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LncRNA AFAP1-AS1 modulates the sensitivity of paclitaxel-resistant prostate cancer cells to paclitaxel via miR-195-5p/FKBP1A axis

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (11)

LncRNA AFAP1-AS1 has been corroborated to function in diverse cancers. Our aim was to investigate the molecular mechanism of AFAP1-AS1 in PTX resistance in PCa. The levels of AFAP1-AS1, miR-195-5p, and FKBP1A were checked by qRT-PCR. 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-Diphenyltetrazolium Bromide (MTT) assay was employed to assess the resistance of PTX-resistant PCa cells to PTX. Flow cytometry was introduced to evaluate cell apoptosis. The protein levels of C-caspase 3 were determined by western blot. The starBase was used to predict the interaction between miR-195-5p and AFAP1-AS1. Xenograft tumor model was established to investigate the biological role of AFAP1-AS1 in PTX resistance in vivo. The levels of AFAP1-AS1 and FKBP1A were upregulated in PCa tissues and cells, as well as PTX-resistant PCa cells, while the expression of miR-195-5p was declined. Knockdown of AFAP1-AS1 promoted the sensitivity of PTX-resistant PCa cells to PTX, induced apoptosis of PTX-resistant PCa cells, whereas the impacts could be reversed by reducing the expression of miR-195-5p. FKBP1A overexpression could rescue the effects of miR-195-5p-mediated enhancement on the sensitivity of PTX-resistant PCa cells to PTX, promotion on apoptosis of PTX-resistant PCa cells. AFAP1-AS1 interacted with miR-195-5p and miR-195-5p could bind to the 3MODIFIER LETTER PRIMEUTR of FKBP1A. AFAP1-AS1 silencing inhibited the tumor growth in mice implanted with PC3-TXR cell. The protein level of PCNA was decreased in PC3-TXR cells transfected with sh-AFAP1-AS1, while the expression of C-caspase 3 was upregulated. AFAP1-AS1 silencing attenuated the resistance of PTX-resistant PCa cells to PTX by downregulating FKBP1A via sponging miR-195-5p.

Nivolumab induced hyperprogressive disease in advanced esophageal squamous cell carcinoma

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (12)

Immune checkpoint inhibitors have demonstrated promising efficacy and tolerable safety for advanced malignancies. However, a proportion of patients who had received immunotherapy may experience hyperprogressive disease and a resultant poor prognosis. Here, we report a patient with advanced esophageal squamous carcinoma who developed hyperprogressive disease shortly after immunotherapy. This patient received nivolumab after multiple lines of treatment, including chemotherapy, radiotherapy, and antiangiogenic therapy. Through the comprehensive analysis of NGS results, we concluded that the PI3K/AKT signaling pathway might be associated with hyperprogressive disease after immunotherapy. Additionally, potential mechanisms underlying hyperprogressive disease after immunotherapy reported in other malignant tumors were also summarized.

A novel prognostic biomarker for muscle invasive bladder urothelial carcinoma based on 11 DNA methylation signature

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (12)

Muscle-invasive bladder urothelial carcinoma (MIBC) is a highly invasive cancer, which leads to prevalent recurrence and poor prognosis. Exploring the association of DNA methylation and the prognosis of MIBC will thus be of important value in clinical management and treatment. Bumphunter method and adaptive lasso regression were used to explore the relationship between different methylation regions (DMRs) and the prognosis of MIBC. Next, we constructed a risk prognosis model and validated this model. Moreover, the performance of this risk model was examined by using time-dependent receiver operating characteristic curve (ROC). We identified 58,449 different methylation sites and 490 different methylation regions. Among them, 11 DMRs were associated with the prognosis of MIBC through rigorous screening. Through the linear combination of 11 DMRs, a putative marker was developed, which can distinguish the survival risk in both the training dataset (HR = 2.58, 95% CI = (1.64, 4.05)) and the verification dataset (HR = 2.77, 95% CI = (1.25, 6.15)). Relatively high predictive values were observed from this model for training dataset (AUC = 0.791) and verification dataset (AUC = 0.668). Stratified analysis showed that the association was independent of gender. A nomogram was additionally generated to predict 5-year survival probability containing risk score and pathological stage. Its performance was evaluated by applying calibration curve. The methylation signature risk model based on 11 DMRs may be a reliable prognostic signature for MIBC, which provides new insights into development of individualized therapy for MIBC.

