Kinesins play important roles in the development and progression of many human cancers. The functions and underlying mechanisms of kinesin family member C1 (KIFC1), a member of the kinesin-14 family, ...in the pathogenesis of hepatocellular carcinoma (HCC) have not been fully elucidated.
In this study, 168 HCC samples were first analyzed to examine the association between KIFC1 expression and patient clinicopathological features and prognosis. The role of KIFC1 in HCC cell proliferation and metastasis was investigated both in vivo and in vitro. The upstream regulation and downstream targets of KIFC1 were studied by qRT-PCR, western blotting, coimmunoprecipitation, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.
KIFC1 was highly expressed in HCC tissues and positively associated with advanced stages and poor prognosis. KIFC1 knockdown suppressed HCC cell proliferation and invasion both in vitro and in vivo. Furthermore, KIFC1 knockdown decreased invadopodia formation and reduced epithelial-mesenchymal transition (EMT). HMGA1, an architectural transcriptional factor, was identified to interact with KIFC1. HMGA1 could bind to the promoters of Stat3, MMP2 and EMT-related genes and promote gene transcription. KIFC1 enhanced HMGA1 transcriptional activity and facilitated HCC proliferation and invasion. Moreover, KIFC1 was activated by TCF-4, and KIFC1 inhibition enhanced HCC cell sensitivity to paclitaxel.
Our findings suggest that KIFC1, activated by TCF-4, functions as an oncogene and promotes HCC pathogenesis through regulating HMGA1 transcriptional activity and that KIFC1 is a potential therapeutic target to enhance the paclitaxel sensitivity of HCC.
Colorectal cancer (CRC) is one of the most common malignancies causing the third highest mortality rate in the world. It is particularly urgent to explore effective therapeutic strategies to overcome ...this disease. We identified a novel benzothiazole derivative (BTD) that may serve as a potentially effective agent against CRC.
MTT assays, cell colony formation assays, EdU staining assays, flow cytometry, RNA-seq, Western blotting, and migration and invasion assays were used to examine the effects of BTD on cell proliferation, apoptosis, metastasis, and the cell cycle. The antitumor activity of BTD
was investigated in a CT26 tumor-bearing mouse model. Immunohistochemistry (IHC) was performed to examine the protein expression in mouse tumors. Hematology, biochemical analysis, and H&E staining were used to assess the biosafety of BTD.
We observed that BTD suppressed cell proliferation and metastasis and promoted the apoptosis of tumor cells
. Treatment with BTD at a tolerable dose significantly reduced tumor growth in CT26-tumor-bearing mice and appeared to be safe. Treatment of BTD induced apoptosis by increasing the generation of reactive oxygen species (ROS) and evoking the loss of mitochondrial transmembrane potential. Overall, BTD suppressed cell proliferation and metastasis, and induced apoptosis of colorectal tumor cells through the ROS-mitochondria-mediated apoptotic pathway. The preliminary proof of the antitumor activity and relative safety of BTD were validated in a mouse model.
Our findings suggest that BTD could serve as a potentially safe and effective candidate for CRC treatment.
Tumor-infiltrating lymphocytes (TILs) are clinically significant in triple-negative breast cancer (TNBC). Although a standardized methodology for visual TILs assessment (VTA) exists, it has several ...inherent limitations. We established a deep learning-based computational TIL assessment (CTA) method broadly following VTA guideline and compared it with VTA for TNBC to determine the prognostic value of the CTA and a reasonable CTA workflow for clinical practice.
We trained three deep neural networks for nuclei segmentation, nuclei classification and necrosis classification to establish a CTA workflow. The automatic TIL (aTIL) score generated was compared with manual TIL (mTIL) scores provided by three pathologists in an Asian (n = 184) and a Caucasian (n = 117) TNBC cohort to evaluate scoring concordance and prognostic value.
The intraclass correlations (ICCs) between aTILs and mTILs varied from 0.40 to 0.70 in two cohorts. Multivariate Cox proportional hazards analysis revealed that the aTIL score was associated with disease free survival (DFS) in both cohorts, as either a continuous hazard ratio (HR)=0.96, 95% CI 0.94–0.99 or dichotomous variable (HR=0.29, 95% CI 0.12–0.72). A higher C-index was observed in a composite mTIL/aTIL three-tier stratification model than in the dichotomous model, using either mTILs or aTILs alone.
The current study provides a useful tool for stromal TIL assessment and prognosis evaluation for patients with TNBC. A workflow integrating both VTA and CTA may aid pathologists in performing risk management and decision-making tasks.
National Natural Science Foundation of China, Guangdong Medical Research Foundation, Guangdong Natural Science Foundation.
Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Recently, targeted therapies including PD1 (programmed cell death 1) antibodies have been used in advanced GC ...patients. However, identifying new biomarker for immunotherapy is still urgently needed. The objective of this study is to unveil the immune evasion mechanism of GC cells and identify new biomarkers for immune checkpoint blockade therapy in patients with GC.
