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Because of its insensitivity to existing radiotherapy, namely chemotherapy and targeted treatments, triple-negative breast cancer (TNBC) remains a great challenge to overcome. Increasing evidence has indicated abnormal Wnt/β-catenin pathway activation in TNBC but not luminal or HER2+ breast cancer, and lncRNAs play a key role in a variety of cancers. Through lncRNA microarray profiling between activated and inactivated wnt/β-catenin pathway of TNBC tissues, lnc-WAL (wnt/β-catenin associated lncRNA; WAL) was selected as the top upregulated lncRNA in wnt/β-catenin pathway activation compared with the inactivation group. RIP-seq was used to compare the β-catenin and IgG groups, where lnc-WAL could interact with β-catenin. Clinically, increased lnc-WAL in TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted EMT, the proliferation, migration and invasion of breast cancer stem cells (BCSCs), and TNBC cells. Mechanistically, lnc-WAL inhibited β-catenin protein degradation via Axin-mediated phosphorylation at serine 45. Subsequently, β-catenin accumulated in the nucleus and activated the target genes. Importantly, wnt/β-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/Axin/β-catenin in the malignant progression of TNBC. Our findings provide important clinical translational evidence that lnc-WAL may be a potential therapeutic target against TNBC. Implications: The positive feedback between lnc-WAL and the Wnt/β-catenin pathway promotes TNBC progression, and lnc-WAL could be a potential prognostic marker for TNBC patients.

Breast phyllodes tumor (PT) is a rare fibroepithelial neoplasm with potential malignant behavior. Long non-coding RNAs (lncRNAs) play multifaceted roles in various cancers, but their involvement in breast PT remains largely unexplored. In this study, microarray was leveraged for the first time to investigate the role of lncRNA in PT. We identified lncRNA ZFPM2-AS1 was significantly upregulated in malignant PT, and its overexpression endowed PT with high tumor grade and adverse prognosis. Furthermore, we elucidated that ZFPM2-AS1 promotes the proliferation, migration, and invasion of malignant PT in vitro . Targeting ZFPM2-AS1 through nanomaterial-mediated siRNA delivery in patient-derived xenograft (PDX) model could effectively inhibit tumor progression in vivo . Mechanistically, our findings showed that ZFPM2-AS1 is competitively bound to CDC42, inhibiting ACK1 and STAT1 activation, thereby launching the transcription of TNFRSF19. In conclusion, our study provides evidence that ZFPM2-AS1 plays a pivotal role in the pathogenesis of breast PT, and suggests that ZFPM2-AS1 could serve as a prognostic indicator for patients with PT as well as a promising novel therapeutic target., Competing Interests: The authors declare that they have no conflict of interest., (© 2024 The Authors.)

We previously reported the results of a phase II trial of anti-PD-1 antibody plus anti-vascular endothelial growth factor receptor 2 inhibitors and eribulin in heavily pretreated advanced triple-negative breast cancer with a favorable objective response rate (ORR) of 37.0% (NCT04303741). Here we report updated survival outcomes and serum metabolite changes of the study. Proton nuclear magnetic resonance spectroscopy was used to detect metabolite dynamics and explore biomarkers for response. We found that treatment-sensitive patients had higher very low-density lipoprotein-related metabolite expression at baseline. A lipid proteomics model consisting of six metabolites predicted ORR and progression-free survival at 6 months with area under the receiver operating characteristic curves of 0.88 and 0.87, respectively. Serum asparagine and sarcosine concentrations were significantly higher after treatment in treatment-resistant patients. In conclusion, we constructed a model consisting of six metabolites to identify patients who benefit more from the triplet treatment, and asparagine and sarcosine may be associated with treatment resistance., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Immunoglobulin G4-related lung disease (IgG4-RLD) is a rare entity. We retrospectively analyzed the clinical and histopathological