Synchronous double primary small cell lung cancer and invasive ductal breast carcinoma: a case report.

BACKGROUND: Although lung and breast cancers are common malignancies, the occurrence of primary synchronous neoplasms involving these organs has been rarely reported in literature. CASE PRESENTATION: A 75-year-old female patient presented at a local hospital with a ten-day history of dizziness and slurred speech. A CT contrast-enhanced scan revealed a 4.2 cm mass in the lower lobe of the right lung and a 3.8 cm space-occupying lesion in the right breast. Subsequent breast ultrasound identified a hypoechoic lesion measuring5.41 × 4.75 × 3.06 cm in the right breast, and an ultrasound-guided biopsy confirmed the presence of infiltrating ductal carcinoma of the right breast. The immunohistochemistry analysis of the breast mass revealed positive staining for ER, PR, HER-2, AR and Ki67 in the tumor cells, while negative staining was observed for P63, Calponin, CK5/6 and CK14. MR imaging of the head detected abnormal signals in the right frontal lobe (3.6 cm×2.9 cm in size), left cerebellar hemisphere, and punctate enhancement in the left temporal lobe, indicating potential metastasis. Pathological examination of a lung biopsy specimen confirmed the presence of small cell lung cancer (SCLC). Furthermore, immunohistochemistry analysis of the lung lesions demonstrated positive staining for TTF-1, CK-Pan, Syn, CgA, CD56, P53 (90%) and Ki67 (70%), and negative staining for NapsinA and P40 in the tumor cells. The patient's diagnosis of SCLC with stage cT2bN0M1c IVB and brain metastases (BM), as well as invasive ductal breast carcinoma (IDC), was confirmed based on the aforementioned results. Whereupon we proposed a treatment plan consisting of whole-brain radiation (40 Gy/20fractions), focal radiotherapy (60 Gy/20fractions), and adjuvant concurrent chemotherapy with oral etoposide (50 mg on days 1 to 20). CONCLUSIONS: To the best of our knowledge, the present case is the first of its kind to describe the synchronous double cancer, consisting of primary SCLC and IDC.

MicroRNA-375 restrains the progression of lung squamous cell carcinoma by modulating the ERK pathway via UBE3A-mediated DUSP1 degradation.

MiRNA-375 has been reported to play critical roles in a variety of cancers. To unravel its biological roles, especially its specific mechanisms of action in lung squamous cell carcinoma (LUSC), LUSC tissue microarrays and miRNAscope were performed to identify the miR-375 expression. Associations with clinicopathologic features, survival, and the prognostic value of miR-375 in LUSC were clarified in a retrospective study of 90 pairs of LUSC tissues. In vitro and in vivo gain- and loss-of-function assays were conducted to validate the effects and mechanism of miR-375 in LUSC. The mechanism responsible for interactions was verified by dual-luciferase reporter gene assay, immunoprecipitation (IP) analysis, immunofluorescence (IF) assay and ubiquitination assay. We found that miR-375 had higher expression in noncancerous adjacent tissues than in LUSC tissues. Clinicopathologic analyses showed that miR-375 expression was correlated with pathologic stage and was an independent predictor of overall survival (OS) for LUSC. MiR-375, as a tumor inhibitor, inhibited proliferation and metastasis while promoting apoptosis of LUSC cells. Mechanistic research indicated that miR-375 targeted ubiquitin-protein ligase E3A (UBE3A), which in turn promoted the activity of the ERK signaling pathway via ubiquitin-mediated dual-specificity protein phosphatase 1 (DUSP1) degradation. Collectively, we propose a novel mechanism of tumorigenesis and metastasis of LUSC via the miR-375/UBE3A/DUSP1/ERK axis, which could potentially facilitate new strategies for the treatment of LUSC.

Expression characteristic, immune signature, and prognosis value of EFNA family identified by multi-omics integrative analysis in pan-cancer.

BACKGROUND: EphrinA (EFNA) are Eph receptor ligands that regulate various disease processes. Nonetheless, the expression characteristics of EFNAs in pan-cancer, their relationship with tumor immune microenvironment, and prognostic value landscape remain unknown. METHODS: A comprehensive landscape of EFNAs was created using various statistical data extracted from 33 cancers. Subsequently, we identified differential expression, genetic variations, potential function enrichment, tumor immune-related analysis, and drug sensitivity. Further, we investigated the clinical features and diagnostic prognostic value of EFNAs. RT-qPCR, western blot and immunohistochemistry (IHC) were used to validate the expression level and significant clinical value of EFNA5 in lung adenocarcinoma cell lines and tissues. RESULTS: EFNAs were highly mutated in various cancers. Genomic and epigenetic alterations of EFNAs were observed in various tumors, where an oncogenic mutation in specific cancer types potentially affected EFNA expression. Moreover, tumor-derived EFNAs were significantly related to the tumor immune microenvironment, suggesting that they are promising therapeutic targets. The majority of EFNA family genes were significantly linked to patient prognosis. Eventually, EFNA5 was an independent prognostic factor in lung adenocarcinoma. CONCLUSION: In summary, EFNAs are crucial in tumor immune regulation, and EFNA5 is a prognostic marker in lung adenocarcinoma. Our findings provide new insights into EFNAs from a bioinformatics standpoint and highlight the significance of EFNAs in cancer diagnosis and treatment.

