The cells with stably expressing high levels of COL10A1 were obtained by recombinant lentivirus infection. The expression of COL10A1 in cells was temporarily downregulated by siRNA interference fragments. Real-time quantitative polymerase chain reaction and western blot analysis were utilized to detect the changes of COL10A1 mRNA and protein expression. The biological functions of the cells were evaluated by colony formation, cell counting kit-8, cell invasion and wound healing experiments. In addition, the effect of COL10A1 on angiogenesis was investigated by tube formation assay. Xenograft tumor model was used to confirm the effect of COL10A1 on tumorigenicity in vivo and multiplex fluorescent immunohistochemistry to detect multiple proteins simultaneously. The possible molecular mechanism of the function of COL10A1 was speculated through the detection of proteins in functionally related pathways. COL10A1 is highly expressed and is significantly associated with worse overall survival (OS) and recurrence-free survival (RFS) in TNBC. Overexpression of COL10A1 increased the clone formation rate and cell migration capacity of TNBC cells. In the COL10A1 overexpression group, the clone formation rates of MD-MB-231 and BT-549 cells (21.5 ± 0.62, 27.83 ± 3.72)% were significantly higher than those in the control group(15.23 ± 2.79, 19.4 ± 1.47)%, and the relative migration ratio (47.40 ± 3.09, 41.26 ± 4.33)% were higher than those in the control group (34.48 ± 2.03, 21.80 ± 1.03)%. When the expression of COL10A1 was downregulated, the ability of clone formation and wound-healing migration capacity in TNBC cells was weakened. Upregulated COL10A1 in TNBC cells generated more junctions and longer total segments between vascular endothelial cells, and promoted angiogenesis of the cells, and thus enhanced the tumorigenesis. In TNBC, it was found that COL10A1 might affect epithelial-mesenchymal transition (EMT) of the cells through Wnt/β-catenin signaling pathway by the detection of the related pathway proteins. COL10A1 is highly expressed in TNBC, and its high expression leads to poor OS and RFS. COL10A1 may enhance TNBC cell proliferation, migration and tumor-related angiogenesis, and promote tumorigenesis in vivo via Wnt/β-catenin signaling.

HER3 is mutated in ~2%-10% of cancers depending on the cancer type. We found the HER3-V104L mutation to be activating from patient-derived mutations introduced via lentiviral transduction in HER3KO HER2 + HCC1569 breast cancer cells in which endogenous HER3 was eliminated by CRISPR/Cas9. Cells expressing HER3-V104L showed higher p-HER3 and p-ERK1/2 expression versus cells expressing wild-type HER3 or HER3-V104M. Patients whose tumor expressed the HER3 V104L variant had a reduced probability of overall survival compared to patients lacking a HER3 mutation whereas we did not find a statistically significant difference in overall survival of various cancer patients with the HER3 V104M mutation. Our data showed that HER2 inhibitors suppressed cell growth of HCC1569HER3KO cells stably expressing the HER3-V104L mutation. Cancer cell lines (SNU407, UC15 and DV90) with endogenous HER3-V104M mutation showed reduced cell proliferation and p-HER2/p-ERK1/2 expression with HER2 inhibitor treatment. Knock down of HER3 abrogated cell proliferation in the above cell lines which were overall more sensitive to the ERK inhibitor SCH779284 versus PI3K inhibitors. HER3-V104L mutation stabilized HER3 protein expression in COS7 and SNUC5 cells. COS7 cells transiently transfected with the HER3-V104L mutation in the presence of HER binding partners showed higher expression of p-HER3, p-ERK1/2 versus HER3-WT in a NRG-independent manner without any change in AKT signaling. Overall, this study shows the clinical relevance of the HER3 V104L and the V104M mutations and its response to HER2, PI3K and ERK inhibitors.