HMGA1 is a Prognostic Biomarker and Correlated with Glycolysis in Lung Adenocarcinoma.

Purpose: Lung cancer is one of the leading causes with high morbidity and mortality. High mobility group A1 (HMGA1) protein participates in the process of tumorigenesis. This study seeks to explore the specific role of HMGA1 in prognostic value based on The Cancer Genome Atlas (TCGA) database of Lung adenocarcinoma (LUAD) and glycolysis progression in LUAD cells. Patients and Methods: In this research, we compared HMGA1 mRNA expression between tumor tissues and normal samples and evaluated the correlations with clinical characteristics in LUAD patients based on the data of TCGA database. The survival outcome with overall survival (OS), disease-specific survival (DSS) and clinicopathologic characteristics associated were performed using the Kaplan-Meier method and Cox regression. In addition, gene-set enrichment analysis (GSEA) was carried out to explore the biological pathways that related to HMGA1. Cell experiments including cell proliferation assay and glycolysis proteins were performed with A549 and H1299 cells. Results: Our results revealed that HMGA1 mRNA expression was higher in LUAD tissues than in normal tissues. Increased HMGA1 expression in LUAD was associated with Gender (p<0.01), Pathologic stage I&II vs stage III&IV (p<0.001), T1&T2 vs T3&T4 stage (p<0.05), N0 vs N2 stage (p<0.01). Furthermore, multivariate analysis revealed that HMGA1 was an independent risk factor of OS and DSS for LUAD patients (p<0.05). HMGA1 were positively correlated with glycolysis gluconeogenesis pathway and glycolysis markers (HK2, GLUT1, PKM2, LDHA) based on GSEA and Gene Expression Profiling Interactive Analysis (GEPIA) database. At the cellular level, the results of qRT-PCR and western blot assays showed that si-HMGA1 markedly decreased the expression of glycolysis markers. HMGA1 promoted cell glycolysis progression via PI3K/AKT pathway transfected with HMGA1-plasmid and the treatment with 20 µM LY294002. Relevant animal experiments were also synchronously validated and si-HMGA1 groups down-regulated xenograft growth including the weights and size in tumor xenografts. Conclusions: In conclusion, our results suggested that HMGA1 was significantly correlated with poor survival for LUAD tissues and involved in the process of glycolysis in LUAD cells.

Imaging Intratumoral Heterogeneity of Diffuse Pancreatic Neuroendocrine Tumor With Multitracer PET/CT.

ABSTRACT: Diffuse involvement of pancreatic neuroendocrine tumor (PNET) is a rare presentation. Here, we report a case of suspected autoimmune pancreatitis with 18 F-FDG and 18 F-FAPI-42 PET/CT showing increased tracer uptake in the entire pancreas, which was eventually confirmed by biopsy pathologic analysis as diffuse PNET. 18 F-AlF-NOTA-octreotide PET/CT imaging showed heterogeneous tracer uptake in the entire pancreas.

Additional Findings of 18 F-AIF-FAPI-42 PET/CT in a Patient With Mycosis Fungoides-Type Cutaneous T-Cell Lymphoma : Comparisons With 18 F-FDG PET/CT.

ABSTRACT: A 44-year-old woman presented with extensive skin patches and pruritus persisting for 3 years. Histopathological examination of the skin from the right abdomen confirmed mycosis fungoides-type cutaneous T-cell lymphoma. Staging PET with 18 F-FDG PET/CT) showed increased uptake in the skin on the right abdomen and left hip. Subsequently 18 F-FAPI-42 PET/CT revealed additional foci of abnormal uptake on the skin of the chest and back.

Gallbladder's Adenocarcinoma With Enteroblastic Differentiation Revealed by 18 F-FDG PET/CT.