MicroRNA-375 is a therapeutic target for castration-resistant prostate cancer through the PTPN4/STAT3 axis.

The functional role of microRNA-375 (miR-375) in the development of prostate cancer (PCa) remains controversial. Previously, we found that plasma exosomal miR-375 is significantly elevated in castration-resistant PCa (CRPC) patients compared with castration-sensitive PCa patients. Here, we aimed to determine how miR-375 modulates CRPC progression and thereafter to evaluate the therapeutic potential of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes loaded with miR-375 antisense oligonucleotides (e-375i). We used miRNA in situ hybridization technique to evaluate miR-375 expression in PCa tissues, gain- and loss-of-function experiments to determine miR-375 function, and bioinformatic methods, dual-luciferase reporter assay, qPCR, IHC and western blotting to determine and validate the target as well as the effects of miR-375 at the molecular level. Then, e-375i complexes were assessed for their antagonizing effects against miR-375. We found that the expression of miR-375 was elevated in PCa tissues and cancer exosomes, correlating with the Gleason score. Forced expression of miR-375 enhanced the expression of EMT markers and AR but suppressed apoptosis markers, leading to enhanced proliferation, migration, invasion, and enzalutamide resistance and decreased apoptosis of PCa cells. These effects could be reversed by miR-375 silencing. Mechanistically, miR-375 directly interfered with the expression of phosphatase nonreceptor type 4 (PTPN4), which in turn stabilized phosphorylated STAT3. Application of e-375i could inhibit miR-375, upregulate PTPN4 and downregulate p-STAT3, eventually repressing the growth of PCa. Collectively, we identified a novel miR-375 target, PTPN4, that functions upstream of STAT3, and targeting miR-375 may be an alternative therapeutic for PCa, especially for CRPC with high AR levels.

Characterization of the prognostic and diagnostic values of ALKBH family members in non-small cell lung cancer.

BACKGROUND: AlkB homolog (ALKBH) family genes have been known to play a crucial role in the development of several types of cancers. Nevertheless, the prognostic and diagnostic values of ALKBH family members have not been systematically investigated in non-small cell lung cancer (NSCLC). METHODS: The mRNA expression, genomic mutations, and biological functions of ALKBH family genes in NSCLC were evaluated using ONCOMINE, UALCAN, Kaplan-Meier Plotter, cBioPortal, Metascape, and SurvivalMeth. ALKBH2 expression and associated clinicopathological features were analyzed in LUAD tissues using immunohistochemistry (IHC). RESULTS: The mRNA levels of ALKBH1/2/4/6 were significantly upregulated in NSCLC patients, while those of ALKBH7 and FTO were downregulated. Also, a higher expression of ALKBH2/4/6 correlated with poor overall survival (OS), first-progression survival (FPS), and post-progression survival (PPS). ALKBH3/8 and FTO were upregulated and related to better OS, FPS, and PPS. ALKBH2/4/6 and FTO showed a higher diagnostic value in differentiating NSCLC patients from healthy individuals. Furthermore, the ALKBH family mutation rate was as high as 57% in lung adenocarcinoma (LUAD) patients and mutations in ALKBHs were related to poor OS. ALKBH family genes were also involved in universal DNA methylation in NSCLC. Finally, it was confirmed using tissues microarray that ALKBH2 shows a high expression and has a great diagnosis value in LUAD. CONCLUSIONS: Firstly, our results provided prognostic and diagnostic values of ALKBH family genes in NSCLC at both the DNA and RNA levels. Secondly, ALKBH2 is a potential novel diagnostic biomarker for LUAD.

Dihydroartemisinin mediating PKM2-caspase-8/3-GSDME axis for pyroptosis in esophageal squamous cell carcinoma.