Coimmunoprecipitation and meRIP were performed to investigate the mechanism of immune evasion of GC cells. Cocuture system was established to evaluate the cytotoxicity of cocultured CD8
T cells. The clinical significance of HSPA4 upregulation was analyzed by multiplex fluorescent immunohistochemistry staining in GC tumor tissues.
Histone acetylation causes HSPA4 upregulation in GC tumor tissues. HSPA4 upregulation increases the protein stability of m
A demethylase ALKBH5. ALKBH5 decreases CD58 in GC cells through m
A methylation regulation. The cytotoxicity of CD8
T cells are impaired and PD1/PDL1 axis is activated when CD8
T cells are cocultured with HSPA4 overexpressed GC cells. HSPA4 upregulation is associated with worse 5-year overall survival of GC patients receiving only surgery. It is an independent prognosis factor for worse survival of GC patients. In GC patients receiving the combined chemotherapy with anti-PD1 immunotherapy, HSPA4 upregulation is observed in responders compared with non-responders.
HSPA4 upregulation causes the decrease of CD58 in GC cells via HSPA4/ALKBH5/CD58 axis, followed by PD1/PDL1 activation and impairment of CD8
T cell's cytotoxicity, finally induces immune evasion of GC cells. HSPA4 upregulation is associated with worse overall survival of GC patients with only surgery. Meanwhile, HSPA4 upregulation predicts for better response in GC patients receiving the combined immunotherapy.
Purpose
Neoadjuvant therapy is routinely used in the management of locally advanced rectal cancer. This study aimed to evaluate the predictive value of pathological parameters in tumor response after ...treatment.
Methods
We reviewed the hematoxylin–eosin slides from pretreatment biopsies of 150 rectal cancer patients who received preoperative chemoradiotherapy (PCRT) at Sun Yat-sen University Cancer Center between May 2013 and June 2016. Pathological and clinical parameters were both studied. The tumor response after chemoradiotherapy was evaluated using the tumor regression grade (TRG). Logistic regression was used to evaluate the relevance between these parameters and tumor response.
Results
Complete tumor response (TRG0 and pCR) to PCRT was identified in 40 (26.7%) patients. The pCR rate was 93.33% (14 of 15) in cases with signet ring cell component versus 19.26% (26 of 135) in those without signet ring cell component (
p
< 0.001). Four cases with signet ring cell component were evaluated as clinical complete response (cCR), all of whom also achieved pCR; in contrast, only 9 of 15 (60%) cCR cases without signet ring cell achieved pCR.
Conclusion
Our data suggest that the signet ring cell component in pretreatment biopsies may be a potential predictor of tumor response to PCRT in rectal cancer. This suggests patients with clinical complete response are more suitable for a wait-and-watch approach.
Cyclin F, capable of forming Skp1‐Cul1‐F‐box protein ubiquitin ligase complex, is implicated in controlling centrosome duplication and preventing genome instability. Cyclin F oscillates during cell ...cycle with a similar pattern to cyclin A. However, its expression and significance in cancer remain obscure. In this study, we showed that cyclin F was noticeably decreased in 16 pairs of tissue samples of hepatocellular carcinoma (HCC) compared to paracarcinoma tissues, at both mRNA and protein levels. Immunohistochemical staining data revealed that in 71.8% (176/245) of HCC cases, cyclin F expression in tumor tissue was much lower than that in nontumorous tissue. Low cyclin F expression, defined by receiver operating characteristic curve analysis, was present in 69.0% of HCC patients. Low expression of cyclin F was significantly correlated with tumor size, clinical stage, serum alpha‐fetoprotein level and tumor multiplicity. Further study showed that cyclin F expression was reversely associated with tumor differentiation in HCC. Kaplan–Meier analysis indicated that low cyclin F expression was related to poor overall survival and recurrence‐free survival. The prognostic impact of cyclin F was further confirmed by stratified survival analysis. Importantly, multivariate analysis revealed that low cyclin F expression was an independent poor prognostic marker for overall survival. We conclude that cyclin F is downregulated in HCC and is a promising prognostic marker for patients suffering from this deadly disease.