ABSTRACT: Gallbladder's adenocarcinoma with enteroblastic differentiation (GAED) is extremely rare. A 43-year-old woman complained of pain in the right upper abdomen, and enhanced CT showed a cystic and solid mixed mass in the hepatic hilar region. Adenocarcinoma with enteroblastic differentiation was pathologically identified. 18 F-FDG PET/CT revealed a lesion in the gallbladder neck with increased FDG uptake, accompanied by a cystic and solid mixed mass in the hepatic hilar region with liver and lymph node metastases. Gallbladder biopsy was also carried out, and GAED was confirmed. 18 F-FDG PET/CT may assist in the evaluation of GAED and guide biopsy.

PTPRH promotes the progression of non-small cell lung cancer via glycolysis mediated by the PI3K/AKT/mTOR signaling pathway.

BACKGROUND: The protein tyrosine phosphatase H receptor (PTPRH) is known to regulate the occurrence and development of pancreatic and colorectal cancer. However, its association with glycolysis in non-small cell lung cancer (NSCLC) is still unclear. In this study, we aimed to investigate the relationship between PTPRH expression and glucose metabolism and the underlying mechanism of action. METHODS: The expression of PTPRH in NSCLC cells was evaluated by IHC staining, qRT‒PCR and Western blotting. The effect of PTPRH on cell biological behavior was evaluated by colony assays, EdU experiments, Transwell assays, wound healing assays and flow cytometry. Changes in F-18-fluorodeoxyglucose (18F-FDG) uptake and glucose metabolite levels after altering PTPRH expression were detected via a gamma counter and lactic acid tests. The expression of glycolysis-related proteins in NSCLC cells was detected by Western blotting after altering PTPRH expression. RESULTS: The results showed that PTPRH was highly expressed in clinical patient tissue samples and closely related to tumor diameter and clinical stage. In addition, PTPRH expression was associated with glycometabolism indexes on 18F-FDG positron emission tomography/computed tomography (PET/CT) imaging, the expression level of Ki67 and the expression levels of glycolysis-related proteins. PTPRH altered cell behavior, inhibited apoptosis, and promoted 18F-FDG uptake, lactate production, and the expression of glycolysis-related proteins. In addition, PTPRH modulated the glycometabolism of NSCLC cells via the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, as assessed using LY294002 and 740Y-P (an inhibitor and agonist of PI3K, respectively). The same results were validated in vivo using a xenograft tumor model in nude mice. Protein expression levels of PTPRH, glycolysis-related proteins, p-PI3K/PI3K and p-AKT/AKT were measured by IHC staining using a subcutaneous xenograft model in nude mice. CONCLUSIONS: In summary, we report that PTPRH promotes glycolysis, proliferation, migration, and invasion via the PI3K/AKT/mTOR signaling pathway in NSCLC and ultimately promotes tumor progression, which can be regulated by LY294002 and 740Y-P. These results suggest that PTPRH is a potential therapeutic target for NSCLC.

LncRNA AP000695.2 promotes glycolysis of lung adenocarcinoma via the miR-335-3p/TEAD1 axis.

AP000695.2 is a novel long non-coding RNA (lncRNA). Its aberrant high expression is remarkably associated with poor prognosis of patients with lung adenocarcinoma (LUAD). However, its role and underlying mechanism in LUAD remains unclear. Previous bioinformatics analysis indicated that AP000695.2 may be closely related to the glycolysis of LUAD. This study aims to verify and explore the mechanism of AP000695.2 in glycolysis of LUAD. Overexpression plasmid and siRNA are used to construct cell models of upregulation and downregulation of AP000695.2, respectively. AP000695.2 is highly expressed in lung cancer cell lines as revealed by qPCR. Western blot analysis, FDG uptake, lactate production assay and ECAR determination results show that high expression of AP000695.2 facilitates glycolysis of LUAD cells. CCK-8, EdU staining, Transwell and wound healing assays show that high expression of AP000695.2 promotes cell growth and migration of LUAD. The relationship between AP000695.2 and miR-335-3p is confirmed by bioinformatics analysis and dual-luciferase reporter assays. Through the dual-luciferase reporter assay, TEA domain transcription factor 1 (TEAD1) is identified as a target gene of miR-335-3p. Rescue experiments are applied to verify the relationship among AP000695.2, miR-335-3p and TEAD1. Our study indicates that AP000695.2 is involved in the mechanism of LUAD through functioning as a ceRNA to competitively sponge miR-335-3p, thereby regulating the expression of TEAD1. In the in vivo models, AP000695.2 depletion restrains tumor growth and glycolysis. AP000695.2 promotes the glycolysis of LUAD by regulating the miR-335-3p/TEAD1 axis, and it may serve as a potential target of anti-tumor energy metabolism therapy.

