(
426). Breast cancer epithelial cells down-regulate ambient microenvironment ECM gene expression including
scgf relative to normal mammary epithelial cells to favor their protrusion and dissemination (
186). Three-day pregnant mice up-regulate
scgf gene expression in mammary stromal fibroblasts to support branching of ductal epithelial cells (
658), which reflects
scgf as a signature gene for poor prognosis in human breast cancer.
Non-tumorigenic human breast carcinoma HMLE cells and tumorigenic HrasV12-intrduced HMLER cells can be induced to acquire cancer stem cell attributes through epithelial-mesenchymal transition by E-cadherin gene
CDH1-targeted shRNA (
208). They are CD44
highCD24
low, can form mammosphere in suspension culture, and are resistant to the usual anti-cancer drugs, e.g. paclitaxel, but still selectively sensitive to salinomycin.
Scgf gene is up-regulated in paclitaxel- versus salinomycin-resistant HMLER cells (3.82-fold), mammosphere-forming versus adherent epithelial cells (3.53-fold) and CD44
+ versus CD24
+ cells (18.65-fold), indicating that
scgf is the gene inherent to
cancer stem cells as well as normal stem cells. Oct4-transduced normal mammary epithelial cells up-regulate
scgf gene expression and acquire cancer stem cell nature (
345). When an aromatase inhibitor, letrozole, is given to postmenopausal patients with estrogen receptor-positive breast cancer,
scgf gene expression is gradually up-regulated in the tumor tissues 14 days after treatment, and reaches a maximal level 3 months after treatment (
359).
SCGF in the plasma of breast cancer-bearing FVB/N-Tg(MMTV-PyVT)634Mul/J mice increases significantly as compared with wild type and PyMT heterozygote mice (
239).
Primary tumor has a significant gain in the chromosome 19 region 54.32-58.34Mb, where
scgf gene is located, as compared with metastatic axillary lymphnode in the matched breast cancer patients (
242). Plasma SCGF level from primary breast cancer patients with circulating epithelial marker KRT19
+ tumor cells is significantly higher than control without circulating tumor cells (
519).
The CpG locus in
scgf gene is hypermethylated in breast cancer cells relative to normal breast tissues (
266).
No unique somatic mutation of
scgf gene has been reported in mammary ductal carcinoma (
Wellcome Trust Sanger
Institute).
HCC1937, SUM102 or SUM149 basal-like breast cancer cells facilitate tumor cell growth with
scgf gene up-regulation relative to MCF-7 (
460), ZR-75-1 or T47D luminal breast cancer cells, when they are cocultured with
HTERT-immortalized fibroblasts from reduction mammoplasty (
328).
Scgf gene is differentially expressed in estrogen receptor
-progesterone receptor
- HER2 amplification
- triple-negative breast cancer cells; down-regulated in basal-like 1 and immunomodulatory subtypes, and up-regulated in mesenchymal stem-like subtype (
330). Estrogen receptor
+ T47D but not triple-negative MDA-MB-231 breast cancer cells educate human macrophages to secrete SCGF (
489). Knockout of
mdig (mineral dust-induced gene) up-regulates repressive H3K9me3, H3K27me3 and H4K20me3 in MDA-MB-231 cells, leading to 10-fold down-regulation of
scgf gene expression (
613). SCGF level is higher in surgical wound fluids from patients with luminal B subtype breast cancer compared to luminal subtype A after breast conserving surgery (
611). Intraoperative radiotherapy facilitates SCGF increase in the fluids from patients with luminal subtype A breast cancer. SCGF secretion is promoted in ER-α
+PR
+ MCF-7 luminal subtype A breast cancer cells treated with LPS+ATP or LPS+tamoxifen compared to untreated or LPS-treated cells (
686).
Conditioned medium of apoptotic MCF-7 breast cancer cells stimulates human primary macrophages to enhance
scgf gene expression for IL-10 induction (
395).
Cardiovascular system
Heterozygously
flk-1 (VEGFR2/KDR)-disrupted
flk-1+/- mice are more susceptible to myocardial ischemia reperfusion injury than wild type mice; Ingenuity Pathway Analysis on down-regulated KDR, syndecan 1 and VCAM-1 genes indicates interacting networks of
scgf gene with
vegf,
Mek and
Akt genes mandatory for myocardial protection (
191). Direct blood-sampling from the coronary collateral and stenotic artery of the patients with coronary arterial disease demonstrates that the former SCGF concentration is significantly lower than the latter (
192). Bioplex assay of SCGF level in hemorrhagic and fibrotic carotid atherosclerotic plaques from patients with coronary arterial disease demonstrates that the former is much lower than the latter (
450). Serum SCGF level is lower in acute coronary syndrome than stable coronary artery disease (
705). SCGF level is significantly higher in the serum from patients with asymptomatic unstable carotid plaques compared to those with stable plaques (
511). SCGF is histochemically detected in all carotid plaques irrespective of being symptomatic or asymptomatic and stable or unstable. Plasma SCGF level cannot be a prognostic biomarker to predict adverse cardiovascular events in patients with coronary arterial disease (
495). Aortoiliac atherosclerosis is significantly associated with increased serum SCGF level (
598).
