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Idiopathic pulmonary fibrosis (IPF) is an aggressive disease in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and TGF-β1 cooperates in the transcriptional control of collagen homeostasis in normal and fibrotic conditions. For this purpose we cultured fibroblasts from IPF patients or control donors on hydrogels with tunable elasticity, including 3D collagen-I gels and 2D polyacrylamide (PAA) gels. We found that TGF-β1 consistently increased COL1A1 while decreasing MMP1 mRNA levels in hydrogels exhibiting pre-fibrotic or fibrotic-like rigidities concomitantly with an enhanced activation of the FAK/Akt pathway, whereas FAK depletion was sufficient to abrogate these effects. We also demonstrate a synergy between matrix stiffening and TGF-β1 that was positive for COL1A1 and negative for MMP1. Remarkably, the COL1A1 expression upregulation elicited by TGF-β1 alone or synergistically with matrix stiffening were higher in IPF-fibroblasts compared to control fibroblasts in association with larger FAK and Akt activities in the former cells. These findings provide new insights on how matrix stiffening and TGF-β1 cooperate to elicit excessive collagen-I deposition in IPF, and support a major role of the FAK/Akt pathway in this cooperation.

Background: Tamoxifen (tam) is widely used to treat estrogen-positive breast cancer. However, cancer recurrence after chemotherapy remains a major obstacle to achieve good patient prognoses. In this study, we aimed to identify genes responsible for epigenetic regulation of tam resistance in breast cancer. Methods: Methylation microarray data were analyzed to screen highly hypomethylated genes in tam resistant (tamR) breast cancer cells. Quantitative RT-PCR, Western blot analysis, and immunohistochemical staining were used to quantify expression levels of genes in cultured cells and cancer tissues. Effects of matrix metalloproteinase-1 (MMP1) expression on cancer cell growth and drug resistance were examined through colony formation assays and flow cytometry. Xenografted mice were generated to investigate the effects of MMP1 on drug resistance in vivo. Results: MMP1 was found to be hypomethylated and overexpressed in tamR MCF-7 (MCF-7/tamR) cells and in tamR breast cancer tissues. Methylation was found to be inversely associated with MMP1 expression level in breast cancer tissues, and patients with lower MMP1 expression exhibited a better prognosis for survival. Downregulating MMP1 using shRNA induced tam sensitivity in MCF-7/tamR cells along with increased apoptosis. The xenografted MCF-7/tamR cells that stably expressed short hairpin RNA (shRNA) against MMP1 exhibited retarded tumor growth compared to that in cells expressing the control shRNA, which was further suppressed by tam. Conclusions: MMP1 can be upregulated through promoter hypomethylation in tamR breast cancer, functioning as a resistance driver gene. MMP1 can be a potential target to suppress tamR to achieve better prognoses of breast cancer patients.

circular RNAs (circRNAs) have been demonstrated to play a crucial role in cancer progression. KIAA1429, a key component of the m6A methyltransferase complex, has recently been reported to promote hepatocellular carcinoma (HCC) progression by regulating the m6A methylation. The aim of present study is to investigate the role of circular RNAs in KIAA1429-mediated HCC progression. RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (m6A-seq) were utilized to identify KIAA1429-regulated circRNAs. The effects of circDLC1 on proliferation and metastasis of hepatoma cells were examined and . RT-qPCR was used to measure the expression of circDLC1 in HCC tissues and hepatoma cells. RNA FISH, RIP assays and biotin-labeled RNA pull-down were used to investigate the downstream effector of circDLC1. The downstream targets of circDLC1 were identified using RNA-seq. Our data demonstrated that circDLC1 was downregulated in HCC tissues and closely relevant to favorable prognosis. Overexpression of circDLC1 inhibited the proliferation and motility of hepatoma cells and while silencing of circDLC1 played the opposite role. Mechanistic investigations revealed that circDLC1 could bind to RNA-binding protein HuR, which subsequently reduced the interaction between HuR and MMP1 mRNAs, and thus inhibited the expression of MMP1, ultimately contributing to inhibition of HCC progression. Our work suggests that circDLC1, a downstream target of KIAA1429, is a promising prognostic marker for HCC patients, and the circDLC1-HuR-MMP1 axis may serve as a potential therapeutic target for HCC treatment.

