Favourable surgical outcomes for either second primary lung cancer or intrapulmonary metastasis after resection of non-small-cell lung cancer.

OBJECTIVES: Metachronous lung cancer arising after resection of non-small-cell lung cancer is either a second primary lung cancer (SPLC) or intrapulmonary metastasis (IPM) of the initial lung cancer; however, differential diagnosis is difficult. We evaluated the surgical outcomes of metachronous lung cancer in a combined population of patients with SPLC and IPM. METHODS: A retrospective study of 3534 consecutive patients with resected non-small-cell lung cancer between 1992 and 2016 was conducted at 4 institutions. RESULTS: A total of 105 patients (66 males; median age, 70 years) who underwent a second pulmonary resection for metachronous lung cancer were included. Most patients (81%) underwent sublobar resection, and there was no 30-day mortality. All metachronous lung cancers were cN0, 5 were pN1-2. The postoperative comprehensive histologic assessment revealed SPLC (n = 77) and IPM (n = 28). The 5-year overall survival rate after the second resection was 70.6% (median follow-up: 69.7 months). A multivariable analysis showed that age >70 years at the second resection (P = 0.013), male sex (P = 0.003), lymph node involvement in metachronous cancer (P < 0.001), pathological invasive size of metachronous cancer >15 mm (P < 0.001) and overlapping squamous cell carcinoma histology of the initial and metachronous cancers (P = 0.003) were significant prognostic factors for poor survival after the second resection, whereas histological IPM was not (P = 0.065). CONCLUSIONS: Surgery for cN0 metachronous lung cancer is safe and shows good outcomes. There were no statistically significant differences in the SPLC and IPM results. Caution should be exercised when operating on patients with overlapping squamous cell carcinoma.

The nonsmokers' and smokers' pathways in lung adenocarcinoma: Histological progression and molecular bases.

There could be two carcinogenetic pathways for lung adenocarcinoma (LADC): the nonsmokers' pathway and the smokers' pathway. This review article describes the two pathways with special reference to potential relationships between histological subtypes, malignant grades, and driver mutations. The lung is composed of two different tissue units, the terminal respiratory unit (TRU) and the central airway compartment (CAC). In the nonsmokers' pathway, LADCs develop from the TRU, and their histological appearances change from lepidic to micropapillary during the progression process. In the smokers' pathway, LADCs develop from either the TRU or the CAC, and their histological appearances vary among cases in the middle of the progression process, but they are likely converged to acinar/solid at the end. On a molecular genetic level, the nonsmokers' pathway is mostly driven by EGFR mutations, whereas in the smokers' pathway, approximately one-quarter of LADCs have KRAS mutations, but the other three-quarters have no known driver mutations. p53 mutations are an important factor triggering the progression of both pathways, with unique molecular alterations associated with each, such as MUC21 expression and chromosome 12p13-21 amplification in the nonsmokers' pathway, and HNF4α expression and TTF1 mutations in the smokers' pathway. However, investigation into the relationship between histological progression and genetic alterations is in its infancy. Tight cooperation between traditional histopathological examinations and recent molecular genetics can provide valuable insight to better understand the nature of LADCs.

[Postoperative Relapse of Combined Large‒Cell Neuroendocrine Carcinoma of the Lung with a Remarkable Transient Response to Amrubicin Monotherapy in an Elderly Patient-A Case Report].

An 86‒year‒old man with chronic kidney disease underwent surgical resection for combined large‒cell neuroendocrine carcinoma of the left lower lobe of the lung(pT2aN1M0, stage ⅡB). Five months later, multiple liver and bone metastases and mediastinal lymph node recurrence were detected. After 9 courses of amrubicin monotherapy(32 mg/m2 for 3 consecutive days), his tumor marker levels normalized, and radiological examination revealed a complete tumor response. Adverse events occurred, but they were tolerable except a decrease in the neutrophil count. The patient remained in good condition for several months but died of tumor relapse 22 months after the initial recurrence. Amrubicin monotherapy was considered to be one of the treatment choices for recurrent large‒cell neuroendocrine carcinoma of the lung in elderly patients.

A method to obtain reproducible Ki-67 indices in lung adenocarcinoma.