Bone marrow cells from patients with acute myocardial infarction (AMI) highly express
scgf gene (
276), which is one of the paracrine mechanisms for improvement of systolic function after AMI by intracoronary infusion of BM cells.
Scgf
gene expression is up-regulated in murine cardiac tissue 7 and 28 days after myocardial infarction relative to uninjured heart (
332).
Scgf gene expression is similarly up-regulated in rat cardiomyocytes surviving experimental myocardial infarction as compared to normal controls (
504).
Hypertrophic cardiac tissue from transgenic mouse constitutively expressing calcineurin A (
282), but not alternative splicing form of calcineurin AΒ lacking autoinhibitory domain (
332), under control of Α-myosin heavy chain promoter up-regulates
scgf gene expression relative to wild type control.
SCGF level in the plasma from patients with advanced heart failure caused by Chagas' disease-associated and idiopathic dilated cardiomyopathy (DCM) is significantly higher than that from heart failure-free DCM and normal controls. However, elevated SCGF level has no significant correlation with left ventricular ejection fraction and percent survival (
408, 644).
Scgf is a signature gene for myocardial cuproptosis with immune cell infiltration in DCM (
701). Plasma SCGF level is significantly elevated early after alcohol septal ablation for symptomatic hypertrophic cardiomyopathy (HCM) (
531).
Scgf is up-regulated in relation to SOX4 up-regulated in the left ventricular myocardium from patients with DCM or HCM (
669).
Scgf gene expression is significantly up-regulated in the ascending aorta with reduced atherosclerosis from ApoE
-/- mice by
in vivo CD40 silencing for 24 weeks (
540). Male apolipoprotein E
-/- hyperlipidemic mice are given s.c. angiotensin II for 13 weeks to develop abdominal aortic aneurysm (AAA).
Scgf gene is up-regulated >2-fold in the angiotensin II-induced AAA aorta relative to the saline controls (
211).
Scgf gene expression is also up-regulated in the non-aneurysmal proximal neck of human AAA just below the renal arteries (
442). SCGF secretion in the conditioned media of human AAA tissues is little affected by pyridone 6, a pan-JAK inhibitor (
579). Higher blood SCGF level is associated with an increased risk of thoracic aortic aneurysm (
702). Proteomic analysis demonstrates up-regulation of SCGF in the dome of densely packed aneurysms relative to loosely packed aneurysms 2 weeks after elastase-induced rabbit aneurysms are treated with platinum coil embolization (
374). Tenascin-knockout mice are susceptible to acute aortic dissection, and periaortic CaCl
2 application plus angiotensin II infusion strongly and weakly up-regulates
scgf gene expression in the suprarenal aorta from wild type and tenascin-knockout mice, respectively (
449).
Pressure overload of transverse aortic constriction up-regulates
scgf gene expression in mouse left ventricular myocardial tissue relative to volume overload of aortocaval shunt (
298). Murine left ventricular tissues up-regulate
scgf gene expression at the heart failure stage 8 weeks after transaortic constriction procedure compared to sham controls (
350).
Scgf gene expression is up-regulated putatively through H3K27 acetylation-activated enhancer in hypertrophic cardiomyocytes from mice subject to traverse aortic constriction (
440).
Right ventricular cardiomyocytes are immunohistochemically positive for SCGF.
Scgf gene expression is up-regulated in the right ventricular tissues from mice treated with pulmonary arterial banding compared to sham controls (
646).
Lung
Bleomycin-induced mouse fibrotic lung up-regulates
scgf gene expression as compared with saline controls (
212).
Scgf gene is up-regulated in the fibrotic lung from patients with idiopathic pulmonary fibrosis (
220). SCGF and MIF levels are significantly higher in the serum from patients with idiopathic and systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) than PAH-lacking SSc controls (
493). Plasma SCGF level is elevated along with progress of PAH to more severe stages (
646). Increased neutrophil elastase in the plasma from PAH patients is associated with higher plasma SCGF level than normal controls (
659).