Fruquintinib effectively controlled the advanced small bowel adenocarcinoma progressed after multiple lines of palliative treatment: a case report and literature review

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (12)

Small bowel cancer is a very rare disease. It can be treated by surgery at early stages; however, there is no standard therapeutic strategy established for the treatment of unresectable and/or metastatic diseases. Here we present a case of metastatic small bowel adenocarcinoma, which progressed after sequential treatment with XELOX (capecitabine and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), cetuximab, HER-2 targeted therapy and apatinib and was then effectively controlled by fruquintinib. Genetic testing showed wild-type KRAS/NRAS/BRAF, HER-2 amplification, and microsatellite stable. Then the patient started to receive fruquintinib and has already achieved a 6-month progression-free survival. Till Jun 2019, the treatment with fruquintinib is still ongoing and no severe adverse effect has been seen so far. Although fruquintinib is not, at present, a standard therapeutic strategy recommended by the treatment guideline for advanced small bowel adenocarcinoma, the significant curative effect has been seen in our clinical practice.

CYP2C8 regulated by GAS5/miR-382-3p exerts anti-cancerous properties in liver cancer

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (12)

A cornucopia of literatures has characterized the involvement of a host of functional molecules in liver cancer. Herein, according to online datasets, we found that cytochrome P450 family 2 subfamily C member 8 (CYP2C8) was downregulated in liver cancer, and high CYP2C8 expression was associated with favorable overall survival. Lower levels of CYP2C8 were confirmed in liver cancer cells. CYP2C8 overexpression efficiently attenuated liver cancer cell proliferation and promoted apoptosis. We then discovered that miR-382-3p directly targeted CYP2C8 to inhibit its expression in liver cancer cells based on bioinformatic prediction and experimental confirmation. Moreover, a cytoplasmic long noncoding RNA (lncRNA), growth arrest-specific 5 (GAS5), sponged and down-regulated miR-382-3p, thus positively modulating CYP2C8 expression. Rescue assays indicated that GAS5 overexpression gave rise to decreased proliferation and increased apoptosis of liver cancer cells, while CYP2C8 knockdown counteracted GAS5-mediated anti-carcinogenic effects. In summary, our work offered a solid experimental foundation for understanding the functional role of CYP2C8 and the mechanism of GAS5/miR-382-3p/CYP2C8 axis in cell proliferation and apoptosis of liver cancer.

Primary squamous cell carcinoma of the breast: report of two cases with HER2 overexpression

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (12)

Objective To investigate the clinicopathologic features and immunophenotype of primary squamous cell carcinoma of the breast (PSCCB) with HER2 overexpression. Methods Two cases of PSCCB with HER2 overexpression were retrospectively reviewed, and the pathological features, immunophenotype and prognosis were discussed. Results The tumor showed malignant squamous cells arranged in sheets, groups and nests, forming keratin-pearl and intercellular bridges. Immunohistochemical (IHC) analysis showed that the tumor cells were positive for 34 beta E12, p63, CK5/6, E-cadherin and P120, while negative for ER and PR. Furthermore, HER2 overexpression showed strong continuous expression in cell membrane with a score of 3+ by IHC, or amplification by FISH. Conclusions PSCCB is a rare tumor in breast cancer and HER2 overexpression is rather unusual in PSCCB. The diagnosis mainly depends on the clinicopathologic features together with the immunophenotype. HER2 positive indicates poor prognosis. However, targeted therapy for HER2 may be a new hope for patients.

The oncogenic role of SOX8 in endometrial carcinoma

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (12)

Endometrial carcinoma (EC) remains one of the most prevalent forms of cancer to impact the female reproductive system, yet the mechanisms governing its development and progression are incompletely understood. We, therefore, sought to assess the relevance of SOX8 to EC progression and patient prognosis. Array comparative genomic hybridization (aCGH) was performed using samples from 50 patients with EC. Samples were separated based upon whether patients were positive for lymph node metastasis (LN+ and LN-, respectively). Based on our initial results, the SOX8 gene was selected for further analysis. Immunohistochemical staining of 630 endometrial tissue samples was conducted to understand how SOX8 expression relates to specific EC clinicopathological characteristics. In addition, we explored the impact of SOX8 expression on the growth, invasion, and migration of EC cells through knockdown and overexpression experiments. In our initial aCGH analysis, SOX family proteins and the Wnt and Notch signaling pathways were significantly associated with EC LN metastasis. SOX8 expression was markedly increased in EC tumor samples relative to normal endometrial tissue (P= .003), and higher SOX8 expression was linked to a high tumor histological grade (P= .032), LN metastasis (P= .027), and shorter patient overall survival (P= .031). When SOX8 was knocked down, this further impaired the proliferative, invasive, and migratory activity of EC cells, whereas overexpressing this gene had the opposite effect. SOX8 may function in an oncogenic manner to drive EC development and progression, and higher SOX8 expression is associated with a poor EC patient prognosis.