AIMS: Proliferative activity, evaluated from the Ki-67 index, is a strong prognostic factor in lung adenocarcinoma (LADC). Here, we optimised a procedure to measure the Ki-67 index and establish the best cut-off value. METHODS AND RESULTS: We examined 342 stage I LADCs for the immunohistochemical expression of Ki-67 using different antibodies, MIB1 and SP6. The results revealed the superior specificity of SP6; therefore, SP6 was used in subsequent analyses. Slides were scanned with a virtual slide system. Using software, tumour cells were counted in a whole tumour. Thereafter, the tumour was evenly subdivided into 0.25-mm2 tiles. The frequency of positive cells was counted in each tile of an invasive area or the whole tumour. We calculated the number of tumour cells required to produce a 95% confidence interval (CI) <0.05. Additionally, we calculated coverage probabilities (CP) using two different methods, counting any number or 200 cells per tile. The results showed that we could meet our goal by counting 2000 cells from 10 random tiles (200 cells each) in invasive areas. CONCLUSIONS: We successfully developed an optimal procedure for determination of the Ki-67 labelling index using an SP6 antibody, which provided CP > 70% and CI of <0.05 in more than 90% of cases. Furthermore, we identified an optimal cut-off value of 0.12 with an alternative of 0.15, based on disease recurrence. This procedure and the cut-off values may be used in the routine pathological diagnosis of LADC.

Multicentre randomised phase II study of the perioperative administration of flurbiprofen axetil in patients with non-small cell lung cancer: study protocol of the FLAX Study.

INTRODUCTION: In patients with non-small cell lung cancer, surgical treatment with postoperative adjuvant chemotherapy is performed. However, the improvement of overall survival achieved by postoperative adjuvant chemotherapy may be insufficient in consideration of the deterioration of quality of life (QOL). Considering the relationships among surgical treatments, inflammation and carcinogenesis, non-steroidal anti-inflammatory drugs (NSAIDs) are a candidate postoperative treatment for preventing recurrence and maintaining QOL. In this study, we investigate the effects of the perioperative administration of flurbiprofen axetil on postoperative recurrence in patients with non-small cell lung cancer. METHODS AND ANALYSIS: This study is a multicentre, parallel group, open label, randomised controlled trial. Patients clinically suspected of non-small cell lung cancer are randomly assigned to the flurbiprofen axetil group or the no-NSAIDs group. A total of 420 patients (210 per group) will be registered. The primary analysis will evaluate the treatment effect of flurbiprofen axetil on postoperative recurrence. ETHICS AND DISSEMINATION: The study protocol was approved by the Clinical Research Review Board of Saitama Medical University in September 2019 (No. 192002) and will be approved by each institutional review board of all participating institutions before patient enrolment. This study complies with the latest version of the Declaration of Helsinki, Clinical Trial Act and related notifications. Results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (jRCTs031190167; Pre-results) (https://jrct.niph.go.jp/).

Clinical Significance of Tumour CD44v and MIST1 Expression in Patients With Non-small-cell Lung Cancer.

BACKGROUND: Cancer stem cells (CSCs) are involved in cancer metastasis and relapse. Therefore, identification of CSC biomarkers might help determine the success of a treatment. In this study, we examined the expression of four CSC markers: Cluster of differentiation 44 variant (CD44v), leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), frizzled 7 (FZD7), and muscle, intestine and stomach expression 1 (MIST1), in cancer tissues of patients with non-small-cell lung cancer at >5 years after resection, and its clinical significance. PATIENTS AND METHODS: We examined the expression of each CSC marker in 360 patients with NSCLC (n=360) who underwent curative resection by immunohistochemical analysis of tissue microarrays, and determined its relationship with survival. RESULTS: High expression of MIST1 was related to better overall survival (p<0.05); high CD44v expression was associated with poor overall and recurrence-free survival (p<0.001 for both) and thus, CD44v was defined as an independent prognostic factor (p<0.05), according to a multivariate analysis. CONCLUSION: Tumoral CD44v expression might be a useful prognostic marker for patients after curative resection of NSCLC.

Giant Solitary Fibrous Tumor of Pleura Presenting Both Benign and Malignant Features.

BACKGROUND The incidence of solitary fibrous tumor of the pleura (SFTP) is less than 5% of all pleural tumors. It is important to determine whether the tumor is benign or malignant in deciding on treatment and estimating prognosis, but this can sometimes be difficult. CASE REPORT A 59-year-old woman with no prior medical history presented with a 4-month history of right back pain and dyspnea. Contrast-enhanced computed tomography revealed a giant oval mass with inhomogeneous intensities, and bloody pleural effusion in the right thoracic cavity, proved to be solitary fibrous tumor of pleura (SFTP) under the complete thoracoscopic resection. The resected tumor seemed to have several malignant features, including large size of tumor, inhomogeneous intensities, and pleural effusion due to intratumor hemorrhage; however, Ki-67 (MIB-I) proliferation index was less than 1%, with no recurrence seen within 2 year after symptom onset. CONCLUSIONS We managed a case of SFTP presenting both malignant and benign features. In patients with SFTP, multi-disciplinary discussion among the clinician, radiologist, and pathologist was considered to be needed for estimating disease prognosis.