Contrary to many reports that antiplatelet agents inhibit cancer growth and metastasis, new solid tumors have been reported in patients receiving long-term antiplatelet therapy. We investigated the effects of these agents directly on cancer cells in the absence of platelets to mimic the effects of long-term therapy. When four antiplatelet agents (aspirin, clopidogrel, prasugrel, and ticagrelor) were administered to colon cancer cells, cancer cell proliferation was inhibited similarly to a previous study. However, surprisingly, when cells were treated with a purinergic P2Y12 inhibitor (purinergic antiplatelet agent), the motility of the cancer cells was significantly increased. Therefore, gene expression profiles were identified to investigate the effect of P2Y12 inhibitors on cell mobility, and Serpin family 1 (SERPINE1) was identified as a common gene associated with cell migration and cell death in three groups. Antiplatelet treatment increased the level of SERPINE1 in cancer cells and also promoted the secretion of SERPINE1 into the medium. Increased SERPINE1 was found to induce MMP1 and, thus, increase cell motility. In addition, an increase in SERPINE1 was confirmed using the serum of patients who received these antiplatelet drugs. With these results, we propose that SERPINE1 could be used as a new target gene to prevent the onset and metastasis of cancer in patients with long-term antiplatelet therapy.

The pathogenesis of oral squamous cell carcinoma (OSCC) remains unclear. Therefore, clarifying its pathogenesis and molecular‐level development mechanism has become the focus of OSCC research. N‐acetyltransferase 10 (NAT10) is a crucial enzyme involved in mRNA acetylation, regulating target gene expression and biological functions of various diseases through mediating N4‐acetylcytidine (ac4C) acetylation. However, its role in OSCC progression is not well understood. In this study, we showed that NAT10 was significantly upregulated in OSCC tissues compared to normal oral tissues. Moreover, lentivirus‐mediated NAT10 knockdown markedly suppressed cell proliferation, migration, and invasion in two OSCC cell lines (SCC‐9 and SCC‐15). Interestingly, MMP1 was found to be significantly upregulated in OSCC tissues and was a potential target of NAT10. N‐acetyltransferase 10 knockdown significantly reduced both the total and ac4C acetylated levels of MMP1 mRNA and decreased its mRNA stability. Xenograft experiments further confirmed the inhibitory effect of NAT10 knockdown on the tumorigenesis and metastasis ability of OSCC cells and decreased MMP1 expression in vivo. Additionally, NAT10 knockdown impaired the proliferation, migration, and invasion abilities in OSCC cell lines in an MMP1‐dependent manner. Our results suggest that NAT10 acts as an oncogene in OSCC, and targeting ac4C acetylation could be a promising therapeutic strategy for OSCC treatment.

CD26 has been reported as a marker for colorectal cancer stem cells endowed with tumor-initiating properties and capable of colorectal cancer (CRC) metastasis. In this study, we investigated the functional effect of CD26 on CRC angiogenesis and metastasis, and the potential underlying mechanism. The functional effects of CD26 overexpression or repression were determined by a wound healing experiment, and cell migration and invasion assays in vitro and in mouse models. Differentially expressed genes regulated by CD26 were identified by genome-wide mRNA expression array and validated by quantitative PCR. CD26 functionally regulated CRC cell migration and invasion in vitro and angiogenesis and metastasis in vivo. Genome-wide mRNA expression array and qPCR showed that MMP1 was up-regulated in CD26+ subpopulation, and a subsequent experiment demonstrated the regulatory effect of CD26 on MMP1 in CRC cell lines with CD26 repression or overexpression. Furthermore, overexpression of CAV1 abrogated the CD26-regulated MMP1 induction in CRC cell lines. This study demonstrated the functional roles of CD26 in inducing CRC migration, invasion, angiogenesis and metastasis and identified the potential involvement of MMP1 and CAV1 in such process. CD26 is an attractive therapeutic target for combating tumor progression to improve the prognosis of CRC patients.

Background Triple-negative breast cancer (TNBC) is highly aggressive with an increased metastatic incidence compared to other breast cancer subtypes. However, due to the absence of clinically reliable biomarkers and targeted therapy in TNBC, outcomes are suboptimal. Hence, there is an urgent need to understand biological mechanisms that lead to identifying novel therapeutic targets for managing metastatic TNBC. Methods The clinical significance of MUC16 and ELAVL1 or Hu antigen R (HuR) was examined using breast cancer TCGA data. Microarray was performed on MUC16 knockdown and scramble TNBC cells and MUC16-associated genes were identified using RNA immunoprecipitation and metastatic cDNA array. Metastatic properties of MUC16 were evaluated using tail vein experiment. MUC16 and HuR downstream pathways were confirmed by ectopic overexpression of MUC16-carboxyl-terminal (MUC16-Cter), HuR and cMyc as well as HuR inhibitors (MS-444 and CMLD-2) in TNBC cells. Results MUC16 was highly expressed in TNBC and correlated with its target HuR. Depletion of MUC16 showed decreased invasion, migration, and colony formation abilities of human and mouse TNBC cells. Mice injected with MUC16 depleted cells were less likely to develop lung metastasis ( P  = 0.001). Notably, MUC16 and HuR were highly expressed in the lung tropic TNBC cells and lung metastases. Mechanistically, we identified cMyc as a HuR target in TNBC using RNA immunoprecipitation and metastatic cDNA array. Furthermore, MUC16 knockdown and pharmacological inhibition of HuR (MS-444 and CMLD-2) in TNBC cells showed a reduction in cMyc expression. MUC16-Cter or HuR overexpression models indicated MUC16/HuR/cMyc axis in TNBC cell migration. Conclusions Our study identified MUC16 as a TNBC lung metastasis promoter that acts through HuR/cMyc axis. This study will form the basis of future studies to evaluate the targeting of both MUC16 and HuR in TNBC patients.