characteristics of patients with pathologically confirmed IgG4-RLD to improve the diagnosis rate and reduce the risk of misdiagnosis., Methods: We screened the pathological reports of 4838 patients with pulmonary surgery and/or biopsy specimens from April 2017 to April 2021 at Sun Yat-Sen Memorial Hospital affiliated with Sun Yat-Sen University, and specimens from 65 patients with suspected IgG4-RLD were subjected to immunohistochemical staining for IgG4 and IgG. Finally, 10 patients with definite IgG4-RLD that was pathologically confirmed were enrolled and analyzed., Results: The incidence of pathologically confirmed IgG4-RLD was 0.2% (10/4838). The ten patients had an average age of 59.7 years at diagnosis, and the male-to-female ratio was 9:1. The initial clinical manifestations were nonspecific, and cough was the most common symptom (4/10). More than one organ was involved in most patients (8/10), and mediastinal/hilar lymph node involvement was often observed (7/10). Serum IgG4 was analyzed in 6 patients and found to be elevated. Serum tumor marker levels were within the normal range or were slightly elevated. Computed tomography (CT) of the chest and/or 18 F-fluorodeoxyglucose positron emission tomography-computed tomography ( 18 F-FDG PET-CT) imaging revealed that 5 patients had a mixed type, 3 patients had the solid nodular type, and 2 patients had the bronchovascular type. All pulmonary masses and large nodules with solid patterns had spiculated margins and inhomogeneous enhancement with or without pleural indentation and a lobulated appearance. Abundant lymphoplasmacytic cell infiltration and fibrosis were observed in all patients. The expression of IgG4 and IgG was upregulated in the pulmonary sections. Seven patients were treated with glucocorticoids with or without additional immunosuppressants and responded well., Conclusions: The results of our study suggest that multiple imaging findings, an elevated serum IgG4 concentration, and no significant increase in serum tumor biomarkers could provide diagnostic support for IgG4-RLD, especially for isolated IgG4-RLD or IgG4-RLD that includes other organ involvement that does not aid in establishing the diagnosis., (© 2021. The Author(s).)

Background: Here we evaluated the feasibility, efficacy, tolerability, and treatment-mediated immune modulation of neoadjuvant everolimus plus letrozole versus chemotherapy in treating postmenopausal patients with ER-positive, HER2-negative breast cancer., Methods: Postmenopausal women with ER-positive, HER2-negative breast cancer who had a primary tumor > 2 cm or positive axillary lymph node(s) proofed by biopsy were randomly (1,1) enrolled to receive neoadjuvant everolimus plus letrozole for 18 weeks or fluorouracil, epirubicin plus cyclophosphamide (FEC) for 6 cycles before surgery. Primary outcome was feasibility of the trial. Secondary outcome included ultrasound response rate, pathological complete response rate, breast-conserving surgery rate, toxicities, treatment-mediated immune modulation and biomarkers., Results: Forty patients were randomized. Completion rate was 90.0% in the neoadjuvant endocrine therapy (NET) arm but 70.0% in the neoadjuvant chemotherapy (NAC) arm. The ultrasound response rate was 65.0% in NET arm and 40.0% in FEC arm, respectively. In terms of the adverse events, clearly favored NET arm. Everolimus plus letrozole increased the ratio of peripheral Tregs to CD4 + T cells and tumor PD-L1 expression, and decreased Ki67 index and tumor-infiltrating Tregs, and patients with a greater increase of tumor-specific CTLs showed more sensitive to NET., Conclusion: This pilot trial showed that neoadjuvant everolimus plus letrozole might achieve a favorable ultrasound response rate with low toxicities in treating postmenopausal ER-positive, HER2-negative breast cancer patients. Everolimus plus letrozole might have positive antitumoral immunity effects. Further large randomized controlled trials are needed to confirm our findings., Trail Registration: A Trial of Neoadjuvant Everolimus Plus Letrozole Versus FEC in Women With ER-positive, HER2-negative Breast Cancer, registered on 07/04/2016 and first posted on 18/04/2016, NCT02742051 ., (© 2021. The Author(s).)