Postoperative changes of the free pericardial fat pad for bronchial stump coverage.

BACKGROUND: Bronchopleural fistula (BPF) remains a serious complication after surgery for lung cancer with bronchial resection. A free pericardial fat pad (FPFP) is applied in high-risk cases to reduce BPF frequency. BPF may occur 6 months after surgery. Thus, we evaluated the residual FPFP volume at 6 months after surgery to estimate the residual FPFP ratio and determine the amount of FPFP to be harvested during surgery. METHODS: We retrospectively investigated 40 patients who underwent lobectomy with bronchial stump coverage using FPFP. During surgery, the volume of the harvested FPFP was measured and the FPFP was affixed to the bronchial stump. Further, 6 months after surgery, the residual volume of the installed FPFP was analyzed using a three-dimensional volume analyzer and the residual ratio was calculated. We also evaluated clinicopathological factors influencing the resected FPFP and residual ratio. RESULTS: The median resected FPFP volume was 11 [3-40] mL. During multivariate analysis, body mass index and surgical approach were found to be significant factors associated with the resected FPFP volume. The median residual FPFP volume was 4.3 (0.4-15.5) mL. The median residual ratio was 0.39 (0.13-0.66). The resected FPFP volume was significantly associated with the residual volume (P<0.001) but not with the residual ratio (P=0.811). No factor was associated with the residual ratio. CONCLUSIONS: In all cases, residual FPFP was confirmed at 6 months after surgery and the residual ratio was 40%. It is necessary to determine the volume of FPFP to be harvested while carefully considering the shrinkage ratio.

Validating margin status in lung wedge resection for clinical stage I non-small cell lung cancer.

Stage I non-small cell lung cancer (NSCLC) is a localized disease without metastasis; therefore, it can be treated effectively with local therapies. Pulmonary resection is the most frequent treatment, performed as pulmonary wedge resection, segmentectomy, lobectomy, or pneumonectomy. Some retrospective clinical studies of pulmonary wedge resection suggest that its outcome may be inferior to that of anatomical pulmonary resection, whereas other recent studies, which assess surgical margin status, leveled acceptable outcomes. Since the outcome of pulmonary wedge resection for lung cancer may depend on tumor size, distance from the surgical margin to the tumor, tumor size/margin distance ratio, and margin cytology results, a prospective study assessing these parameters is ongoing. This will allow us to identify the clinical implications of these factors and predict which patients are likely to have a good outcome.

The potential significance of alpha-enolase (ENO1) in lung adenocarcinomas - A utility of the immunohistochemical expression in pathologic diagnosis.

We herein analyzed the relationships among the immunohistochemical expression of alpha-enolase (ENO1) and clinicopathological factors in order to define the significance of ENO1 in lung adenocarcinomas (ADCs). ENO1 expression was detected in most of the ADCs examined (95.8%), but not in bronchial and alveolar epithelia. ENO1 expression was typically observed in the cytoplasm among most ADCs (95.8%), but was also detected in the nucleus (56.3%). The levels were significantly higher in terminal respiratory unit (TRU) cytological subtype ADCs. Neither cytoplasmic nor nuclear expression was associated with any other clinicopathological factors including post-operative survival and growth activity. These results suggest that ENO1 is a crucial factor promoting neoplastic transformation exclusively in TRU subtype ADCs. We also investigated the potential utility of the immunohistochemical expression of ENO1 to differentiate TRU-type ADC cells from the reactive hyperplasia of pneumocytes and bronchiolar epithelial cells because difficulties are associated with discriminating these lesions in small biopsy specimens. The sensitivity and specificity of ENO1 (cytoplasmic/nuclear) were 87.5%/37.5% and 88.9%/100%, respectively, which are superior to those of p53 (18.8% and 100%). ENO1 has potential as a biomarker to assist in the histopathological detection of TRU subtype ADC cells.

Does lung cancer surgery cause circulating tumor cells?-A multicenter, prospective study.