It is challenging to find a therapeutic Chinese medicine monomer (CHMs) for platinum-resistant patients, who currently have few treatment options, due to the complex mechanisms and the large number of CHMs available. This study aimed to identify CHM to overcome cisplatin resistance in EOC through bioinformatics analysis with experiment. This study used a strategy opposite to conventional network pharmacology. RNA expression of cisplatin sensitive and resistant EOC cell lines was obtained from the GEO database. Through differential expression gene (DEG) analysis, PPI network analysis, and survival analysis, we identified hub genes related to platinum resistance. CHMs targeting these hub genes were identified from the HIT 2.0 and molecular docking, molecular dynamics (MD) simulations, and SPR assay were used to validate their binding ability. Then, the anti-cancer effects of CHM in cisplatin-resistant cell lines were verified via experiment. 16 hub genes were selected through DEG and PPI network analysis. Following validation via survival analysis in the TCGA-OV cohort, the investigation ultimately focused on MMP1. Western blotting results demonstrated that MAPK signaling pathway activation induced MMP1 expression in cisplatin-resistant EOC cells. 22 CHMs targeting MMP1 were found in HIT 2.0 and quercetin was demonstrated the strong affinity of quercetin for MMP1 via molecular docking, MD simulations and SPR assay. Quercetin also exhibited strong binding affinity to other hub genes, including EGR1, STAT1, and PRKCA. experiments demonstrated that quercetin effectively inhibited the proliferation, apoptosis resistance, invasion, and migration of cisplatin-resistant EOC cells. The combination of cisplatin and quercetin had a strong synergistic effect, as indicated by the ZIP synergy score (≥10). Our study identified quercetin, which functions by targeting multiple cisplatin resistance-related proteins, including MMP1, as a potential therapeutic CHM for cisplatin resistant EOC. This study also explored quercetin's mechanisms against platinum-resistant ovarian cancer. By identifying hub platinum-resistance associated genes and screening potential CHMs through bioinformatics, computer simulation, and experiments, this integrated analytical approach also offers a reference for discovering CHMs for other diseases.

Background Pancreatic cancer remains one of the most lethal malignancies worldwide, underscoring the urgent need for reliable biomarkers to predict prognosis and guide therapy. This study aimed to identify and characterize such biomarkers using an integrated bioinformatics and experimental approach. Methods The GEO database was used to screen genes differentially expressed in pancreatic cancer. Next, the DAVID database was used for GO functional enrichment and KEGG pathway analyses. STRING database and Cytoscape software were utilized to generate PPI networks and identify key genes. The prognostic value was then evaluated by utilizing the GEPIA database and Cox regression analysis. The relationship between key genes and clinicopathological parameters was analyzed using the UALCAN database. The TISCH2, TIMER, and TISDB databases were used for immune infiltration analysis. The functional role of the key gene was ultimately confirmed through in vitro experiments. Results Through multiple rounds of strict screening, 10 key genes were obtained. After further verification, it was determined that MMP1 was significantly upregulated in pancreatic cancer tissue and correlated with poor prognosis in patients. Immunological analysis revealed correlations between MMP1 expression and the infiltration of specific immune cells (B cells, M1 macrophages, neutrophils, and monocytes) as well as the expression of immune checkpoint genes (VTCN1, LGALS9, TGFBR1, and IL10RB). In vitro functional assays confirmed that MMP1 knockdown in pancreatic cancer cells suppressed proliferation, migration, and invasion, while promoting apoptosis. Furthermore, a co-culture model demonstrated that MMP1 facilitated the recruitment of M1-polarized macrophages. Conclusion MMP1 is an independent prognostic biomarker that drives pancreatic cancer progression through direct oncogenic effects and modulation of the tumor immune microenvironment. Thus, it emerges as an attractive, multifunctional therapeutic target, which calls for future research to confirm its translational potential and delineate the underlying molecular pathways.

Background Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process. Methods We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens. Results We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 − 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 − 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p < 0.01). Conclusion Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.