No therapeutic targets have been identified for lung squamous cell cancer (SqCC) which is the second most prevalent lung cancer because its molecular profiles remain unclear. This study aimed to ...unveil disease-related protein networks by proteomic and bioinformatic assessment of laser-microdissected cancerous cells from seven SqCCs compared with eight representative lung adenocarcinomas. We identified three network modules significant to lung SqCC using weighted gene co-expression network analysis. One module was intrinsically annotated to keratinization and cell proliferation of SqCC, accompanied by hypoxia-induced aerobic glycolysis, in which key regulators were activated (HIF1A, ROCK2, EFNA1-5) and highly suppressed (KMT2D). The other two modules were significant for translational initiation, nonsense-mediated mRNA decay, inhibited cell death, and interestingly, eIF2 signaling, in which key regulators, MYC and MLXIPL, were highly activated. Another key regulator LARP1, the master regulator in cap-dependent translation, was highly suppressed although upregulations were observed for hub proteins including EIF3F and LARP1 targeted ribosomal proteins, among which PS25 is the key ribosomal protein in IRES-dependent translation. Our results suggest an underlying progression mechanism largely caused by switching to the cap-independent, IRES-dependent translation of mRNA subsets encoding oncogenic proteins. Our findings may help to develop therapeutic strategies to improve patient outcomes.
Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine lung carcinoma (LCNEC) are high-grade lung neuroendocrine tumors (NET). However, comparative protein expression within SCLC and LCNEC ...remains unclear. Here, protein expression profiles were obtained via mass spectrometry-based proteomic analysis. Weighted gene co-expression network analysis (WGCNA) identified co-expressed modules and hub genes. Of 34 identified modules, six were significant and selected for protein-protein interaction (PPI) network analysis and pathway enrichment. Within the six modules, the activation of cellular processes and complexes, such as alternative mRNA splicing, translation initiation, nucleosome remodeling and deacetylase (NuRD) complex, SWItch/Sucrose Non-Fermentable (SWI/SNF) superfamily-type complex, chromatin remodeling pathway, and mRNA metabolic processes, were significant to SCLC. Modules enriched in processes, including signal recognition particle (SRP)-dependent co-translational protein targeting to membrane, nuclear-transcribed mRNA catabolic process of nonsense-mediated decay (NMD), and cellular macromolecule catabolic process, were characteristically activated in LCNEC. Novel high-degree hub genes were identified for each module. Master and upstream regulators were predicted via causal network analysis. This study provides an understanding of the molecular differences in tumorigenesis and malignancy between SCLC and LCNEC and may help identify potential therapeutic targets.
The tumourigenesis of early lung adenocarcinomas, including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant invasive adenocarcinoma (LPA), remains ...unclear. This study aimed to capture disease-related molecular networks characterising each subtype and tumorigenesis by assessing 14 lung adenocarcinomas (AIS, five; MIA, five; LPA, four). Protein-protein interaction networks significant to the three subtypes were elucidated by weighted gene co-expression network analysis and pairwise G-statistics based analysis. Pathway enrichment analysis for AIS involved extracellular matrix proteoglycans and neutrophil degranulation pathway relating to tumour growth and angiogenesis. Whereas no direct networks were found for MIA, proteins significant to MIA were involved in oncogenic transformation, epithelial-mesenchymal transition, and detoxification in the lung. LPA was associated with pathways of HSF1-mediated heat shock response regulation, DNA damage repair, cell cycle regulation, and mitosis. Genomic alteration analysis suggested that LPA had both somatic mutations with loss of function and copy number gains more frequent than MIA. Oncogenic drivers were detected in both MIA and LPA, and also LPA had a higher degree of copy number loss than MIA. Our findings may help identifying potential therapeutic targets and developing therapeutic strategies to improve patient outcomes.