Background: In addition to protein tyrosine kinases, accumulating evidence has shown that protein tyrosine phosphatases (PTPs) are suitable therapeutic targets in cancer. PRL-3 is a PTP member that has been well studied in many malignant tumours. The goal of the present study was to elucidate the role of PRL-3 in hepatocellular carcinoma (HCC), which remains largely unknown. Methods: Bioinformatic and immunohistochemical analyses were performed to analyse PRL-3 expression in HCC tissue samples and determine its clinical relevance. PRL-3 gene copy number variations were evaluated by bioinformatic analysis and quantitative-genomic polymerase chain reaction. The biological functions of PRL-3 were investigated in vivo and vitro. Gene microarray assays, RT-qPCR, western blotting and luciferase experiments were performed to identify the downstream effectors of PRL-3 that mediate its functions in HCC. Results: PRL-3 expression was upregulated in HCC samples from public databases and in cohort samples from our centre. High PRL-3 expression was associated with poor prognosis. Copy number gains and amplification of chromosome 8q24.3 in HCC were determined to be positively correlated with the PRL-3 overexpression. PRL-3 overexpression promoted HCC cell proliferation, migration and adhesion, while its loss had the opposite effects. Further study showed that focal adhesion kinase (FAK) was co-amplified and co-expressed with PRL-3 in HCC. Interestingly, PRL-3 also promoted the phosphorylation of FAK, which subsequently mediated the oncogenic functions of PRL-3 in HCC cells. Moreover, TGFB1 was identified as a downstream molecule of PRL-3. TGF-β signalling was shown to mediate the PRL-3-induced activation of FAK. Furthermore, the p38 and PI3K/AKT pathways were observed to mediate the PRL-3-induced expression of TGFB1 and the subsequent activation of FAK, while the activation of FAK in turn stimulated activation of the p38 and PI3K/AKT pathways, forming a PRL-3-triggered AKT/p38/TGFB1/FAK positive feedback loop. Conclusion: Collectively, our findings indicate that the PTP PRL-3 plays a crucial role in the progression of HCC and provides an example of how co-amplified genes work together in HCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: To investigate the relationship between gasdermin D (GSDMD) expression and the invasion of adenoid cystic carcinoma (ACC)., Methods: Immunohistochemistry (IHC) was used to examine GSDMD expression in tumours and adjacent non-cancerous (ANC) tissues from 33 patients with salivary ACC patients and in tumour samples from 29 patients with pleomorphic adenoma (PA). Lentiviral infection was used to stably overexpress GSDMD in ACC-LM and ACC-83 cells (GSDMD-ov cells), which were subjected to transwell and scratch tests to assess their invasive abilities compared to control cells. Cells overexpressing GSDMD were treated with siRNA targeting GSDMD, and their invasive ability was subsequently examined., Results: GSDMD expression was significantly higher in ACC tissues than in corresponding ANC tissues (P<0.001). After 24 hours, both the ACC-83 and ACC-LM GSDMD-ov cell lines had more cells that moved through the membrane than did the control cells (P<0.05). For the wound healing experiment, the diameter of the wound in the GSDMD-ov cell lines was smaller than that of the control cells (P<0.001) after 24 hours. The ACC cell lines expressing high GSDMD showed stronger metastatic ability than did the control., Conclusion: GSDMD was highly expressed in ACC tissues compared to ANC tissues, and high GSDMD expression promoted the invasion of ACC cells. These findings suggest that GSDMD expression is related to the invasion of ACC. Our data indicate that we may be able to use GSDMD as an indicator of the invasive or metastatic potential of tumour cells in future research., Competing Interests: None., (IJCEP Copyright © 2020.)