Highlighting Fibroblasts Activation in Fibrosis: The State-of-The-Art Fibroblast Activation Protein Inhibitor PET Imaging in Cardiovascular Diseases.

Fibrosis is a common healing process that occurs during stress and injury in cardiovascular diseases. The evolution of fibrosis is associated with cardiovascular disease states and causes adverse effects. Fibroblast activation is responsible for the formation and progression of fibrosis. The incipient detection of activated fibroblasts is important for patient management and prognosis. Fibroblast activation protein (FAP), a membrane-bound serine protease, is almost specifically expressed in activated fibroblasts. The development of targeted FAP-inhibitor (FAPI) positron emission tomography (PET) imaging enabled the visualisation of FAP, that is, incipient fibrosis. Recently, research on FAPI PET imaging in cardiovascular diseases increased and is highly sought. Hence, we comprehensively reviewed the application of FAPI PET imaging in cardiovascular diseases based on the state-of-the-art published research. These studies provided some insights into the value of FAPI PET imaging in the early detection of cardiovascular fibrosis, risk stratification, response evaluation, and prediction of the evolution of left ventricular function. Future studies should be conducted with larger populations and multicentre patterns, especially for response evaluation and outcome prediction.

Asymptomatic Prostate Cancer Metastasis in Rectal Mucosa Revealed by 18 F-PSMA-1007 PET/CT.

ABSTRACT: Prostate cancer metastasis to the rectal mucosa, a relatively rare metastatic site, leads to a higher clinical stage and poorer prognosis. A 65-year-old man with prostate cancer underwent 18 F-prostate-specific membrane antigen (PSMA) PET/CT for staging. Intense 18 F-PSMA uptake occurred at the primary lesion, bladder, adjacent seminal vesicle, and rectum. PET/CT imaging revealed increased homogeneous round activity of the rectal wall. The final diagnosis was prostate cancer metastasis to the rectal mucosa. This case suggested that 18 F-PSMA PET/CT may assist in locating rare metastases of prostate cancer, with potential value for early staging.

FAPI PET/CT in Diagnostic and Treatment Management of Colorectal Cancer: Review of Current Research Status.

FAPI PET/CT is a novel imaging tool targeting fibroblast activation protein (FAP), with high tumor uptake rate and low background noise. Therefore, the appearance of FAPI PET/CT provides a good tumor-to-background ratio between tumor and non-tumor tissues, which is beneficial to staging, tumor description and detection. Colorectal cancer has the biological characteristics of high expression of FAP, which provides the foundation for targeted FAP imaging. FAPI PET/CT may have a potential role in changing the staging and re-staging of colorectal cancer, monitoring recurrence and treatment management, and improving the prognosis of patients. This review will summarize the application status of FAPI PET/CT in colorectal cancer and provide directions for further application research.

Metastatic Papillary Thyroid Cancer Mimicking Hypopharyngeal Carcinoma.

ABSTRACT: Papillary thyroid cancer (PTC) metastasizing to the hypopharynx is extremely rare. Here, we describe FDG PET/CT findings of lesions in the posterior hypopharyngeal wall and left parapharyngeal space in a 58-year-old man who complained of blood in the sputum. The patient had a history of postoperative PTC. Therefore, hypopharyngeal carcinoma with lymph node metastasis was suspected. However, metastasis of PTC was pathologically confirmed after surgery. Hypopharyngeal metastasis of PTC is rare, which should be differentiated from hypopharyngeal carcinoma with metastasis.