It is unclear how epidermal growth factor receptor EGFR major driver mutations (L858R or Ex19del) affect downstream molecular networks and pathways. This study aimed to provide information on the ...influences of these mutations. The study assessed 36 protein expression profiles of lung adenocarcinoma (Ex19del, nine; L858R, nine; no Ex19del/L858R, 18). Weighted gene co-expression network analysis together with analysis of variance-based screening identified 13 co-expressed modules and their eigen proteins. Pathway enrichment analysis for the Ex19del mutation demonstrated involvement of SUMOylation, epithelial and mesenchymal transition, ERK/mitogen-activated protein kinase signalling via phosphorylation and Hippo signalling. Additionally, analysis for the L858R mutation identified various pathways related to cancer cell survival and death. With regard to the Ex19del mutation, ROCK, RPS6KA1, ARF1, IL2RA and several ErbB pathways were upregulated, whereas AURK and GSKIP were downregulated. With regard to the L858R mutation, RB1, TSC22D3 and DOCK1 were downregulated, whereas various networks, including VEGFA, were moderately upregulated. In all mutation types, CD80/CD86 (B7), MHC, CIITA and IFGN were activated, whereas CD37 and SAFB were inhibited. Costimulatory immune-checkpoint pathways by B7/CD28 were mainly activated, whereas those by PD-1/PD-L1 were inhibited. Our findings may help identify potential therapeutic targets and develop therapeutic strategies to improve patient outcomes.
Solid-predominant lung adenocarcinoma (SPA), which is one of the high-risk subtypes with poor prognosis and unsatisfactory response to chemotherapy and targeted therapy in lung adenocarcinoma, ...remains molecular profile unclarified. Weighted correlation network analysis (WGCNA) was used for data mining, especially for studying biological networks based on pairwise correlations between variables. This study aimed to identify disease-related protein co-expression networks associated with early-stage SPA.
We assessed cancerous cells laser-microdissected from formalin-fixed paraffin-embedded (FFPE) tissues of a SPA group (
= 5), referencing a low-risk subtype, a lepidic predominant subtype group (LPA) (
= 4), and another high-risk subtype, micropapillary predominant subtype (MPA) group (
= 3) and performed mass spectrometry-based proteomic analysis. Disease-related co-expression networks associated with the SPA subtype were identified by WGCNA and their upstream regulators and causal networks were predicted by Ingenuity Pathway Analysis.
Among the forty WGCNA network modules identified, two network modules were found to be associated significantly with the SPA subtype. Canonical enriched pathways were highly associated with cellular growth, proliferation, and immune response. Upregulated HLA class I molecules HLA-G and HLA-B implicated high mutation burden and T cell activation in the SPA subtype. Upstream analysis implicated the involvement of highly activated oncogenic regulators, MYC, MLXIPL, MYCN, the redox master regulator NFE2L2, and the highly inhibited LARP1, leading to oncogenic IRES-dependent translation, and also regulators of the adaptive immune response, including highly activated IFNG, TCRD, CD3-TCR, CD8A, CD8B, CD3, CD80/CD86, and highly inhibited LILRB2. Interestingly, the immune checkpoint molecule HLA-G, which is the counterpart of LILRB2, was highly expressed characteristically in the SPA subtype and might be associated with antitumor immunity.
Our findings provide a disease molecular profile based on protein co-expression networks identified for the high-risk solid predominant adenocarcinoma, which will help develop future therapeutic strategies.
A 31‐year‐old man suffered from headaches and presented at a hospital after the symptom worsened. Obstructive hydrocephalus and a pineal tumor were identified, and he was transferred to our hospital ...for further investigation and treatment. Cranial computed tomography revealed a hypodense mass lesion on the right of the pineal region, and calcifications and enlargement of the lateral and third cerebral ventricles were also evident. Blood tests were negative for all tumor markers. Laparoscopic biopsy and third‐ventricle fenestration were performed that day as an emergency surgery to treat the obstructive hydrocephalus. Postoperative cranial magnetic resonance imaging revealed a solid tumor that was hypointense on T1‐weighted imaging, hyperintense on T2‐weighted imaging, and heterogeneously enhanced by Gd. Subsequently, the tumor increased in size, and craniotomy and tumorectomy were performed. Histologically, the tumor proliferated as round or short spindle‐shaped cells in a myxoid matrix, forming arrays that surrounded the blood vessels. As a few cells with eosinophilic cytoplasm were also present and immunostaining for INI‐1 was negative, the patient was diagnosed with atypical teratoid/rhabdoid tumor (AT/RT). AT/RT of the pineal region in adults is rare, and herein, we report the morphological characteristics of this case and reviewed the relevant literature.