BACKGROUND: Cancer relapse is caused by residual isolated tumor cells (ITCs) remaining in the body after surgery. It is speculated that surgical manipulation may cause circulating tumor cells (CTCs) which are the origin of ITCs in the body. The occurrence of CTCs in surgical patients with non-small cell lung cancer (NSCLC) has been shown in retrospective observation, but not prospectively, thus we conducted a multicenter prospective study regarding the occurrence of CTCs by surgical manipulation. METHODS: Patients with T1b-2N0M0 lung cancer were studied. Blood samples were collected from the peripheral artery in the operating room at both pre- and post-lobectomy to extract CTCs by a size selection method. The CTCs detection rate, pathological findings, and background of each patient were studied. RESULTS: The histological diagnosis of 29 patients were adenocarcinoma in 24 patients, squamous cell carcinoma in 3 patients, and other types in 2 patients. The number of pre-CTCs positive patients was 13 and the number of post CTCs positive patients was 17. Among the 16 patients who were pre-CTCs negative, 4 patients showed post CTCs positive, while all pre-CTCs positive patients remained post-CTCs positive. CONCLUSIONS: The likelihood of CTC dislodgement by surgical manipulation is indicated based on the result that CTCs were detected after lung cancer surgery, where there were no cases of pre-CTCs positive and post CTCs negative.

The pathological features of idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas.

AIMS: To investigate the pathological features of idiopathic interstitial pneumonia (IIP)-associated pulmonary adenocarcinoma. METHODS AND RESULTS: Surgically resected adenocarcinomas associated with IIP (the IIP group) and adenocarcinomas without IIP (the non-IIP group) were subjected to analysis. Adenocarcinomas in the IIP group were subdivided into two groups: one group included tumours connected to bronchiolar metaplasia in honeycomb lesions (the H-IIP group), and the other included tumours unrelated to honeycomb lesions (the NH-IIP group). Histomorphological appearance and immunohistochemical expression were compared among the H-IIP group, the NH-IIP group, and the non-IIP group. Most of the tumour cells in the H-IIP group had a tall, columnar shape that showed similar features to proximal bronchial epithelium, whereas tumour cells in the NH-IIP group and the non-IIP group had a club-like shape that showed similar features to respiratory bronchiolar/alveolar epithelium. Adenocarcinomas in the H-IIP group tended to be negative for thyroid transcription factor-1 (TTF-1) and positive for hepatocyte nuclear factor-4α (HNF-4α). The frequency of EGFR mutations was significantly lower in adenocarcinomas in the H-IIP group, although the frequencies of KRAS and ALK mutations did not differ among the three groups. CONCLUSIONS: Idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas, especially those arising from honeycomb lesions, have distinct pathological features.

A Histopathological Feature of EGFR-Mutated Lung Adenocarcinomas with Highly Malignant Potential - An Implication of Micropapillary Element.

The purpose of this study was to define histological features determining the malignant potential of EGFR-mutated lung adenocarcinoma (LADC). Surgically resected tumors (EGFR-mutated LADCs with (21) and without (79) lymph node metastasis and EGFR wild-type LADCs with (26) and without (108) lymph node metastasis) and biopsy samples from inoperably advanced tumors (EGFR-mutated LADCs (78) and EGFR wild-type LADCs (99)) were examined. In surgically resected tumors, the EGFR-mutated LADCs with lymph node metastasis had the micropapillary element in a significantly greater proportion than others (Mann-Whitney tests P ≤0.026). The proportion of micropapillary element was higher in the EGFR-mutated LADC at the advanced stage (stage II, III, or IV) than in the tumor at the early stage (stage I) (Mann-Whitney test, P<0.0001). In the biopsy samples from inoperably advanced LADCs (177), EGFR-mutated tumors also had micropapillary element at a higher frequency than EGFR-wild type tumors (53/78 (68%), versus 30/99 (30%), Pearson x2 test, P<0.0001). In stage I EGFR-mutated LADCs (84), the tumors with the micropapillary element (34) exhibited a significantly higher recurrence rate than tumors without micropapillary element (50) (5-year Recurrence-free survival 64.4% versus 93.3%, log-rank test P = 0.028). The micropapillary element may be an exclusive determinant of malignant potential in EGFR-mutated LADC. It is suggested that EGFR-mutated LADC may develop through a distinct histogenesis, in which the micropapillary element is important for promoting progression.

Alterations in cathepsin L expression in lung cancers.