The long noncoding RNA HOXA11-AS promotes lung adenocarcinoma proliferation and glycolysis via the microRNA-148b-3p/PKM2 axis.

BACKGROUND: Lung cancer is the most common malignancy in the world and a growing number of researches have focused on its metabolic characteristics. Studies have shown that the long non-coding RNA (lncRNA) HOXA11-AS is aberrantly expressed in many tumors. However, the role of HOXA11-AS in lung adenocarcinoma (LUAD) glycolysis and other energy metabolism pathways has not been characterized. METHOD: The mRNA levels of HOXA11-AS, microRNA-148b-3p (miR-148b-3p), and pyruvate kinase M2 (PKM2) were detected using qRT-PCR. The expression levels of proteins were measured using immunohistochemistry and western blot. The CCK-8, EdU, and colony formation assays were used to assess proliferation. Glycolytic changes were assessed by measuring lactate production, ATP production, and 18 F-FDG uptake. Bioinformatics analysis and dual-luciferase reporter assays were used to characterize the relationship between HOXA11-AS, miR-148b-3p, and PKM2. Proliferation and glycolytic changes were analyzed in xenograft tumor experiments using Micro-PET imaging after downregulation of HOXA11-AS in vivo. RESULTS: The expression of HOXA11-AS was markedly increased in LUAD, and was strongly associated with a poor prognosis. In addition, HOXA11-AS promoted proliferation and glycolysis in LUAD, and miR-148b-3p inhibited proliferation and glycolysis in LUAD. Mechanistically, HOXA11-AS positively regulated PKM2 expression by binding to miR-148b-3p, thereby promoting LUAD proliferation and glycolysis. In addition, HOXA11-AS inhibited LUAD xenograft growth and glycolysis via upregulation of miR-148b-3p expression and downregulation of PKM2 expression in vivo. CONCLUSIONS: These results showed that HOXA11-AS enhanced LUAD proliferation and glycolysis via the miR-148b-3p/PKM2 axis. The findings in this paper expanded our understanding of the molecular mechanisms of LUAD tumorigenesis and glycolysis and showed that HOXA11-AS could be useful as a diagnostic and prognostic marker for LUAD. 18 F-FDG PET/CT can be used to visually evaluate the therapeutic effect of targeting HOXA11-AS.

Upstream stimulatory factor 2 inhibits erastin-induced ferroptosis in pancreatic cancer through transcriptional regulation of pyruvate kinase M2.

Ferroptosis is considered as a potential target in cancer treatment including chemotherapy and radiotherapy, however, its regulatory mechanism on pancreatic cancer (PC) is not fully understood. Herein, we explored the role of upstream stimulatory factor 2 (USF2) and pyruvate kinase M2 (PKM2) in ferroptosis in PC cells. USF2 and PKM2 were highly expressed in PC tissues and USF2 was positively correlated with PKM2. PC cell lines BxpC-3 and AsPC-1 were transfected with small interfering RNAs against USF2/PKM2 or USF2 overexpressing plasmids or co-transfected with small interfering RNAs against PKM2 and USF2 overexpressing plasmids. Twenty-four hours after cell transfection, ferroptotic cell death was induced by incubation with 20 µmol/l erastin for 24 h. Ferroptotic cell death was promoted by USF2 knockdown and inhibited by USF2 overexpression. USF2 knockdown increased lipid reactive oxygen species and malonaldehyde generation and decreased glutathione concentration and glutathione peroxidase 4 expressions, indicating the enhanced lipid peroxidation. USF2 knockdown also increased ferrous iron levels and ferritin heavy chain expressions and reduced solute carrier family 7 member 11 expressions. However, USF2 overexpression reversed these changes. Furthermore, dual-luciferase reporter assay, chromatin immunoprecipitation assay and DNA pull down assay validated that USF2 transcriptionally regulated PKM2 expression through binding to its promoter. Interestingly, PKM2 also negatively regulated ferroptosis and PKM2 knockdown markedly impaired the effects of USF2 on lipid peroxidation and ferroptotic cell death. This study demonstrated that USF2 negatively regulated ferroptosis in PC cells through transcriptional regulation of PKM2, providing new evidences for uncovering the regulatory mechanism of ferroptosis on PC.