Pyroptosis is a novel type of pro-inflammatory programmed cell death that has been strongly reported to be related to inflammation, immune, and cancer. Dihydroartemisinin (DHA) has good anti-tumor properties. However, the exact mechanism by which DHA induces pyroptosis to inhibit esophageal squamous cell carcinoma (ESCC) remains unclear. After applying DHA treatment to ESCC, we found that some dying cells exhibited the characteristic morphology of pyroptosis, such as blowing large bubbles from the cell membrane, accompanied by downregulation of pyruvate kinase isoform M2 (PKM2), activation of caspase-8/3, and production of GSDME-NT. Meanwhile, it was accompanied by an increased release of LDH and inflammatory factors (IL-18 and IL-1ß). Both knockdown of GSDME and application of caspase-8/3 specific inhibitors (z-ITED-FMK/Ac-DEVD-CHO) significantly inhibited DHA-induced pyroptosis. However, the former did not affect the activation of caspase-3. In contrast, overexpression of PKM2 inhibited caspase-8/3 activation as well as GSDME-N production. Furthermore, both si-GSDME and OE-PKM2 inhibited DHA-induced pyroptosis in vivo and in vitro. Therefore, the results suggest that DHA can induce pyroptosis of ESCC cells via the PKM2-caspase-8/3-GSDME pathway. Implication: In this study, we identified new mechanism of DHA in inhibiting ESCC development and progression, and provide a potential therapeutic agent for the treatment of ESCC.

eEF2K as a novel metastatic and prognostic biomarker in gastric cancer patients.

BACKGROUND: Although eukaryotic elongation factor 2 kinase (eEF2K) has been reported to be a potential oncogenic factor in many human cancers, its usefulness as a clinical prognostic biomarker for gastric cancer has not been investigated. METHODS: In this study, data about 540 patients with stomach adenocarcinoma (STAD) were analyzed from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases to determine the expression of eEF2K. Immunohistochemistry (IHC), western blots, and real-time polymerase chain reaction (RT-PCR) were also performed to determine the clinical significance of eEF2K expression in 96 postoperative patients with gastric cancer. Among the 96 patients, 36 had low expression of eEF2K and 60 had high expression. RESULTS: Analysis of the TCGA and GEO datasets revealed that eEF2K expression was significantly higher in the STAD tissue samples than in the non-tumorous gastric tissues. IHC, western blots, and RT-PCR confirmed these findings. The high expression level of eEF2K was found to be related to the presence of lymph node metastasis (p = 0.002). Moreover, multivariate analysis showed that eEF2K was an independent indicator of prognosis for overall survival (OS) (hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.06-2.79; p = 0.03) and disease-free survival (DFS) (HR = 1.66, 95% CI = 0.997-2.765; p = 0.052) in patients with surgically resected STAD. CONCLUSION: Collectively, our findings suggest that eEF2K is a clinical indicator of metastatic and prognostic significance for STAD survival and could serve as a potential therapeutic target.

Pyroptosis, a new bridge to tumor immunity.

Pyroptosis refers to the process of gasdermin (GSDM)-mediated programmed cell death (PCD). Our understanding of pyroptosis has expanded beyond cells and is known to involve extracellular responses. Recently, there has been an increasing interest in pyroptosis due to its emerging role in activating the immune system. In the meantime, pyroptosis-mediated therapies, which use the immune response to kill cancer cells, have also achieved notable success in a clinical setting. In this review, we discuss that the immune response induced by pyroptosis activation is a double-edged sword that affects all stages of tumorigenesis. On the one hand, the activation of inflammasome-mediated pyroptosis and the release of pyroptosis-produced cytokines alter the immune microenvironment and promote the development of tumors by evading immune surveillance. On the other hand, pyroptosis-produced cytokines can also collect immune cells and ignite the immune system to improve the efficiency of tumor immunotherapies. Pyroptosis is also related to some immune checkpoints, especially programmed death-1 (PD-1) or programmed death- ligand 1 (PD-L1). In this review, we mainly focus on our current understanding of the interplay between the immune system and tumors that process through pyroptosis, and debate their use as potential therapeutic targets.

Photodynamic therapy induces human esophageal carcinoma cell pyroptosis by targeting the PKM2/caspase-8/caspase-3/GSDME axis.

Photodynamic therapy (PDT) uses a photosensitizer (PS) and visible light to induce cancer cell death. Pyroptosis is a new type of programmed cell death that is associated with the gasdermin protein family. However, the precise mechanism of pyroptosis in PDT-induced suppression of esophageal cancer remains unknown. We demonstrate that PDT can induce gasdermin E (GSDME)-mediated pyroptosis, which is characterized by the formation of pyroptotic blebs in esophageal squamous cell carcinoma (ESCC), which burst and release intracellular contents and pro-inflammatory mediators. Mechanistically, PDT may inhibit pyruvate kinase M2 (PKM2) and consequently, activate caspase-8 and caspase-3, which ultimately releases N-GSDME and triggers pyroptosis in ESCC. Moreover, PDT decreased the efficiency of pyroptosis in the presence of a glycolytic inhibitor. Overall, our results show that PDT induces pyroptosis in ESCC by targeting the PKM2/caspase-8/caspase-3/GSDME axis. This is the first in-depth study of the specific mechanism underlying PKM2-mediated pyroptosis under PDT in ESCC, and potentially has great implications for the clinical application of PDT in ESCC.