Background: The prognosis of breast phyllodes tumors (PTs) largely depending on the pathological grading, which lacks objectivity. This study aimed to develop a nomogram based on clinicopathological features to evaluate the recurrence probability of PTs following surgery., Methods: Data from 334 patients with breast PTs, who underwent surgical treatment at Sun Yat-sen Memorial Hospital from January 2005 to December 2014, were used to develop a prediction model. Additionally, data of 36 patients from Peking University Shenzhen Hospital (cohort 1) and data of 140 patients from Sun Yat-sen University Cancer Center (cohort 2) during the same period were used to validate the model. The medical records and tumor slides were retrospectively reviewed. The log-rank and Cox regression tests were used to develop a clinical prediction model of breast PTs. All statistical analyses were performed using R and STATA., Results: Of all 334 patients included in the primary cohort, 224 had benign, 91 had borderline, and 19 had malignant tumors. The 1-, 3-, and 5-year recurrence-free survival was 98.5%, 97.9%, and 96.8%, respectively. Ultrasound-guided vacuum-assisted biopsy (UGVAB) is a non-inferior treatment application in benign PTs compared with open surgery [hazard ratio (HR), 2.38; 95% confidence interval (CI), 0.59-9.58]. Width of surgical margin, mitoses, and tumor border were identified as independent risk factors for breast PTs. A nomogram was developed based on these three variables. The C-index of internal and external validation was 0.71, 0.67 (cohort 1) and 0.73 (cohort 2), respectively., Conclusions: The study model presented more concise and objective variables to evaluate the recurrence-free survival of patients after surgery, which can help deciding whether to do a re-excision or "wait and watch"., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Background: In microenvironment of malignant tumors, Hypoxia-Inducible Factors (HIF), most importantly HIF-1α, play an important role in regulation of adaptive biological response to hypoxia, promoting angiogenesis and metastasis. However, the underlying mechanism that HIF-1α regulates metastasis needs to be further clarified. Methods: The expressions of HIF-1α and SP1 were detected in 182 samples of esophageal squamous cell carcinoma (ESCC) and adjacent normal tissues by immunohistochemistry (IHC), and the correlation between the expression levels of HIF-1α and SP1 was analyzed. The expression of HIF-1α in ESCC cell lines TE1 and KYSE30 was then detected using qRT-PCR and western blot. The potential binding sites of HIF-1α on the SP1 promoter were analyzed using UCSC and JASPAR databases, verified by chromosomal immunoprecipitation (ChIP) assay and qRT-PCR. The effects of HIF-1α and SP1 on ESCC cell migration and invasion were then tested with Transwell and Matrigel experiments. Results: The expression of HIF-1α in cancer tissues is higher than adjacent normal tissues, and is correlated with metastasis, recurrence and poor prognosis. Upon silencing HIF-1α by siRNA, the invasion and migration ability of ESCC cells were significantly inhibited, which could be restored by the overexpression of SP1. Hypoxic conditions significantly increased the expression of HIF-1α and SP1 at both protein and mRNA levels in ESCC cells. HIF-1α enhanced SP1 transcription through binding to the promoter region. The expression of protein and mRNA levels of SP1 was decreased by silencing HIF-1α in cells. In contrast, overexpression of HIF-1α significantly increased the mRNA and protein levels of SP1. The expression of SP1 in ESCC was positively correlated with the protein expression of HIF-1α and poor prognosis. Conclusion: The results of our study indicate that HIF-1α promotes metastasis of ESCC by targeting SP1 in a hypoxic microenvironment. Further study on this mechanism may elucidate the possibility of HIF-1α and SP1 as new targets for the treatment of ESCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Circular RNAs (circRNAs), a novel class of noncoding RNAs, have recently drawn much attention in the pathogenesis of human cancers. However, the role of circRNAs in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we aimed to identify novel circRNAs that regulate ESCC progression and explored their regulatory mechanisms and clinical significance in ESCC., Methods: Differentially expressed circRNAs between ESCC and paired adjacent normal tissues were identified using microarrays. The effects of a specific differentially expressed circRNA (circGSK3β) on tumor progression were explored in vitro and in vivo. Plasma samples from patients with ESCC, benign lesions and healthy controls were subjected to droplet digital PCR (ddPCR) analyses for circGSK3β, and the detection rates of plasma circGSK3β for ESCC were investigated., Results: We demonstrated that upregulated expression of circGSK3β was positively associated with advanced clinical stage and poor outcome in patients with ESCC. We further revealed that circGSK3β promoted ESCC cell migration and invasion via direct interaction with GSK3β and inhibiting GSK3β activity, providing a novel mechanism of circRNA in cancer progression. Importantly, we identified that circGSK3β expression in plasma was a biomarker for detection of ESCC and early stage of ESCC with the area under curve (AUC) of 0.782 and 0.793, respectively., Conclusions: CircGSK3β exerts critical roles in promoting ESCC metastasis and may serve as a novel therapeutic target for ESCC patients. The plasma level of circGSK3β have potential to serve as a novel diagnostic and prognostic biomarker for ESCC detection.