18F-FDG PET/CT for assessing heterogeneous metabolic response between primary tumor and metastases and prognosis in non-small cell lung cancer.

INTRODUCTION: This study aimed to use 18F-fluorodeoxyglucose positron emission tomography and/or computed tomography (18FDG-PET/CT) imaging to evaluate the heterogeneous metabolic response between primary tumor and metastases in NSCLC after therapy and explored its correlation with prognosis. METHODS: The data of patients with NSCLC who underwent 18FDG-PET/CT before and after treatment were retrospectively analyzed. Heterogeneous metabolic response (HR), defined as the difference in metabolic response between any metastases and primary lesion, was evaluated using 18FDG-PET/CT. And the correlation between HR and clinical prognosis was also analyzed. RESULTS: A total of 56 patients with NSCLC including 56 primary lesions and 491 metastases were enrolled in the study. 46.4% (26/56) of patients had HR, especially in patients with stage IV disease and whose metastases with high metabolic burden. HR was significantly correlated with poorer overall survival (OS) and progression-free survival (PFS) (P < .001 and P = .045, respectively). The multivariate analysis suggested that HR was an unfavorable independent prognostic factor for OS (HR = 4.36; 95% CI, 2.00-9.49; P < .001) but not for PFS (P = .469). HR between lymph node metastases was correlated with shorter OS (P < .001) but not with PFS (P = .370). CONCLUSION: HR was observed between primary and metastatic lesions in NSCLC after treatment using PET/CT. HR is significantly associated with poor prognosis and is an independent prognostic factor for OS.

Extrauterine Endometrial Stromal Sarcoma Mimicking Colorectal Cancer With Metastases.

ABSTRACT: Extrauterine endometrial stromal sarcoma (EESS) is extremely rare, especially with the colorectum involvement. We describe 18 F-FDG PET/CT findings of EESS in the sigmoid colon and rectum in a 46-year-old woman who complained diarrhea. 18 F-FDG PET/CT revealed multiple hypermetabolic lesions in the abdomen and pelvis, including the sigmoid colon and rectum. Therefore, colorectal cancer with metastases was initially suspected; however, ultimately low-grade EESS was pathologically confirmed. Widespread EESS with intestine involvement revealed by 18 F-FDG PET/CT should be carefully distinguished from colorectal cancer with metastases.

J-aggregates albumin-based NIR-II fluorescent dye nanoparticles for cancer phototheranostics.

Phototheranostics, relying on energy conversions of fluorophores upon excitation, integrating diagnostic fluorescence imaging and photo-driven therapy, represents a promising strategy for cancer precision medicine. Compared with the first near-infrared biological window (NIR-I), fluorophores imaged in the second window (NIR-II, 1000-1700 â€‹nm) exhibit a higher temporal and spatial resolution and tissue penetration depth. Polymethine cyanine-based dye IR1061 is a typical NIR-II small-molecule organic fluorophore, but its low water solubility and short circulation time limiting its biological applications. Therefore, human serum albumin (HSA) nanoparticles with great biocompatibility and biosafety were employed to fabricate hydrophobic IR1061, which exhibited red-shifted absorption band as typical for J-aggregates. Moreover, IR1061@HSA nanoparticles can be successfully used for NIR-II imaging to noninvasively visualize the tumor vascular networks, as well as real-time intraoperative image-guided tumor resection. Interestingly, benefiting from the high photothermal conversion efficiency brought by J-aggregates, IR1061@HSA nanoparticles were also explored for photothermal therapy (PTT) and cause efficient thermal ablation of tumors. Overall, IR1061@HSA, as a novel J-aggregates albumin-based NIR II dye nanoparticle with high biocompatibility, provides an integrated versatile platform for cancer phototheranostics with promising clinical translation prospects.