We herein investigated the potential role of cathepsin L in lung carcinogenesis. Lung cancer cell lines and surgically resected tumors were examined for the expression of the cathepsin L protein and copy number alterations in its gene locus. Cathepsin L was stably expressed in bronchiolar epithelial cells. Neoplastic cells expressed cathepsin L at various levels, whereas its expression was completely lost in most of the lung cancer cell lines (63.6%, 7/11) examined. Furthermore, expression levels were lower in a large fraction of lung tumors (69.5%, 139/200) than in bronchiolar epithelia. The expression of cathepsin L was lost in some tumors (16.0%, 32/200). In adenocarcinomas, expression levels were significantly lower in high-grade tumors than in low-grade tumors (one-way ANOVA, P < 0.0500). Copy number alterations were found in 18.0% (36 [32 gain + 4 loss] /200) of lung tumors. No relationship existed between cathepsin L protein expression levels and the copy number of its gene locus (Spearman's rank-order correlation, P = 0.3096). Collectively, these results suggest that the down-regulated expression of cathepsin L, which is caused by an undefined mechanism other than copy number alterations, is involved in the progression of lung adenocarcinomas.

Expression of tropomyosins in lung cancer - a potential role in carcinogenesis and its utility in a histopathological diagnosis.

We herein analyzed the relationships between tropomyosin protein expression levels and clinicopathological factors in order to determine the significance of tropomyosins in lung cancers. Although neoplastic cells expressed different isoforms of tropomyosin, overall expression levels were lower than those in bronchial and alveolar epithelial cells. In adenocarcinomas, tropomyosin levels were markedly reduced in poorly differentiated or solid subtype carcinomas, suggesting that a loss in the expression of tropomyosins is involved in the progression of lung adenocarcinomas. The potential utility of the immunohistochemical expression of tropomyosins for a histopathological diagnosis was also investigated. The sensitivity and specificity of a loss in the expression of tropomyosins were 100% and 50%, respectively, which were superior to those for the strong expression of p53 (sensitivity 100% and specificity 44%), a conventional biomarker. An immunohistochemical examination of tropomyosins may assist in the histopathological detection of lung cancer cells in small biopsy specimens.

Up-Regulation of S100A11 in Lung Adenocarcinoma - Its Potential Relationship with Cancer Progression.

We previously reported that patients with lung adenocarcinomas with KRAS gene mutations and strong proliferating activity had poorer outcomes, even in the early stage of the disease. The aim of the present study was to elucidate the potential molecular basis of these highly malignant lung tumors by focusing on S100 proteins (S100A2, S100A7, and S100A11), which are downstream targets of oncogenic KRAS and promoters of tumor progression. The immunohistochemical expression of S100 proteins was examined in 179 primary lung adenocarcinomas, and the potential relationships between their levels and clinicopathologic factors were analyzed. Among the three subtypes, S100A11 levels were significantly higher in adenocarcinomas with KRAS mutations and strong proliferating activity. They were also higher in adenocarcinomas with poorly differentiated tumors. Furthermore, higher levels of S100A11 were associated with shorter disease-free survival. These results suggest that the up-regulation of S100A11 plays a role in tumor progression, particularly in KRAS-mutated lung adenocarcinomas.

Pre-operative chemotherapy for non-small cell lung carcinoma.

The roll by the cytotoxic chemotherapy and its efficacy in the treatment of non-small cell carcinoma (NSCLC) was not clearly identified until the 1980s when studies showed that cisplatin was beneficial in the treatment of NSCLC. The first randomized controlled trial (RCT) to evaluate the efficacy of post-operative (adjuvant) chemotherapy using the cisplatin regimen for resectable NSCLC was reported in 1988. Since then, an increasing number of RCTs have been carried out to evaluate post-operative chemotherapy. Pre-operative (neo-adjuvant) chemotherapy is a relatively new treatment strategy, as its name indicates. Compared with post-operative chemotherapy, fewer RCTs have been carried out to evaluate pre-operative chemotherapy. Given the inconsistency of the results from the RCTs, at least 12 meta-analyses have been published. Most of these meta-analyses reported overall survival (OS) benefit with hazard ratios (HRs) in the range of 0.81 to 0.89 in favor of pre-operative chemotherapy. An individual patient data meta-analysis by Burdett in 2014 indicates that the option of pre-operative chemotherapy + surgery is associated with better OS (HR 0.87, 95% CI, 0.78-0.96, P=0.007) and recurrence-free survival (RFS) (HR 0.85, 95% CI, 0.76-0.94, P=0.002) survival for operable NSCLC when compared with treatment with surgery alone. Although the current consensus recommends the use of post-operative chemotherapy, pre-operative chemotherapy has equivalent efficacy. Both strategies should be regarded as the first choice treatment options. Despite Burdett's comment, indication of pre-operative chemotherapy for stage IA disease should be judged carefully.