Obesity and metabolic syndrome related macrophage promotes PD-L1 expression in TNBC through IL6/JAK/STAT pathway and can be reversed by telmisartan

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (12)

Breast cancer is the most common malignant tumor in women. Its incidence is associated with obesity and metabolic syndrome (MetS), which are highly prevalent world widely and have been identified as poorer prognosis factors in breast cancer including triple-negative breast cancer (TNBC), which has poorer response to chemotherapy, radiotherapy, and endocrine therapy. Programmed death ligand 1 (PD-L1) is one of the immune checkpoints ligands that facilitates tumor escape and progress. Obesity/MetS could cause systemic inflammation and immune disorders, however, whether and how obesity/MetS affect PD-L1 expression in breast cancer had not been clarified. In the present study, we examined the PD-L1 expression profile in breast cancer either in online database or cell lines. We found higher PD-L1 mRNA level but not DNA copy number in breast cancer than normal breast tissue, and higher PD-L1 expression in TNBC than other subtypes. Moreover, we found a positive relationship between PD-L1 expression in TNBC and metabolic complications in patients. Next, obesity/MetS related M1 macrophage was found to promote the expression of PD-L1 in breast cancer cells cocultured with polarized macrophages derived from either monocyte-like cell line THP-1 or Wistar rat models. IL6/JAK/STAT pathway was further identified to be involved in the process. In addition, we discovered that the PD-L1 expression promoted by obesity/MetS could be restored by telmisartan, one of the angiotensin II receptor blockers (ARBs) and could affect macrophage polarization, through its selective peroxisome proliferator-activated receptor-gamma (PPARG) activation and NFKB p65 inhibition and therefore downregulates IL6 secretion from M1 macrophage.

rAAV9-UPII-TK-EGFP can precisely transduce a suicide gene and inhibit the growth of bladder tumors

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (12)

Bladder cancer is a common and widespread cancer of the human urinary system, and its incidence is increasing. Gene therapy is a promising treatment of bladder cancer. In our study, a recombinant adeno-associated virus (rAAV9-UPII-TK-EGFP) driven by a UPII promoter was constructed. The efficacy and safety of infection of bladder cells was tested in vivo and in vitro. The ability of rAAV9-UPII-TK-EGFP to penetrate the glycosaminoglycan (GAG) layer on the surface of bladder cells and to transduce the bladder cells in vivo was very high. Additionally, we confirmed that the TK/GCV system has a powerful cytotoxic effect on bladder tumor cells in vitro and in vivo. Thus, our data indicate that rAAV9-UPII-TK-EGFP is a precise gene drug delivery system for the treatment of bladder cancer, and the TK/GCV therapeutic strategy has a powerful antitumor effect. These ?ndings can be widely used in clinical and scientific studies.

miR-219a-1 inhibits colon cancer cells proliferation and invasion by targeting MEMO1

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (12)

Colon cancer is the third most common cancer worldwide. Many miRNAs have been reported to be involved in colon cancer progression. However, there are only a few studies on the role of miR-219a-1 in colon cancer, and the molecular mechanisms involved remain unclear. The aim of this study was to investigate the miR-219a-1 level in patients with colon cancer and to explore both the effects and regulatory mechanisms of miR-219a-1 in the malignancy of colon cancer cells. Real-time PCR and western blot analysis were used to analyze the expression levels of miR-219a-1 and mediator of ErbB2-driven cell motility 1. Cell Counting Kit-8, transwell and wound-healing assays were performed to investigate the malignant ability of colon cancer cells. A luciferase assay was performed to explore whether miR-219a-1 could directly bind to 3MODIFIER LETTER PRIME-UTR region of MEMO1. miR-219a-1 was found to be downregulated in colon cancer cell lines and in patients with colon cancer. Additionally, miR-219a-1 could inhibit colon cancer cell proliferation, invasion and migration. We identified MEMO1 as a novel potential target gene of miR-219a-1. Luciferase assays showed that miR-219a-1 could directly bind to 3 '-UTR of MEMO1. Overexpression of miR-219a-1 in colon cancer cells could inhibit the expression of MEMO1. Furthermore, MEMO1 was upregulated in patients with colon cancer, which was inversely correlated with miR-219a-1 levels. In conclusion, our study revealed that miR-219a-1 exerts anti-tumor effects and regulates colon cancer cell proliferation, invasion and migration by targeting MEMO1, suggesting that miR-219a-1 could act as a therapeutic target in colon cancer.