Scgf gene expression is significantly up-regulated when
ATAD2 gene is knocked down by treating human lung adenocarcinoma cell line, A549, with an
ATAD2-targeting siRNA (
261). Knockout of
mdig (mineral dust-induced gene) up-regulates repressive H3K9me3, H3K27me3 and H4K20me3 in A549 cells, leading to 10-fold down-regulation of
scgf gene expression (
613).
Scgf gene expression is significantly down-regulated in the lung adenocarcinoma cells with
K-ras amplification (
539). Inorganic arsenic-transformed human BEAS-2B bronchial epithelial cells up-regulate
scgf gene expression with hypermethylation of
scgf gene body (
546).
Scgf gene expression in lung cancer tissues usually indicates unfavorable prognosis (
562). SCGF alone has no angiogenic ability
in vitro, but facilitates endothelial proliferation in the presence of VEGF or FGF. SCGF over-produced by H1299 or HCC827 lung cancer cells exhibits chemotactic activity on ambient vascular endothelial cells and promotes tumor growth with enhanced angiogenesis when cancer cells are transplanted into nude mice (
671). The chemotactic activity is mediated through integrin activation different from conventional FAK or p130 signaling. SCGF-promoted tumor growth is suppressed with
scgf shRNA treatment. SCGF suppression could be applied to a novel anti-cancer therapy.
An SCGF level in the plasma from patients with early-stage non-small cell lung cancer is within normal limits and little altered after treatment with pazopanib, an inhibitor for VEGFR, PDGFR and c-kit (
236). Higher baseline plasma SCGF level correlates with poor disease control for non-small cell lung cancer after chemotherapy with carboplatin/paclitaxel/cetuximab/bevacizumab following cetuximab/bevacizumab (
492).
Scgf is one of the postoperative recurrence-related gene signatures in stage I non-small cell lung cancer patients (
358). Stage I non-small cell lung cancer patients with moderately methylated CpG site of
scgf gene promoter have better prognosis than those with hypomethylation (
381).
Scgf gene expression is down-regulated in the lung granuloma of rhesus macaque at early (week 4) stage of Mycobacterium tuberculosis infection, but repressed at late (week 13) stage, relative to normal lung (
263). An SCGF concentration in the sera from patients with pulmonary sarcoidosis is lower than that from patients with pulmonary tuberculosis or healthy individuals (
372).
Scgf gene expression is up-regulated in the tissue specimens from patients with pulmonary capillary hemangiomatosis relative to normal lung tissue (
269).
Scgf gene expression in the lung of irradiated mice is significantly up-regulated relative to non-irradiated mice and in interstrain comparison of irradiated mice (
240).
Scgf gene expression is up-regulated in the lung tissue from Pneumocystis murina-infected BALB/c mice compared to noninfected BALB/c mice or infected C57BL/6 mice (
362).
Respiratory syncytial viral infection stimulates human primary small airway epithelial cells and A549 alveolar basal epithelial adenocarcinoma cells to up-regulate
scgf gene expression and SCGF production, the up-regulation of which is suppressed by knock-down of RIG-1, MDA5 or LGP2 but not of Trif (
474).
Scgf gene expression is up-regulated in porcine alveolar macrophages within 24 hours after porcine reproductive and respiratory syndrome virus infection (
634).
Serum SCGF level determines onset of SARS-CoV-2 infection. Machine learning indicates with 100% accuracy that SARS-CoV-2-infected patients with higher (>127ng/ml) and lower (<127ng/ml) serum SCGF level are asymptomatic and symptomatic respectively (
632). When SCGF is excluded, serum levels of IL-16 (>45pg/ml) and M-CSF (>57pg/ml) are asymptomatic marker. SCGF is a prognostic biomarker for symptom onset and, more importantly, SCGF could control a novel protective immune mechanisms against infection.
Scgf gene expression is down-regulated in the bronchial tissues from patients with chronic mucus hypersecretion-associated chronic obstructive pulmonary disease (
589).
Cigarette smoking does not affect
scgf gene expression in the large and small airway epithelium (
259).
Serum SCGF levels are significantly higher in poorly controlled asthmatic patients than well-controlled patients (
310).
An SCGF concentration and CD45
+collagen-1
+ fibrocyte progenitors are elevated in the peripheral blood from patients with bronchiolitis obliterans syndrome after lung transplantation relative to disease-free post-transplants (
311). CCSP
+ epithelial-like cells in the BM- and PB-MNCs from patients with end-stage lung disease but not from healthy controls are stimulated
in vitro to migrate in response to SCGF (
425). Plasma SCGF level is found to correlate significantly with the number of BM- and PB-CCSP
+ cells.