Background: Non-small cell lung cancer (NSCLC) is one of the most common human malignancies and the leading cause of cancer-related death. Over the past few decades, genomic alterations of cancer driver genes have been identified in NSCLC, and molecular testing and targeted therapies have become standard care for lung cancer patients. Here we studied the unique genomic profile of driver genes in Chinese patients with NSCLC by next-generation sequencing (NGS) assay., Materials and Methods: A total of 1,200 Chinese patients with NSCLC were enrolled in this study. The median age was 60 years (range: 26-89), and 83% cases were adenocarcinoma. NGS-based genomic profiling of major lung cancer-related genes was performed on formalin-fixed paraffin-embedded tumor samples and matched blood., Results: Approximately 73.9% of patients with NSCLC harbored at least one actionable alteration recommended by the National Comprehensive Cancer Network guideline, including epidermal growth factor receptor ( EGFR ), ALK , ERBB2 , MET , BRAF , RET , and ROS1 . Twenty-seven patients (2.2%) harbored inherited germline mutations of cancer susceptibility genes. The frequencies of EGFR genomic alterations (both mutations and amplification) and ALK rearrangement were identified as 50.1% and 7.8% in Chinese NSCLC populations, respectively, and significantly higher than the Western population. Fifty-six distinct uncommon EGFR mutations other than L858R, exon19del, exon20ins, or T790M were identified in 18.9% of patients with EGFR -mutant NSCLC. About 7.4% of patients harbored both sensitizing and uncommon mutations, and 11.6% of patients harbored only uncommon EGFR mutations. The uncommon EGFR mutations more frequently combined with the genomic alterations of ALK , CDKN2A , NTRK3 , TSC2 , and KRAS . In patients <40 years of age, the ALK -positive percentage was up to 28.2%. Moreover, 3.2% of ALK -positive patients harbored multi ALK rearrangements, and seven new partner genes were identified., Conclusion: More unique features of cancer driver genes in Chinese NSCLC were identified by next-generation sequencing. These findings highlighted that NGS technology is more feasible and necessary than other molecular testing methods, and suggested that the special strategies are needed for drug development and targeted therapy for Chinese patients with NSCLC., Implications for Practice: Molecular targeted therapy is now the standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC). Samples of 1,200 Chinese patients with NSCLC were analyzed through next-generation sequencing to characterize the unique feature of uncommon EGFR mutations and ALK fusion. The results showed that 7.4% of EGFR-mutant patients harbored both sensitizing and uncommon mutations and 11.6% harbored only uncommon mutations. Uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. ALK fusion was more common in younger patients, and the frequency decreased monotonically with age. 3.2% of ALK-positive patients harbored multi ALK rearrangement, and seven new partner genes were identified., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Accumulating evidence indicates that CCL18 and the long non-coding RNA, HOTAIR, have critical roles in cancer progression and metastasis, but the correlation between CCL18 and HOTAIR in esophageal squamous cell carcinoma (ESCC) and their downstream molecular mechanisms remain unclear. Overexpression of CCL18 in ESCC tissues was associated with a worse survival in patients with ESCC. CCL18 enhanced the invasiveness of ESCC cells in a dose-dependent manner, whereas CCL18 knockdown inhibited their invasiveness. In particular, CCL18 expression was positively associated with HOTAIR expression in ESCC tissues. Furthermore, CCL18 upregulated the expression of HOTAIR, and knockdown of HOTAIR alleviated the CCL18-induced invasiveness of ESCC cells. HOTAIR may act as a competing endogenous RNA and could effectively becoming a sponge for miR-130a-5p, thereby