LINC00641/miR-4262/NRGN axis confines cell proliferation in glioma

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (8)

Glioma is the most prevalent brain malignancy with high mortality. In recent decades, the regulatory role of long noncoding RNAs (lncRNAs) has been unmasked in glioma. In this study, we focused on the function and mechanism of LINC00641 in glioma. First of all, we found that LINC00641 was expressed at a low level in glioma cell lines. Importantly, overexpression of LINC00641 prevented cell proliferation but enhanced cell apoptosis. Meanwhile, NRGN, a previously-reported downregulated mRNA in GBM, was disclosed as a tumor suppressor in glioma cells. Besides, we verified that NRGN could be positively regulated by LINC00641 in glioma cells. Moreover, the cellular distribution of LINC00641 was identified to be cytoplasmic. Therefore, bioinformatics analysis and mechanism experiments were carried out and we determined that miR-4262 was the shared miRNA between LINC00641 and NRGN. In contrast to LINC00641 and NRGN, miR-4262 was dramatically upregulated in glioma cells. Furthermore, we confirmed that LINC00641 acted as a ceRNA in glioma cells via absorbing miR-4262 to upregulate NRGN. More importantly, silenced NRGN countervailed the repression on glioma cell proliferation caused by LINC00641 upregulation. Collectively, our findings unveiled that LINC00641 serves as a tumor inhibitor in glioma by targeting miR-4262/NRGN axis, providing a new potential therapeutic target for glioma patients.

Dysregulated circRNA_100876 contributes to proliferation and metastasis of colorectal cancer by targeting microRNA-516b (miR-516b)

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (8)

Colorectal cancer (CRC) is globally one of the most common malignant tumors. Increasing number of studies indicate that circular RNAs (circRNAs) play a significant role in the initiation and progression of CRC. However, the role of circRNA_100876 in CRC progression remains unclear. In this study, we investigated the expression and function of circRNA_100876 in CRC progression. The expression of circRNA_100876 and microRNA-516b (miR-516b) was compared in normal and CRC tissues using quantitative real-time polymerase chain reaction (RT-qPCR). In addition, proliferation, metastasis, and apoptosis of the cells were analyzed using Cell Counting Kit-8 (CCK-8) assay, Transwell assay, and flow cytometry, respectively. The relationship between circRNA_100876 and miR-516b was further verified using dual-luciferase reporter assay. Our data showed that circRNA_100876 was highly expressed in CRC tumor tissues, and the high expression gtransition (EMT)-related proteins. Furthermore, we found that the addition of miR-516b reversed the anti-tumor effect induced by the downregulation of circRNA_100876. In conclusion, this study revealed that circRNA_100876 is overexpressed in CRC tissues and represents a promising therapeutic target for CRC.

Distinctive targetable genotypes of younger patients with lung adenocarcinoma: a cBioPortal for cancer genomics data base analysis

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (1)