Scgf gene expression is up-regulated in malignant pleural mesothelioma (
458). However SCGF level in the sera from patients with asbestos-induced malignant pleural mesothelioma and asbestos workers without mesothelioma is significantly lower than healthy controls (
469). Patients with malignant pleural mesothelioma exhibit much higher SCGF level in pleural fluid than that in serum (
520).
Scgf gene mutation is present in 211H malignant mesothelioma cells (GCCCA insertion between C819 and G820 with amino acid Gly273-Ala274 frameshift) but not in other mesothelioma cells including H28, H2052, H2452, MESO-1 and MESO-4 (
497).
Exposure by inhalation to 2 ppm formaldehyde down-regulates scgfgene expression in the rat nasal respiratory epithelium (448).
Liver
Retinyl palmitate vitamin A-storing hepatic stellate cells express
scgf gene (see
Gene Expression section), lose vitamin A to be transformed into myofibroblasts following hepatic injury, and produce a-smooth muscle actin and collagen type I to induce liver fibrosis (
78).
SCGF levels significantly increase in the sera from patients with hepatocellular carcinoma (HCC) following HCV-related cirrhosis (
376). Higher serum SCGF level is a useful biomarker for refractoriness to therapy, recurrence and poor prognosis in HCC (
587). Higher serum SCGF level in patients with advanced HCC treated with atezolizumab and bevacizumab is correlated with reduced overall and progression-free survival, indicating that SCGF is a predictive marker of response to chemotherapy and prognosis in HCC (
697). Dicyclanil is an insecticide that causes HCC. When dicyclanil is given to mice for 2 weeks,
scgf gene is up-regulated in the liver (
194). Up-regulated
scgf gene expression correlates with heparin-degrading endosulfatase 1 and 2 in human HCC (
326).
Scgf DNA is significantly hypermethylated in the liver tissues from patients with HCC compared to normal controls (
Pat33). Up-regulated plasma methylated
scgf DNA can be one of the biomarkers indicative of HCC with or without cirrhosis (
596).
Scgf DNA is hypermethylated in the liver tissues from patients with non-cirrhotic HCC compared to other hepatic lesions including hepatitis, adenoma and cirrhosis (
693). SCGF secretion is up-regulated in hepatocytes and myofibroblast-like cells isolated from HCC tissues (
439). B-Raf/TYK inhibitors, Sorafenib and Vemurafenib (PLX4720), and MEK inhibitors, U0126, Selumetinib (AZD6244) and PD0325401, stimulate SCGF-secretion by HepG2 HCC cells but not by Hep3B, Huh-7 and surrounding tumor-free liver cells (
455). Human peri-HCC tissue-associated fibroblasts secrete significantly higher levels of SCGF than HCC tissue-associated fibroblasts (
563). Anti-SCGF neutralizing antibody dramatically inhibit matrigel invasion and sphere colony-forming ability of CD326 (EpCAM)
+ SMMC-7721 cancer stem cells, when added into the co-culture of CD326
+ SMMC-7721 cells with peri-HCC tissue-associated fibroblasts.
Scgf gene expression is significantly down-regulated in AKT-1 and Β-catenin-induced mouse HCC with chronic portal inflammation by 1,5-diethoxycarbonyl-1,4-dihydrocollidine as compared to normal PBS-treated liver tissue (
527).
Plasma SCGF level is elevated in patients with chronic hepatitis C as compared to healthy controls (
501). SCGF level is elevated in the sera from patients with advanced nonalcoholic steatohepatitis compared to normal controls (
580). High SCGF level is histologically correlated with steatosis, inflammation, ballooning, but not with fibrosis. Elevated serum SCGF level could correlate with insulin resistance and increased serum level of inflammatory proteins such as CRP and IL-6 in male but not female obesity-related nonalcoholic steatohepatitis (
623).
Scgf gene expression is significantly down-regulated in mouse liver 24 hours after ConA-induced hepatitis (
521).
Proliferative activity of cholangiocarcinoma cells resistant to Gefitinib and Erlotinib correlates with their
scgf gene expression; resistant HuCCT1 cells up-regulate
scgf gene expression 3-5 times higher than sensitive SNU-308, GBH-3, GBD-1, EGF-1, TFK1 and SNU-1079 cells (
157).
Cholangiocytes from NOD.c3c4 model mice of primary biliary cirrhosis are deficient in Fas antigen (CD95) and down-regulate
scgf gene expression to induce cholangial hyperplasia (
193).