Polo-like kinase 4 (PLK4), belonging to serine/threonine kinase family, is critical for centriole replication and cell cycle progression. PLK4 has been proposed as a tumor suppressor in ...hepatocellular carcinoma (HCC). However, its expression and significance in HCC have not been well studied. In the present study, we found that PLK4 was markedly downregulated in both HCC cell lines and fresh cancer tissues, using quantitative real-time-PCR and western blot. Immunohistochemistry data also revealed that decreased expression of PLK4 was present in 72.4% (178/246) of HCC tissues, compared with the corresponding adjacent nontumorous tissues. Furthermore, PLK4 expression significantly correlated with clinicopathological parameters, including clinical stage (P=0.034), serum α-fetoprotein (AFP) (P=0.019) and tumor size (P=0.032). Moreover, HCC patients with low PLK4 expression survived shorter than those with high PLK4 expression, as indicated by overall survival (P=0.002) and disease-free survival (P=0.012) assessed by the Kaplan-Meier method. In addition, multivariate analysis suggested PLK4 as an independent predictor of overall survival (HR, 0.556; 95%CI, 0.376-0.822; P=0.003) and disease-free survival (HR, 0.547; 95%CI, 0.382-0.783; P=0.001). Collectively, our study demonstrated that PLK4 was remarkably downregulated in HCC and could be served as a potential prognostic marker for patients with this deadly disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although many studies have compared tumor fibroblasts (T-Fbs) and nontumor fibroblasts (N-Fbs), less is understood about the stromal contribution of metastatic lymph node fibroblasts (LN-Fbs) to the ...evolving microenvironment. Here, we explored the characteristics of LN-Fbs in esophageal squamous cell carcinoma (ESCC) and the interactions between fibroblasts and ESCC tumor cells in metastatic lymph nodes. Fibroblasts were isolated from tumor, nontumor and metastatic lymph node tissues from different patients with ESCC. Transcriptome sequencing was performed on the fibroblasts. Tumor growth and drug-resistance assays were carried out, and characteristics of T-Fbs, N-Fbs and LN-Fbs were determined. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to assay the culture medium of fibroblasts. The results demonstrated that fibroblasts derived from different tissues had different characteristics. Coculture with LN-Fbs conditioned medium inhibited ESCC tumor cell growth and induced chemoresistance in ESCC cells. LN-Fbs induced chemoresistance to cisplatin in ESCC cells by secreting PI16. Coculture with LN-Fbs conditioned medium decreased cisplatin-induced apoptosis in ESCC cells by regulating the p38 and JNK cell signaling pathways. Survival analyses showed that patients with high PI16 expression in Fbs of lymph nodes exhibited worse overall survival. We also examined PI16 expression in interstitial tissues in ESCC tumor samples of patients receiving platinum-based therapy postsurgery and found that high PI16 expression in tumor interstitial tissues was an independent prognostic factor for ESCC patients. In addition, an in vivo assay demonstrated that PI16 knockdown increased the sensitivity of ESCC cells to cisplatin. Our results suggest that fibroblasts in metastatic lymph nodes decrease apoptosis of ESCC cells via PI16, thereby providing a cisplatin-resistance niche and supporting ESCC tumor cells to survive in metastatic lymph nodes. PI16 is also a potential target for effectively blocking the chemoresistance niche signaling circuit in response to cisplatin.
Objective
This study aimed to develop an artificial intelligence model for predicting the pathological complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) of locally advanced rectal ...cancer (LARC) using digital pathological images.
Background
nCRT followed by total mesorectal excision (TME) is a standard treatment strategy for patients with LARC. Predicting the PCR to nCRT of LARC remine difficulty.
Methods
842 LARC patients treated with standard nCRT from three medical centers were retrospectively recruited and subgrouped into the training, testing and external validation sets. Treatment response was classified as pCR and non-pCR based on the pathological diagnosis after surgery as the ground truth. The hematoxylin & eosin (H&E)-stained biopsy slides were manually annotated and used to develop a deep pathological complete response (DeepPCR) prediction model by deep learning.
Results
The proposed DeepPCR model achieved an AUC-ROC of 0.710 (95% CI: 0.595, 0.808) in the testing cohort. Similarly, in the external validation cohort, the DeepPCR model achieved an AUC-ROC of 0.723 (95% CI: 0.591, 0.844). The sensitivity and specificity of the DeepPCR model were 72.6% and 46.9% in the testing set and 72.5% and 62.7% in the external validation cohort, respectively. Multivariate logistic regression analysis showed that the DeepPCR model was an independent predictive factor of nCRT (
P
=0.008 and
P
=0.004 for the testing set and external validation set, respectively).
Conclusions
The DeepPCR model showed high accuracy in predicting pCR and served as an independent predictive factor for pCR. The model can be used to assist in clinical treatment decision making before surgery.
It has long been observed that many cancer cells exhibit increased aerobic glycolysis and rely more on this pathway to generate ATP and metabolic intermediates for cell proliferation. ...Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme in glycolysis and has been known as a housekeeping molecule. In the present study, we found that GAPDH expression was significantly up-regulated in human colorectal carcinoma tissues compared to the adjacent normal tissues, and also increased in colon cancer cell lines compared to the non-tumor colon mucosa cells in culture. The expression of GAPDH was further elevated in the liver metastatic tissues compared to the original colon cancer tissue of the same patients, suggesting that high expression of GAPDH might play an important role in colon cancer development and metastasis. Importantly, we found that 3-bromopyruvate propyl ester (3-BrOP) preferentially inhibited GAPDH and exhibited potent activity in inducing colon cancer cell death by causing severe depletion of ATP. 3-BrOP at low concentrations (1–10 μM) inhibited GAPDH and a much higher concentration (300 μM) was required to inhibit hexokinase-2. The cytotoxic effect of 3-BrOP was associated with its inhibition of GAPDH, and colon cancer cells with loss of p53 were more sensitive to this compound. Our study suggests that GAPDH may be a potential target for colon cancer therapy.
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