Bronchial schwannoma is extremely rare, accounting for a small percentage of benign bronchial tumors, with no determined standardized treatment. An 89-year-old woman with a persistent cough underwent ...CT scan which revealed a tracheal tumor. A diagnosis of endobronchial schwannoma was confirmed based on tissue obtained by high-frequency snare polypectomy. A hybrid stent was implanted in the trachea due to tumor regrowth; however, stent migration occurred, and it was removed after 1 month. Subsequently, radiation therapy was performed, and airway patency was well maintained for over 3 years. In general, surgical resection is recommended for endobronchial schwannoma; however, due to the age of this patient, resection was deemed invasive. Therefore, radiation therapy was administered as an alternative treatment.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is an extremely rare and deadly cancer with a poor prognosis. Unfortunately, the causes that lead to the development of SCCOHT are ...unknown. In this study, we present a case in which SCCOHT and low-grade serous carcinoma (LGSC) occurred in the same ovary. The patient, a woman in her 30s, visited the obstetrics and gynecology department for weight loss and abdominal distension. Imaging examinations indicated an ovarian malignancy. Therefore, simple total hysterectomy, bilateral adnexectomy, and omentectomy were performed. The left ovary was enlarged with proliferation of SCCOHT and LGSC. The tumor had metastasized to the right ovary and multiple metastatic dissemination sites were found in the abdominal cavity. This case of combined SCCOHT and LGSC suggests that SCCOHT arises from the dedifferentiation of LGSC.
The differential diagnosis of epithelial proliferative disease using core needle biopsy (CNB) is problematic because it is difficult to differentiate between intraductal papilloma, ductal ...hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Many studies have reported that breast cancer lesions are positive for neuroendocrine (NE) markers, whereas only a small number of studies have reported immunopositivity for NE markers in normal mammary tissues or benign lesions. We asked whether NE factors could be used as markers of breast cancer. We determined the immunopositivity rate of synaptophysin, an NE marker, in 204 lesions excised from the breast using CNB in patients who visited a university‐affiliated comprehensive medical facility and examined whether synaptophysin is a marker of breast cancer. The specimens were classified as synaptophysin‐negative cases (56 benign, 99 malignant); equivocal cases (<1 %: 2 benign, 15 malignant); and synaptophysin‐positive cases (1 benign, 31 malignant). The sensitivity, specificity, positive predictive value, and negative predictive value for malignancy of the lesions classified as synaptophysin positive were 23.3 %, 98.2 %, 96.9 %, and 36.1 %, respectively. The respective values for lesions classified as equivocal were 11.6 %, 96.6 %, 88.2 %, and 36.1 %. Synaptophysin may provide a marker of breast cancer diagnosed by CNB.
Malignant melanoma (MM), an aggressive skin neoplasm, can be difficult to differentiate histologically from benign melanocytic nevi (BMN). Although immunohistochemical analysis could facilitate ...diagnosis of MM, markers that discriminate between benign and malignant lesions have not yet been established. However, CD10 expression is associated with MM progression. We immunostained 36 MM and 50 BMN specimens for CD10 to evaluate whether CD10 immunostaining could distinguish between BMN and MM tumors. In the 36 MM samples, we found CD10 expression in 17 (47.2%) sample tumor cells and 32 (88.9%) stromal cells, for 34 of the 36 MM specimens (94.4%) overall. In contrast, no BMN (0/50) samples had CD10+ tumor cells, although a few (8/50, 16.0%) showed stromal staining. The two specimen types thus significantly differed in CD10 expression (P<0.01), indicating that melanocytic CD10+ tumor cells are likely to be malignant. Also, melanocytic stromal cells with diffuse, strong CD10 expression are more likely to be malignant than those with light, focal CD10 expression. Although hematoxylin and eosin staining is fundamental to the diagnosis of melanocytic lesions, CD10 immunostaining may help distinguish between BMN and MM.
PDF