Allelic imbalance in the miR-31 host gene locus in lung cancer--its potential role in carcinogenesis.

Small non-protein coding RNA, microRNA (miR), which regulate messenger RNA levels, have recently been identified, and may play important roles in the pathogenesis of various diseases. The present study focused on miR-31 and investigated its potential involvement in lung carcinogenesis. The expression of miR-31 was altered in lung cancer cells through either the amplification or loss of the host gene locus. The strong expression of miR-31 in large cell carcinomas was attributed to the gene amplification. Meanwhile, the loss of miR-31 expression was more frequently observed in aggressive adenocarcinomas. Thus, miR-31 may play a pleiotropic role in the development of lung cancers among different histological types. To the best of our knowledge, this is the first study to show the potential causative mechanism of the altered expression of miR-31 and suggest its potentially diverse significance in the different histological types of lung cancers.

Comparison between CT tumor size and pathological tumor size in frozen section examinations of lung adenocarcinoma.

OBJECTIVE: We examined the appropriate measurement for pathological tumor size by comparing radiological and pathological tumor size of resected lung adenocarcinoma in FSE. MATERIALS AND METHODS: We reviewed records of 59 resected specimens of lung adenocarcinoma for FSE from January to December 2008. Specimens were well-inflated with saline by using an injector before cutting into segments. After selecting the tumor segment of maximal diameter, we compared three ways of measuring pathological tumor size by using paired t-test: (I) macroscopic tumor size (MTS), measured with a metal straight ruler, (II) microscopic frozen section tumor size (FSTS), and (III) microscopic paraffin section tumor size (PSTS). We compared each discrepancy rate (DR) [DR=(CT tumor size-pathological tumor size)/CT tumor size×100] (%) between tumors that were air-containing type and solid-density type on CT scans, and also compared the tumors with lepidic component rates (LCR) ≥50% and LCR <50%, by using Mann-Whitney U-tests. RESULTS: FSE could diagnose malignancy with 100% accuracy. The mean CT tumor size was 18.36mm, and the mean pathological tumor sizes (MTS, FSTS, and PSTS) were 17.81, 14.29, and 14.23mm, respectively. FSTS and PSTS were significantly smaller than CT tumor size (p<0.001). The DR calculated with PSTS was significantly larger in air-containing than in solid-density tumors, and also larger in LCR ≥50% than in LCR <50% tumors. CONCLUSION: FSE with the inflation method diagnosed malignancy with 100% accuracy. The lung specimen must be sufficiently inflated to prevent tissue shrinking, and we propose MTS as the definition for pathological tumor size in FSE. The greater discordance observed between CT tumor size and microscopic tumor size was assumed to be due to shrinkage of the lepidic component in the tumor.

Proteome analysis for downstream targets of oncogenic KRAS--the potential participation of CLIC4 in carcinogenesis in the lung.

This study investigated the proteome modulated by oncogenic KRAS in immortalized airway epithelial cells. Chloride intracellular channel protein 4 (CLIC4), S100 proteins (S100A2 and S100A11), tropomyosin 2, cathepsin L1, integrinsα3, eukaryotic elongation factor 1, vimentin, and others were discriminated. We here focused on CLIC4 to investigate its potential involvement in carcinogenesis in the lung because previous studies suggested that some chloride channels and chloride channel regulators could function as tumor suppressors. CILC4 protein levels were reduced in some lung cancer cell lines. The restoration of CLIC4 in lung cancer cell lines in which CLIC4 expression was reduced attenuated their growth activity. The immunohistochemical expression of the CLIC4 protein was weaker in primary lung cancer cells than in non-tumorous airway epithelial cells and was occasionally undetectable in some tumors. CLIC4 protein levels were significantly lower in a subtype of mucinous ADC than in others, and were also significantly lower in KRAS-mutated ADC than in EGFR-mutated ADC. These results suggest that the alteration in CLIC4 could be involved in restrictedly the development of a specific fraction of lung adenocarcinomas. The potential benefit of the proteome modulated by oncogenic KRAS to lung cancer research has been demonstrated.