There is still limited comprehensive genotyping data about young patients with lung adenocarcinoma. Herein, next generation sequencing (NGS) data of lung adenocarcinoma patients was retrospectively analyzed to evaluate the relationship between young age at diagnosis and the comprehensive molecular characteristics. The cBioPortal for Cancer Genomics database was queried for cancer genomic studies of lung adenocarcinoma and a cohort of 773 patients with complete cancer genomics data was selected from 2 of 11 studies. The relationship between age at diagnosis and frequency of targetable genotypes was analyzed and verified in another cohort composed of 177 Chinese lung adenocarcinoma patients undergoing NGS assay. Of the 773 eligible lung adenocarcinoma patients, younger age was associated with an increased likelihood of a targetable genotype (P < .001). Specifically, a higher prevalence of EGFR mutations (P = .005), ALK arrangements, ROS1 arrangements (P = .035) and RET arrangements (P < .001) were identified in younger patients. The frequency of KRAS mutations (P < .001) was significantly associated with older age at diagnosis and a similar trend existed for MET (P = .057) but not BRAF-V600E (P = .686) and ERBB2 (P = .083). Additionally, an age at diagnosis of 45 years was found to be a feasible cutoff point to differentiate the younger from the older patients by comprehensive molecular characteristics. These results indicated that younger patients with lung adenocarcinoma were associated with an increased likelihood of harboring a targetable genotype. Distinctive molecular characteristics were identified in patients younger than 45 years with lung adenocarcinoma, which highlights the importance of the NGS assay and personalized therapy in this subpopulation.

Dexamethasone enhances the antitumor efficacy of Gemcitabine by glucocorticoid receptor signaling

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (4)

Gemcitabine (Gem) is currently used as the first-line therapy for liver and pancreatic cancer but has limited efficacy in most cases. Dexamethasone (Dex) have been applied as a chemoprotectant and chemosensitizer in cancer chemotherapy. This study further explored the potential of combination of Gem and Dex and tested the hypothesis that glucocorticoid receptor signaling is essential for the synergistic antitumor activity. In the HepG2 and AsPC-1 xenograft models, the combination treatment showed a significantly synergistic antitumor activity. Immunohistochemistry of post-treatment tumors showed a significant decrease in proliferation and angiogenesis as compared to either of the treatments alone. Dex alone and the combination with Gem inhibited the expression of glucocorticoid receptor. The combination of Dex and Gem showed synergistic cytotoxicity in cell lines in vitro. The antiproliferative synergism is prevented by used glucocorticoid receptor (GR) small interfering RNA, demonstrating that the glucocorticoid receptor is required for the antiproliferative synergism of Gem and Dex. The inhibition of glucocorticoid receptor signaling pathway and induction of apoptosis via activation of caspases 3, 8 and 9, PARP, contributed to the synergistic effect of this combination therapy. These results demonstrate that Dex could potentiate the antitumor efficacy of Gem. The synergistic antitumor activity of the combination of Dex and Gem was through glucocorticoid receptor signaling. Taken together, a combination of Dex and Gem shows a significant synergistic antitumor activity and lesser toxicity both in vitro and in vivo and could be a combination chemotherapy for the treatment of highly expression of glucocorticoid receptor patients.

Associations between genetic polymorphisms in interleukin-10 and hematological oncology: evidence from a meta-analysis

期刊: CANCER BIOLOGY & THERAPY, 2020; 21 (4)

Background: Associations between polymorphisms in interleukin-10 (IL-10) and hematological oncology were already explored by many genetic association studies, with controversial findings. The aim of this meta-analysis was to more comprehensively analyze associations between polymorphisms in IL-10 and hematological oncology by combing the results of all relevant studies. Methods: Eligible articles were searched from Pubmed, Embase, WOS and CNKI. The latest literature searching update was performed on 8 October 2019. We used Review Manager to combine the results of eligible studies. Results: Forty-one articles were included in this meta-analysis. IL-10 rs1800890 polymorphism was found to be significantly associated with hematological oncology under AA vs. TT+TA (recessive comparison, OR = 1.12, 95% CI 1.02-1.24), and rs1800896 polymorphism was also found to be significantly associated with hematological oncology under AA vs. AG+GG (dominant comparison, OR = 0.89, 95% CI 0.83-0.95) in overall combined analyses. In subgroup analyses, we observed positive results for rs1800871 (recessive comparison), rs1800872 (dominant, recessive and allele comparisons), and rs1800896 (dominant and allele comparisons) polymorphisms in the non-Hodgkin's lymphoma (NHL) subgroup. Besides, we also detected positive associations between rs1800872 polymorphism and acute leukemia (AL) (dominant and recessive comparisons) and found significant associations between rs1800896 polymorphism and chronic leukemia (CL) (recessive comparison). Conclusion: In summary, this meta-analysis demonstrated that IL-10 rs1800890, rs1800896, rs1800871 and rs1800872 polymorphisms may confer susceptibility to hematology oncology, especially for NHL.

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