modulating the derepression of ZEB1 and promoting epithelial-mesenchymal transition in ESCC. Our study suggests that CCL18 contributes to the malignant progression of esophageal cancer by upregulating HOTAIR expression. HOTAIR overexpression may promote tumor invasiveness and progression in ESCC, given that HOTAIR functions as a miR-130a-5p sponge, positively regulating ZEB1. This provides new therapeutic targets for early diagnosis and treatment of ESCC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Triple negative breast cancer (TNBC) is an aggressive and heterogeneous disease. Nomograms predicting outcomes of TNBC are needed for risk management., Methods: Nomograms were based on an analysis of 296 non-metastatic TNBC patients treated at Sun Yat-sen Memorial Hospital from 2002 to 2014. The end points were disease-free survival (DFS) and overall survival (OS). Predictive accuracy and discriminative ability were evaluated by concordance index (C-index), area under the curve (AUC) and calibration curve, and compared with the American Joint Committee on Cancer (AJCC) staging system, PREDICT and CancerMath. Models were subjected to bootstrap internal validation and external validation using independent cohorts of 191 patients from the second Xiangya Hospital and Peking University Shenzhen Hospital between 2007 and 2012., Results: On multivariable analysis of training cohort, independent prognostic factors were stromal tumor-infiltrating lymphocytes (TILs), tumor size, node status, and Ki67 index, which were then selected into the nomograms. The calibration curves for probability of DFS and OS showed optimal agreement between nomogram prediction and actual observation. The C-index of nomograms was significantly higher than that of the seventh and eighth AJCC staging system for predicting DFS (training: 0.743 vs 0.666 (P = 0.003) and 0.664 (P = 0.024); validation: 0.784 vs 0.632 (P = 0.02) and 0.607 (P = 0.002)) and OS (training: 0.791 vs 0.683 (P = 0.004) and 0.677 (P < 0.001); validation: 0.783 vs 0.656 (P = 0.006) and 0.606 (P = 0.001)). Our nomograms had larger AUCs compared with PREDICT and CancerMath. In addition, the nomograms showed good performance in stratifying different risk groups of patients both in the training and validation cohorts., Conclusion: We have developed novel and practical nomograms that can provide individual prediction of DFS and OS for TNBC based on stromal TILs, tumor size, node status, and Ki67 index. Our nomograms may help clinicians in risk consulting and selection of long term survivors.

Our previous study demonstrated that long non-coding RNA (lncRNA) HOTTIP was maximally expressed in PDAC, and promoted cancer cell progression and epithelial to mesenchymal transition (EMT). Numerous studies indicated that lncRNAs or EMT supported cancer stem cells. However, the role of HOTTIP in pancreatic cancer stem cells (PCSCs) remains unclear. Here, we evaluated the role and mechanism of HOTTIP in PCSCs. First, we analyzed the relationship between HOTTIP expression and overall or disease-free survival in 90 patients with PDAC after radical resection. Patients with higher HOTTIP expression had shorter disease-free survival and overall survival than those with lower expression. Expression of HOTTIP and other lncRNAs was detected in PCSCs and non-PCSCs by laser capture microdissection (LCM). HOTTIP was highly expressed in PCSCs. In addition, in vitro assays showed that HOTTIP alterations affected stemness, including sphericity, tumorigenesis, and stem factors (LIN28, NANOG, OCT4, and SOX2) and markers (ALDH1, CD44, and CD133). Mechanistically, HOTTIP mediated HOXA9 to enhance the Wnt/β-catenin pathway by binding to WDR5 in PCSCs. In vivo results showed that HOTTIP or HOXA9 alterations influenced stemness. Our results indicate that the HOTTIP/WDR5/HOXA9/Wnt axis contributes to PCSC stemness and is a potential therapeutic target for PDAC., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)