Corrigendum: Systematic Analysis of Expression Profiles and Prognostic Significance for FAM83 Family in Non-Small-Cell Lung Cancer.

[This corrects the article DOI: 10.3389/fmolb.2020.572406.].

Systematic Analysis of Expression Profiles and Prognostic Significance for FAM83 Family in Non-small-Cell Lung Cancer.

BACKGROUND: Lung cancer remains a common malignancy and the leading cause of cancer-related deaths in the world. Although dramatic progress made in multimodal therapies, it still has a poor prognosis. The Family with sequence similarity 83 (FAM83) of poorly characterized proteins are defined by the presence of the conserved DUF1669 domain of unknown function at their N-termini, most of which significantly elevated levels of expression in multiple cancers. However, the expression and prognostic values of different FAM83 family in lung cancer, especially in non-small-cell lung cancer (NSCLC), have not been clarified. METHODS: ONCOMINE, UALCAN, GEPIA, Kaplan-Meier Plotter, cBioPortal, and STRING databases were utilized in this study. RESULTS: The transcriptional levels of FAM83A/B/C/D/F/G/H were up-regulated in patients with NSCLC. A noticeable correlation was found between the over-expressions of FAM83A/B/D/F/H and clinical cancer stages in NSCLC patients. Besides, higher mRNA expressions of FAM83A/B/C/D/F/H were discovered to be expressively associated with overall survival (OS) in lung cancer patients, furthermore, FAM83A, FAM83C, and FAM83H in OS group achieved 0.9475/1, 0.971897/1, and 0.9454545/0.8974359 specificity/sensitivity in distinguishing short survivors from long survivors, respectively. Moreover, a high mutation rate of FAM83 family (51%) was also observed in lung adenocarcinoma (LUAD) patients, and genetic alteration in the FAM83 family was associated with shorter OS and disease-free survival (DFS) in LUAD patients. CONCLUSION: Our results indicated that FAM83A/H might play important roles in NSCLC tumorigenesis and might be risk factor for the survival of NSCLC patients.

The influence of photodynamic therapy on the Warburg effect in esophageal cancer cells.

To investigate whether the Warburg effect is a key modulator on the resistance mechanism of photodynamic therapy (PDT). Glycolysis was examined by the test of lactate product and glucose uptake at different post-PDT time points. Cell viability was detected by the CCK-8 assay and cell proliferation was detected by colony formation assay. The expression of glycolysis and related proteins were examined by western blotting. Target gene was silenced by RNAi. In the present study, we assessed the effect of PDT on cancer cell glycolysis. Our team has demonstrated that pyruvate kinase M2 (PKM2), a key speed-limiting enzyme of glycolysis, was significantly overexpressed in patients with esophageal cancer. Our results in the present study showed that PKM2 was downregulated, and lactate product and glucose uptake were inhibited in cells exposed to 5-aminolevulinic acid (5-ALA)-mediated PDT at 4 h after treatment. However, at 24 h after PDT, we observed a substantial increase in PKM2 expression, lactate product, and glucose uptake. Moreover, silencing of PKM2 gene abrogated the upregulatory effect of PDT on glycolysis at late post-PDT period. 2-Deoxy-D-glucose (2-DG) is a recognized chemical inhibitor of glycolysis. The combined treatment of 2-DG and PDT significantly inhibited tumor growth in vitro at 24 h. These results demonstrate that PDT drives the Warburg effect in a time-dependent manner, and PKM2 plays an important role in this progress, which indicated that PKM2 may be a potential molecular target to increase the sensitivity of esophageal cancer cells to PDT.

Dihydroartemisinin represses esophageal cancer glycolysis by down-regulating pyruvate kinase M2.

Esophageal cancer, especially esophageal squamous cell carcinoma (ESCC) threatens so many lives in China every year. Traditional treatment of ESCC has usually been disappointing. The development of novel therapy is worth investigation. We have previously demonstrated that dihydroartemisinin (DHA) has anticancer effect on esophageal cancer. However, the mechanism has not been completely known. In this present study, we explored the effect of DHA on cancer cell glycolysis, also known as Warburg effect. Pyruvate kinase M2 (PKM2) is a key regulatory factor of glycolysis, and our results showed that it is significantly overexpressed in patients with ESCC and ESCC cell lines. In DHA treatment cells, PKM2 was down-regulated and lactate product and glucose uptake were inhibited. Overexpression of PKM2 by lentiviral transfection abrogated the inhibition effect of DHA. These results suggested that DHA might repress esophageal cancer glycolysis partly by down-regulating PKM2 expression. We believe that DHA might be a prospective agent against esophageal cancer.