Fuzzy Planar Cell Polarity Gene (FUZ) Promtes Cell Glycolysis, Migration, and Invasion in Non-small Cell Lung Cancer via the Phosphoinositide 3-Kinase/Protein Kinase B Pathway.

Purpose: Fuzzy planar cell polarity gene (FUZ) is regarded as a planar cell polarity effector that controls multiple cellular processes during vertebrate development. The role of FUZ in glucose metabolism, invasion, and metastasis of non-small cell lung cancer (NSCLC) is unclear. The aims of this study were to investigate the relationship between FUZ and glucose metabolism and its mechanism of action. Materials and methods: Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was used to detect FUZ expression in A549 and H1299 cells. Additionally, qRT-PCR and western blot analysis were used to detect the expression of related glucose metabolism indicators, and lactate and 18 Fluorine fludeoxyglucose (18F-FDG) uptake assays used to detect changes in glucose metabolites. Further, cell invasion and migration behavior were evaluated by transwell and wound healing assays. In vivo tumor growth assay was conducted to assess the effect of FUZ. Results: We found that FUZ was significantly upregulated in the NSCLC cell lines compared to that in the normal HBE cells. FUZ was found to promote energy metabolism through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, and overexpression of FUZ increased both lactic acid and 18F-FDG uptake. Moreover, FUZ knockdown significantly inhibited the migration and invasion of NSCLC cells. In vivo, FUZ knockdown can significantly inhibit tumor proliferation in the xenograft model, which was well identified by Micro-PET scan. Conclusion: The present finding in vitro and vivo show that FUZ is involved in NSCLC cell energy metabolism, invasion and migration via the PI3K/AKT signaling pathway, suggesting that FUZ can be a potential therapeutic target for NSCLC.

HER2-Negative Schnitzler Metastasis to the Rectum Detected Using 18 F-FDG PET/CT.

ABSTRACT: Gastric carcinoma metastasis occurs via hematogenous, lymphatic, or peritoneal seeding. We describe FDG PET/CT findings of Schnitzler metastasis to the rectum in a 39-year-old woman who had radical gastrectomy for signet ring gastric adenocarcinoma 2 years prior. FDG PET/CT demonstrated increased homogeneous round activity in the inner layer of rectal wall. Occult metastases of gastric carcinoma tend to be difficult to treat and have a poor prognosis. However, in some cases, FDG PET/CT might be beneficial for early detection and diagnosis of Schnitzler metastasis.

Discordant Metabolic Response on 18F-FDG PET/CT in Synchronous Primary Gastric Lymphoma and Gastric Adenocarcinoma.

ABSTRACT: An 84-year-old man presented with dysphagia for 20 days. The biopsies of the multiple lesions through gastroscopy revealed gastric diffuse large B-cell lymphoma and gastric adenocarcinoma. Staging 18F-FDG PET/CT showed multiple hypermetabolic lesions in the stomach, abdomen, and pelvis. After 4 courses of chemotherapy, except for the lesion of biopsy-proven gastric adenocarcinoma, other hypermetabolic lesions in stomach and other sites returned to normal on posttherapy 18F-FDG PET/CT. This case indicated that 18F-FDG PET/CT can track differential treatment response of synchronous gastric tumors and guide subsequent therapy.

A Renal Cyst Invaded by Infiltrating Renal Cell Carcinoma With Multiple Hypermetabolic Bone Metastases as the Initial Presentation.

ABSTRACT: Cystic renal cell carcinoma (RCC) refers to an indolent version of RCC composed predominantly of cysts, and it is associated with good prognosis. We showed the FDG PET/CT findings in a patient with multiple hypermetabolic bone metastases presenting with pain in the left shoulder and upper abdomen, who was later found to have cystic RCC. FDG PET/CT demonstrated hypermetabolic bone lesions and slight thickening of the renal cyst wall with light metabolism. This report indicates the risk of misdiagnosing cystic RCC as a renalcyst.